PHYSIOLOGICAL MAMMALOGY VOLUME I Mammalian Populations Physiological Mammalogy VOLUME I Mammalian Populations CONTRIBUTIONS BY JOHN B. CALHOUN J. J. CHRISTIAN VOLUME II Mammalian Reactions to Stressful Environments PHYSIOLOGICAL MAMMALOGY EDITED BY WILLIAM V. MAYER Department of Biology, Wayne State University, Detroit, Michigan and RICHARD G. VAN GELDER Department of Mammalogy, The American Museum of Natural History New York, New York VOLUME I Mammalian Populations 1963 ACADEMIC PRESS— New York and London COPYKIGHT © 1963, BY ACADEMIC PrESS InC. ALL RIGHTS RESERVED \0 PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM, BY PHOTOSTAT, MICROFILM, OR ANY OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS. ACADEiMIC PRESS INC. 1 1 1 Fifth Avoniie, New York o. New York United Kingdom Edition published by ACADEMIC PRESS INC. (LONDON) LTD. Berkeley' Square House, London W.l Library of Congress Card Number: 63-23422 PRINTED IN THE UNITED ST.\TES OF AMERICA Contributors to Volume I JOHN B. CALHOUN Laboratory of Psychology National Institute of Mental Health Bethesda, Maryland J. J. CHRISTIAN Division of Endocrinology and Reproduction Research Laboratories, Albert Einstein Medical Center Philadelphia, Pennsylvania PREFACE The field of mammalogy has, until very recently, been largely concerned with morphology and systematics; investigators have done little to bring together experimental work on the widely divergent mammalian types of which we have knowledge. The treatise "Physiological Mammalogy" was, therefore, conceived as a device to bring together the existing knowledge of an experimental nature on those animals usually regarded as "wild." Approximately fifteen themes, on which a considerable body of evidence has been accumulated over the years, provide the central organizing core around which various authors have been asked to make their contribu- tions. The amount of material available on the non-classic laboratory animals has been difficult to synthesize ; but the experts who were asked to contribute to the planned original single volume have proven so knowl- edgeable about the areas of their specialities and have made such a truly impressive survey of the experimental literature on their topics that it has become necessary to expand the work from the original single volume of relatively short essays to a minimum of three and perhaps even more additional volumes. The plan of this work is such that anyone working with mammals will find it an indispensable reference. It is particularly valuable to experi- mentalists working with mammals in the areas of physiology, mammalogy, and ecolog3^ Within these volumes will be found comprehensive essays on specific topics in physiological mammalogy, as well as a cogent analysis of the experimental field developing both what is known and what needs yet to be done. The research worker will find, in perusing these pages, chal- lenging obser\'ations to which he might well address future researches. The student will find reference material and previous observations which will make these volumes useful as a baseline from which additional studies can be begun. ]\Iost of the authors have, in addition to providing a com- prehensive review article, intercalated their own observations and com- mentary to the point where the articles themselves constitute original contributions to the field. This treatment provides a comprehensive analy- sis of the over-all specified topic. These volumes will provide the investigator with information that will enable him to choose experimental animals previously little used in the laboratory because their specific physiological properties and behavior were formerly not well known. As a compendium on physiology of nor- mally non-laboratory mammals, this treatise will be of value to anyone who works with mammals and to any experimental animal biologist. viii Preface The first volume consists of two comprehensive articles dealing with the physiology of populations. Calhoun's "The Social Use of Space" presents many interesting new ideas on the behavior of animals in populations and the effects of grouping of individuals upon the physiology of the organism. Where many workers have thought of the experimental animal only as an individual apparently divorced from his environment and other members of the species, Calhoun points out the fallacy of this view in providing experimental data that demonstrate the effects of numbers of individuals on the behavior of each individual. Christian's article on population growth treats the problem largely from an ecological viewpoint in dealing with limiting factors of natural populations and population interrelationships. Volume II will consist of three contributions dealing with natural populations and their adaptations to stressful environments. Dr. Charles Kayser treats the mammalian phenomenon of hibernation as a mechanism for avoiding periods of unfavorable environment, and Dr. Robert Chew deals with water balance in desert rodents. Inasmuch as reproduction is considerably affected by the environment, it too can be considered a process modified by environmental stresses, and is discussed in the second volume. Subsequent volumes will include articles on such topics as temperature and metabolism, physiological genetics, photoperiod, and orientation by echo- location. The Editors will conclude the series with a summary article on the phylogeny of physiology. The Editors feel particularly fortunate in that they have received fine cooperation from outstanding authorities in the specific subject matter topics covered. It is the caliber of the individual author on which these volumes base their contribution to science; and while the Editors assume any responsibility for defects of organization or inadvertent errors, the credit for the success of the volumes, as a whole, rests on the indi^'idual contributors. October, 1963 William V. Mayer Richard G. Van Gelder INTRODUCTION The development of the biological sciences has been largely through the observational method. In the nineteenth century descriptive biologists came to occupy a preeminent and leading position in the field of biology. With the advent of the twentieth century, however, biology began to emphasize the experimental; and today, biology is an experimental science in practically all of its branches. However, experimentation in animal biology has very largely concentrated on a relatively few species which have come to be classic. These animals were selected because of their tractability and availability, and because of the fund of existing knowledge about them. Therefore, animal experimental biology has been largely oriented around the dog, cat, rabbit, mouse, guinea pig, and white rat. Despite the fact that again and again it has become obvious that there are wide varieties of metabolic patterns and inter-specific difl^erences in physiology as well as morphology, the bulk of experimentation continues to be done with relatively few classic types. Despite this concentration of effort, over the years numerous researchers have investigated the use of different animals for experimental purposes, including mammals ranging from aardvarks to zebras. The writings of these investigators, however, are scattered widely both in literature and in time, making it diflScult for an experimental biologist to draw on the fund of already available knowledge about animals other than those most frequently used. The basic thesis guiding the preparation of "Physiological Mammalogy" has been to make available to the experi- mental biologist the wealth of data in the work of widely geographically scattered research scientists of diverse experimental interests. :S\ca7 TABLE OF CONTENTS LIST OF CONTRIBUTORS V PREFACE Vii INTRODUCTION ix CHAPTER 1 The Social Use of Space John B. Calhoun I. Introduction 2 II. The Bivariate Normal Type of Home Range 4 III. Behavioral Origins of the Bivariate Normal Type of Home Range 8 IV. Use of a Two-Dimensional Field 19 V. Summary of the Concept of Home Range 25 VI. Continuous Removal Trapping of Small Mammals 26 VII. Toward a General Theorj^ of Interspecific and Intraspecific Use of Space 34 VIII. Interpretations of Observed Data Derived from Removal Trapping of Small Mammals 52 IX. A Theoretical Conceptualization of the Evolution of a Social Hierarchy among Species in the Utilization of Space 70 X. Psychological Dominance as the Primary Component of the Niche 77 XI. An Induced Invasion 80 XII . Derivation of Compact Colonies from Constellations 86 XIII. A Formulation of Group Dynamics 101 XIV. Consequences and Examples of Social Interaction Systems 148 XV. Conclusion 184 References 185 xi xii Table of Contents CHAPTER 2 Endocrine Adaptive Mechanisms and the Physiologic Regulation of Population Growth J. J. Christian General Introduction 189 PART 1. THE ENDOCRINE ADAPTIVE MECHANISMS I . Introduction 191 II. The Endocrine Glands of Adaptation 192 PART 2. PHYSIOLOGIC ADAPTION AND MAMMALIAN POPULATIONS I. Introduction 261 II. Endocrine Responses to Social Pressures and to Population Density 263 III. Conclusion 325 References 328 AUTHOR INDEX 355 SUBJECT INDEX 363 The Social Use of Space JOHN B. CALHOUN Laboratory of Psydwlogy, National Institute of Mental Health, Bethesda, Maryland TABLE OF CONTENTS I. Introduction 2 II. The Bivariate Normal Type of Home Range 4 III. Behavioral Origins of the Bivariate Normal Type of Home Range. _ 8 A. Activity in a One-Dimensional Habitat 8 IV. Use of a Two-Dimensional Field 19 A. Theoretical Origin 19 B. Travel-Path Home Range 24 V. Summary of the Concept of Home Range 25 VI. Continuous Removal Trapping of Small Mammals 26 A. Rich Lake Island, New York, 1952, Sixty-Day Removal Study — Data Contributed by William L. Webb 27 B. Chadwick Woods, Montgomery County, Maryland, Removal Study, 1958-1959— Data Contributed by Kyle R. Berbehenn 29 C. Comparative Catches, Huntington Wildlife Forest, 1952-1953 — Data Contributed by Earl F. Patric and WilUam L. Webb_ . . 29 D. Comparative Catches, Huntington Wildlife Forest, 1951 — Data Contributed by William L. Webb 30 E. Comparative Catches in Maine (1950) and Maryland (1953) ... 31 F. Comparative Catches of Peromyscus and Clethrionomys 32 VII. Toward a General Theory of Interspecific and Intraspecific Use of Space 34 A. A Two-Species System 36 B. The Nature of the Inhibitory Influence 38 C. The Learning of Signals 39 D. The Distance between Neighbors of the Same Species 42 E. Methods of Calculating Data Relative to the Distance between Neighbors 44 F. Further Comment on the Impact of All Individuals on the Environment 44 G. Contacting Neighbors 45 H. Sign Field of All Neighbors 47 I. Signal Field of Neighbors 47 J. Hum Field 50 K. General Conclusion Concerning the Distance between Neighbors 50 L. The Number of Neighbors Perceived 51 1 John B. Calhoun VIII. Interpretations of Observed Data Derived from Removal Trapping of Small Mammals 52 A. The Relationship between Two Dominant Species 52 B. Removal Captures of Socially Dominant Species 55 C. Constellation Formation — An I ntraspecific Phenomenon 57 D. Expected Variability in the Number of Individuals Forming Constellations 62 E . Social Rank and Intraspecific Associations 64 F. The Instability of Social Relations 67 IX. A Theoretical Conceptualization of the Evolution of a Social Hierarchy among Species in the Utilization of Space 70 X. Psycholo.2;ical Dominance as the Primary Component of the Niche. . 77 XI. An Induced Invasion 80 XII. Derivation of Compact Colonies from Constellations 86 A. Compact Colony Formation in the Norway Rat 87 B. Howler Monkeys, a Compact Colony Living Species 90 C. Behavioral Sink D;>velopment by the Norway Rat 92 D. Yarding by Deer in Northern Wisconsin 95 E. Concerning Basic Numl;ers, A^d, for Man 97 XIII. A Formulation of Group Dyi amies 101 A. The Model of Social Intera.'tion 101 B. Basic Processes Involved in Social Interaction 116 XIV. Consequences and Examples of Social Interaction Systems 148 A. Velocity Reduction in a Hierarchy of Mice 148 B. The Choosing of a Partner 154 C. The Response-Evoking Capacity Circumplex 155 D. Conformity, Withdrawal, and Creativity 162 E. Velocity and Home Range 164 F. Velocity in High-Density Rat Societies 168 G. Exploratory Behavior 175 XV. Conclusion 184 References 185 I. Introduction During recent years many investigators have considered the physiological consequences to the individual of altering the size of the group of which it is a member. Inherent in such studies is the assumption that for a particular species there is some optimum group size, above or below which the altered frecjuency or type of interactions are either stressful or fail to elicit optimum physiological states. My purpose wall be to develop formulations con- cerning the social use of space to determine whether there might be certain optimum group sizes. I shall consider only indirectly the physiology of individuals. Instead, emphasis will be upon relationships which determine the "physiology" of the community. The basic particle is the individual mammal. In any total 1. The Social Use of Space 3 assembly of such particles inhabiting a particular environment, taxonomic categories, such as species and genera, represent general classes of particles. Although several classes may share certain characteristics, each possesses characteristics peculiar to itself, which on the average differentiate it from all other classes. Furthermore, the properties of any particular particle may change through time as a function of maturation and experience. Such changes are reflected in the individual's internal milieu. Only at this level are we concerned with physiology in its classical sense. A social system consists of particles moving through space and time. In the course of evolution and maturation, such particles may develop en- hanced capacities for affecting others and, in turn, for being more affected by them. This inquiry seeks that essential nature of these particles which influences the course of social evolution. It concludes that each category of particles which we designate as a species must develop a basic group size, designated as its basic number, Nb. Then, assuming the validity of the concept of an Nb, the inquiry is extended to encompass the following questions : 1. How do changes in TV from Nb alter the social system? 2. Given a species, whose groups are of the optimum Nb type, how do changes in the environment or in the nature of the particles affect the social system? 3. What are the basic organizational and interactional properties of the group? I found very few prior studies in the literature suitable for guiding me in developing formulations adequate to satisfy these objectives. Therefore, this discourse will be neither a review of the literature nor even an adequate presentation of empirical data. Instead, the major theme concerns develop- ment of a logically sound, theoretical framework of processes underlying social phenomena. In the course of this development some empirical data will be presented. These data are not meant to prove the correctness of the formulations. They are presented simply as background for the origin of ideas or to show that there at least exist some data which are harmonious with the developed concepts. Much of such data is presented here for the first time. I am in- debted to many persons for their permission to cite such original data. I have attempted to place many of the concepts in sufficiently precise mathematical form to permit a better understanding of the dynamics in- volved. My inadequacy in the field of mathematics has been buffered by the advice of several competent mathematicians : James U. Casby, Murray Eden, Samuel W. Greenhouse, Seymour Geisser, Clifford Patlak, and 4 John B. Calhoun John Gilbert. However, I assume full responsibility for any errors, in- adequate presentation, or overextension from their initial guidance. I have found this effort a rewarding one for the development of insight into complex social systems, and I can only hope that in some small meas- ure it may serve as a bridge for others in their design of experiments or in their further theorizing. II. The Bivariate Normal Type of Home Range Home range denotes the area covered by an individual in its day-to- day activities. Field studies of many species of mammals have revealed that each individual customarily stays within a restricted area for long periods. The individual utilizes the center of such an area most inten- sively. With increasing radial distance from this home range center (HRC) the relative frequency of visitation per unit of area decreases. Calhoun and Casby (1958) found that the bivariate normal distribution function adequately describes home range. The following is a summary of their analyses. In home range studies, "density function" is a mathematical expression representing the probability of an animal being present in some arbitrarily small area. Three assumptions are made : The home range is fixed. In other words, the statistics of the home range are stationary or time independent. There is a true center of activity although the apparent center, the mean coordinate point of capture, of activity may deviate from it. The probability of an animal being in a unit of area decreases with in- creasing distances from the true center of activity. This and the second assumption suggest a bivariate normal distribution of the density function : f{x, 7j) dxdy = — — - exp [- (a:^ + if)/2a^'] dxdy (1) where o- is the standard deviation of the distances in the x and y direction and is assumed to be equal for both, and x and y are measured from their respective means. This density function may be used to represent the percentage of time spent in the area dxdy located at the Cartesian coordi- nates X, y, or in polar coordinates: /(/•, 6) rdedr = — — exp (-r'^/'Ia^) rdddr (2) zcrV Here, the area rdddr is determined by r. The density function in terms of the Cartesian coordinates is more 1. The Social Use of Space meaningful from an ecological standpoint because it states in comparative terms the amount of time spent by an animal in a small standard area at any position in the home range. However, for the initial mathematical manipulation, it was found more convenient to express the density func- tion in terms of polar coordinates. Then the probability of finding the animal between the radii r and r -\- dr about the true center of the home range is: 2 f{r)dr = — - exp ( — r~/2a'^) rdr If Eq. (3) is integrated over the range 0 to o- we have r 2r / T- exp (-rV2(r2) rfr = 1 - g-'/^ = 0.3940 'o -^0- (3) (4) In the above eciuations a, the standard deviation of the normal distribu- tion function, is the value of a radius within w^hich the probability of the animal being present is 39.4%, if its movements can be described by a bivariate normal density function. Similarly, integrating Eq. (3) over the range 0 to 2o- gives 1 - e-4/2 ^ 0.8645 (5) Similarly, integrating Eq. (3) over the range 0 to 3o- gives 1 _ p-9/2 = 0. f6) The above sigma thus delineates a single distance term by which home range may be described. The term "home range sigma" will be so utilized in following sections. Although this sigma may be calculated from a series of coordinate points of capture by equations presented in the original paper, use of recapture radii provide a more direct means, adequate for most purposes. Calculate the mean coordinate point of capture, the approximate home range center. Then on a large scale grid map of the study area measure recapture radii, r, from this mean coordinate point of capture. Unbiased estimates of sigma, s and Si may be calculated by the following equations: s = &i = _2(A^ - n). Ki 3=1 _2(/:.- 1) (7) (8) 6 John B. Calhoun where : s = unbiased estimate of the home range sigma for all the animals in a sample St = unbiased estimate of the home range sigma for any particular animal Ki = number of captures of ith animal n = number of animals n N = total captures = ^ Ki ij = jih observation of the iih. animal A detailed analysis of the home range for 25 male harvest mice (Reithrodontomys) on which there were 10 to 24 captures each indicated that there was a significant variation of sigma among animals. In other words, some animals had significantly larger home ranges than others. Therefore, in order to compare the observed recapture radii with the theoretical (Table II in Calhoun and Casby, 1958), each recapture radius was normalized into a standard measure denoted by Z in which the home range sigma for each animal was assigned a value of 1.0 and all recapture radii expressed as a proportion of this. As may be seen from Fig. 1, the theoretical closely approximated the observed. Although this detailed analysis has been applied only to this one species, it shall be assumed for the purpose of developing further formula- tion that the bivariate normal distribution function adequately describes fixed home ranges of other species. Comparison of observed and theoretical distribution of home range radii required viewing home range as a probability of capture which changes with radial distance from the home range center. Bands of equal width increase in area with radial distance from the home range center, while probability of capture per unit area decreases with increase in radial dis- tance. Interaction of these two factors results in more captures at about one sigma from the home range center than at any other distance (Fig. 1). However, the ecologically important aspect of the bivariate normal dis- tribution as an expression of home range is the relative probability that an animal will be in a unit of area with respect to the radial distance of that unit area from the home range center (Fig. 2). For any given sigma char- acterizing a particular species, its density function in terms of area curve may be obtained by multiplying the relative sigma value on the abscissa by the observed sigma and dividing the density function values on the ordinate by the square of the observed sigma. 1. The Social Use of Space 70 1 r Rodius from center of home range Fig. 1. Observed (histogram) and theoretical distribution of 348 recapture radii (Z) of 25 male harvest mice from the center of their home range. Z here represents a normalized measure of the bivariate normal home range sigma. 0 .6 1.2 1.8 2.4 3.0 Radius from center of home ronge in units of cr 3.6 Fig. 2. Cross section of the density function of home range in terms of area. Rotation of this curve about its axis reveals the mountain-shaped topography of home range. 8 John B. Calhoun III. Behavioral Origins of the Bivariate Normal Type of Home Range The fact that a particular equation happens to describe home range enables derivation of several principles regarding the use of space by an entire community. Discussion of these principles follows in Section VII. However, as a background to this discussion it will be advantageous to seek an understanding of the biological basis for the bivariate normal type of home range. A. Activity in a One-Dimensional Habitat Admittedly, animals rarely live in essentially one-dimensional environ- ments. However, I suspected that if animals were placed in such environ- ments certain regularities of behavior might be revealed which would pro- vide insight into their use of two-dimensional environments. To this end, four 14-foot long alleys were constructed. Each had a channel 8 inches wide. Each 8 X 12-inch segment of the floor was so suspended that when a domesticated Norway rat, used as a subject, stood on such a segment a microswitch closed. This closure initiated a signal such that the exact position at every point in time was recorded on a recording oscillograph. A partition between the first and second treadles formed a home compart- ment. A 3 X 3-inch opening through this partition provided access to the rest of the alley. Food and water placed in this compartment further en- hanced the role of this compartment as a "home." A ground glass plate, through which shone the light from a 100-watt lamp, formed the opposite end of the alley. This light served to concentrate the activities of the rats emanating from the home compartment. It was as if every foot of the alley were several feet long. Details of the effect of varying light intensity at the end of the alley on explorations will be presented elsewhere. This ap- paratus is referred to as the Ferguson Activity Alley. Suffice it to consider the results from 73 rats, each run for 72 hours in the alley. Each rat made from 10 to 30 excursions out into the alley each night. Despite the presence of the bright light at the end of the alley, one- fourth of the trips terminated at the end of the alley. In other words, the end of the alley formed a barrier. Most of the trips thus terminated at the end of the alley presumably would have represented trips of greater length had the alley only been longer. Most of the time a rat would go out to some intermediate distance, stop momentarily, and then turn around and go directly back home. Occasionally, a rat would wander back and forth from the point of initial termination. All trips with such vacillations and those ending at the barrier were excluded from the initial analysis. 1. The Social Use of Space 9 1. Trip-Terminations in an Unstructured One-Dimensional Habitat The initial investigation focused upon examination of the distances from the home compartment at which nonvacillating trips terminated in the unstructured alley. "Unstructured" denotes the absence along the alley of any stimuli likely to elicit responses and so induce a rat to stop. Rats were placed in the alley during the middle of the afternoon, a time of minimal activity within their normal 24-hour rhythm of activity. And yet when placed in the alley every rat exhibited a 2- to 3-hour period of hyper- activity. Further details of the decay curve of this hyperactivity are dis- cussed in Section III, A, 3. For 73 rats complete records (Table la) were available for all trip- Tablk la Number of Trips Terminated with Reference to Distance from Home Unstructured alley Structured alley T^' A feet of During first During next 3 Strips of Pellets termination 2.5 hours 6 A.M.-6 P.M. periods paper of food 1 274 558 1053 955 2 204 407 839 643 3 150 315 723 509 4 104 277 302 375 5 99 294 194 288 6 81 219 230 258 7 56 139 151 163 8 58 115 149 137 9 47 98 112 119 10 39 113 57 104 V 1112" 2535" 3810 3551 Barrier and vacillat- 502 1458 59* 127* ing trips Total trips 1614 4023 3869 3678 Trips/rat/hour 8.844 1..531 " Only nonvacillating trips included. * Vacillating trips and trips at whose end an object was transported home are not included since the termination of trips determined was solely by the number of tran.s- I)ortt'd objects. 10 John B. Calhoun terminations during both the initial 150 minutes of hyperactivity and the following three, 6 p.m. to 6 a.m., 12-hour periods of normal heightened nocturnal activity. The frequency, y, of terminating trips as a function of distance, x, from home is described by the equation : y = exp (o 4- bx) (9) where h is the slope. The slope for trip-terminations during the hyper- active period, 6i, is —0.2099; while 62, the slope for trip-terminations during the 36 hours of normal nocturnal activity, is —0.1924. The t test 61 — 62 = -0.682 VVar. (61 - 62) has a p value of 0.051 which indicates that slopes 61 and 62 do not differ significantly. Therefore, it is concluded that the neural mechanism producing termina- tion of trips is unaltered by the nearly sixfold increase in the incidence of initiating trips accompanying initial exposure to a strange environment. For this reason, the mean slope of —0.20115, i.e., (61 + 62) /2, was fitted to both these sets of data shown in Fig. 3 as trips per rat per hour for compara- tive purposes to emphasize the hyperactivity of initial exposure to a strange environment. 2.0 1.0 .02 "eMOTlONAL " I si. 2.5 hours of Hyperaclivily 10 TERMINATION OF TRIP IN FEET Fig. 3. Frequency of terminating trips at successive distances from the home com- partment in the unstructured Ferguson Alley. See Table la. 1. The Social Use of Space 11 2. The Role of a Structured Environment on the Termination OF Trips Natural habitats possess structures which elicit responses. Items of food and nesting material represent structures normally causing animals such as rats to terminate trips. When such items are transported home the trip resembles the nonvacillating ones in the one-dimensional alley in the sense that there is a direct outward phase, terminated by the object being picked up, followed by a direct homeward trip transporting the item. In order to explore the effect of such structuring in the one-dimensional habitat upon termination of trips, one of two procedures was followed; At each one- foot interval from home along the alley, there was placed a pad of paper strips or an open hopper of food pellets. During any particular rat's stay of 3-12 days in the alley, only nesting material or only food pellets were available. Periodic replenishment of each source ensured a continuous supply at each distance. Nevertheless, the rats removed items from each distance (Table la) even though this necessitated passing by opportunities to respond while on the outward journey. Each item removed at a particular distance from home is considered to indicate a trip-termination at that distance. Examination of the oscillograph record confirmed this inter- pretation. The frequency of termination of such trips as a function of distance is also described by the equation, y = exp (a -\- bx) . The slope for trips termi- nated by picking up paper strips, 63, is —0.3027; while 64, the slope relating to securing food pellets, is —0.2481. The t test, 63 — hi = -2.128 VVar. (63 - 64) has a p value between 0.05 and 0.01 which indicates a statistically signifi- cant difference between these two slopes. However, examination of Fig. 4 reveals a marked dispersion about the best-fit line of the observed points relating to nesting material. For this reason, the interpretation that the 63 and 64 slopes differ statistically is open to question that this difference in slope implies biological significance. I therefore believe it wisest to as- sume that 63 and 64 are really identical, or nearly so. If this is so, we may compare the slopes of the mean of 61 + 62 with that of 63 -f 64. Here the t test Uh + 62) - 1(63 + 6.) ^ ^^^25 VVar. Uh + 62) - K&3 + 64) with a p value less than 0.001. 12 John B. Calhoun 5 o 1000 1 1 1 1 1 1 I 1 1 /I Paper strips ' B Food pellets - - \-v ~ o\ " - - — — - • - ~ 1 1 1 1 1 1 1 1 1 1 DISTANCE FROM HOME IN FEET FROM WHICH OBJECTS WERE TAKEN Fig. 4. Frequency of transporting nesting material and food into the home com- partment from points at successively greater distance from it. A, 3810 strips of paper; B, 3551 pellets of food. See Table la. It is therefore concluded that structuring the environment with items inducing responses leads to a reduction of the distance from home at which trips are terminated. 3. The Prob.\bility of Terminating Trips The two prior sections merely demonstrate an effect produced by struc- turing the environment. They do not further our understanding of the underlying biological process. The behavior of rats in the structured environment provides the clue. During any period of intensive transportation, one trip almost immediately followed the preceding one. And yet the distance at which a particular trip terminated bore no relationship to the distance at which the previous or following one terminated. It was as if the rat w^as blind to its surroundings on the outward trip until some neural switching mechanism became acti- vated in a random fashion with reference to the time of the trip's initiation. This switching on (or off?) placed the rat in a perceptive phase at which time it responded by picking up the nearest relevant object and trans- porting it into the home compartment. Therefore, it will be helpful to deter- 1. The Social Use of Space 13 mine the probability of this switching, which is synonymous with the probability of terminating a trip. Let: tj = the number of trips reaching any jth distance from home. Nj = the number of trips that stop at the jth. distance. Pj = probability of stopping at the jth distance. Then: tj~i - tj = Vi-itj-i (10) Nj = p,tj (11) Nj - Nj_i =pjtj - pj-it.j^i (12) If Pj = p (a constant independent of j), then: Nj - Nj^i = p(ij - ij_i) = -p(tj-i - l.j) (13) Nj - iVy_i = -piptj^i) (14) And by analogy to Eq. (11): iVy_i = pti^i (15) Substituting Eq. (15) into Eq. (14): Nj - Nj^i = -pNj^i (16) Therefore p = (Nj_r - Nj)/Nj_r (17) This p represents a constant probability of terminating trips which arrive at a point regardless of the distance from home. Rigorous proof that this p actually is a constant is difficult from present data because of the barrier produced by the relatively short alley. However, the validity of a constant p, independent of distance, may be arrived at intuitively since an equation of the form y = exp (a + hx) best represents the observed data. In other words, log ij plotted against x forms a straight line. Whenever this is so, Eq. (17) must be true. Utilizing Eq. (9) stated in the form : loge?/ = a - bx (18) the expected number of trips terminating at Nj^i and Nj, where j = 2, were found to be as shown in Table lb, along with the p values calculated from Eq. (17). Thus, the probability of 0.182 of terminating trips arriving at any distance in the unstructured alley is increased to 0.24 by structuring. 14 John B. Calhoun Table lb Probability of Terminating Trips with Respect to Environmental Structure AND Level of Activity Alley Secondary condition Expected number of trips terminating at: A^,-i A^i Mean During first 2.5 hr. of hyper- 237.5 194.3 0.182« activity Unstructured 0 . 182 During normal nocturnal ac- 510 417 0.182° tivity Structured Paper transportation Food transportation 999 783.3 0.261 837 653.5 0.220 0.240 " The mean b value of —0.20115 used in the calculation of p. 1000 i 100 50 ~>s^ — 1 1 A ■ 1 1 1 1 I 1 — — /f£ Trips terminated Z RE Objects transported _ - \ — . 1. .. 1 . 1 . . 1 ~ 10 DISTANCE FROM HOME IN FEET Fig. 5. Theoretical curves depicting relative likelihood of trips going beyond suc- cessive distances from home based upon an initial 1000 departures. A, in an unstructured alley (see Fig. 3) ; B, in an alley structured with objects available for transport back home. 1. The Social Use of Space 15 The amount of structuring used here increased the probability of stopping by 32% [i.e., (0.240 - 0. 182) /0. 182]. The extent to which this difference modifies the use of a field may be visualized by considering the following: Of every 1000 trips arriving 1 foot from home in the unstructured alley, 30 would stop at the tenth foot and 134 would continue farther, whereas in the structured environment only 20 would stop at the tenth foot and only 64 would continue farther (see Fig. o). In closing this section it should be emphasized that the probability of stopping is basically a function of time. In the particular situation, the p's refer to the time required for the rats to travel a distance of 1 foot. A further question may be asked: "How does structuring increase the probability of stopping if the animals are perceptually 'blind' to specific stimuli to the extent of being unable to exhibit directed responses to them?" One may visualize the situation in general terms: There is some assembly of neurons which provides a signal terminating an ongoing behavior, such as outward locomotion from home. The magnitude of this signal neces- sary for behavioral termination reciuires simultaneous firing of some x number of neurons. This assembly of neiu'ons may be called a "governor." It must be located anatomically in some subcortical portion of the brain precluding conscious awareness of its functioning. During any ongoing behavior all perceivable stimuli unrelated to the ongoing behavior initiate impulses which arrive at the behavior terminating governor. Each unit of impulse causes an increase in the rate of firing of the neuronal net forming the governor. The greater the intensity of such stimuli, or the greater the number of stimuli of a given intensity, the more rapidly will the neurons of the governor fire and thus the shorter will be the interval between emis- sion of effective signals by the governor. This signal both terminates the ongoing behavior and produces awareness of stimuli appropriate to eliciting those responses appropriate to initiating some other behavior. 4. Initial Hyperactivity in a Strange Environment For the rats discussed in Section III, A, 1 the level of activity in terms of trips per rat per hour (Fig. 3 and Table la) was approximately six times as high during the first 150 minutes of exposure to a strange environment in comparison with the later periods following adjustment. This observa- tion requires postulation of a second governor, one which determines the probability of initiating trips. Initiating trips is here considered to be synonymous with initiation of periods of diffuse undirected motor activity. Examination of the expression of hyperactivity during the first 2-2| hours of exposure to a strange environment provides insight into the func- tioning of this governor of trip-initiations. 16 John B. Calhoun For 71 of the 73 rats previously discussed with reference to the distaiu^o of trip-terminations, a count was made of the total feet traveled each half- hour during the first 2| hours of exposure to the alley. A similar analysis was prepared for the 26 rats, considered further in Section III, A, 5, which emerged into the alley more than momentarily and for which the recording system functioned properly. For each set of data, results are quite similar (Fig. 6). Activity con- tinuously declines during initial exposure to a strange environment. But the important point is that this decline begins from an extremely elevated state of hyperactivity. From Table la it may be calculated that the average z i 100 K I I- U. — llJ tt ^ X *- < Q 2 10 1 1 1 1 1 - 4 By ^/ Flats ^\. B By 26 Rats — \\. — - \\ — - "^"^^ >v^ - - 'x - N. 1 1 t I 1 12 3 4 5 CONSECUTIVE 30 MINUTES IN ALLEY Fig. 6. Hyperactivity in a strange environment: Curve A represents the mean activity level of 71 rats immediately after first exposure to the Ferguson Alley. Curve B similarly gives the mean response of 26 rats to the NIH Emotional Activity Alley. round trip approximates 10.44 feet. During the normal nocturnal period of activity, trips occur at the rate of 1.58 per hour. This means that in this one-dimensional alley rats travel 8 feet per half-hour on the average when adjusted to their environment. As may be seen from Fig. 3 the activity is in(;reased nearly twenty times normal during the initial half-hour in this strange environment. Projection of the curves, shown in Fig. 6, indicates that a normal level of activity will be reached by 3—4 hours of adjustment. Such decay curves of hyperactivity suggest that the rats secrete some humoral agent upon their initial exposure to strange stimuli such as repre- sented by the activity alley. This humoral substance increases the rate of firing of the neuronal net comprising the governor which determines onset of diffuse motor activity, such as trips out into the alley. As this substance is degraded, the frequency with which this governor emits signals initiating trips decreases until normal behavior is achieved. 1. The Social Use of Space 17 5. Avoidance of a Strange Field During the pursuit of these studies on behavior in a one-dimensional habitat, a few rats failed to emerge into the alley until after the lapse of several hours. ]VIost frequently such rats were members of subgroups having had less opportunity to adjust to novel stimuli. This suggested that the less opportunity an animal had to make adjustments to strange stimuli, or the more novel was the strange environment, the more likely it would be avoided. New alleys were constructed to permit exploration of this hypothesis. These alleys consisted of an 8 X 8-inch channel 15 feet long. At one end a home nest box could be attached from which the rat gained access to the alley by way of a 3 X 3-inch door. At the opposite end of the alley, light from two 60-watt lamps shone through a ground glass plate. Unless other- wise modified, the floor was stationary. A photoelectric cell at each 3-foot interval along each alley initiated a signal to an Esterline-Angus event recorder each time a rat passed. This apparatus is called the "NIH Emo- tional Activity Alley." Each of the 7(i subjects, Osborne-]Mendel male rats, was housed alone for 3 months from weaning in a smaD cage precluding the visual perception of any object outside the cage. Cages were not opened. Food and water were delivered into the cage through channels making it unnecessary to open them. These procedures minimized opportunity for adjusting to new configurations of stimuli. In the terminology of Section XIV, G, 1, the isolation cage represents an Ei configuration of stimuli. Under this termi- nology El • • ' En represent a series of discrete configurations of stimuli which an individual may encounter for the first time in that order. Twenty rats were transferred directly from the isolation cages into the activity alley for a 2-hour exposure. Of the remaining 56 rats, 24 were ex- posed to an E2 configuration for 2 hours for 10 days prior to being placed in the alley. Similarly, 16 others were exposed to an E-^ configuration, while the remaining 16 were exposed to E2 for 2 hours, then immediately exposed to Es for 2 hours for 10 days. Three days after these exposures, which pro- vided opportunity to adjust to the new stimuli of E2, E:^, or Ei and £"3, each rat was given a 2-hour trial in the activity alley, which represented an Ei configuration. Half of each of these four groups were placed in the alley with a stationary floor, an Eu. configuration; while for the other half the alley contained sections of tilting floor, an E^v, configuration, which clanged when the rats passed over them. Greater detail of these studies are presented in Section XIV, G, 4 and in Table lib. However, the results presented in Table Ila suflfice for the present purposes. Both aspects of the hypothesis were confirmed. The 18 John B. Calhoun Table Ila Effect of Training and Degree of Strangeness of a Field upon Its Being Entered during 2 Hours of Exposure by Each of 76 Rats" B 'Training" in adjusting to Response strange stimuli Degree of strangene.ss of alle}' alley Yes No High Low (tilting floor) (stationary floor) Entered Avoided 37 19 4 16 13 30 25 8 -A data: x^ = 10.8045; p less than 0.001; B data; x'' = 13.7110; p less than 0.005. stranger a field or the less opportunity there has been to adjust to novel stimuli, the greater will be the tendency for an animal to avoid that field. 6. Probability of Vacillating at the Termination of Trips In the unstructured Ferguson Activity Alley, rats usually went directly out to the point where the trip terminated, then turned around and went directly back to the home compartment. Yet occasionally when a rat made an excursion out into the alley, it would wander back and forth Table Hb Effect of Kind and Sequence of "Training" in Adjustment to Strange Stimuli UPON Avoidance of an Activity Alley Group" E,A Alley EiB Alley Total trials Trials entered Proportion entered Total trials Trials entered Proportion entered A B C D 40 48 32 32 11 33 31 24 0.275 0.688 0.969 0.750 40 48 32 32 2 24 22 6 0.050 0.500 0.688 0.188 Total 152 99 0.651 152 54 0.355 " See Section XIV, G, 4 for details of treatment of the four groups. J. The Social Use of Space 19 about the place where the trip terminated. Two hundred and fifty-six of the total 2357 trips studied with reference to the initial period of hyper- activity, terminated in such vacillations. As graphically shown in Fig. 7 the probability of vacillating is proportional to the length of the trip. 0 5 10 LENGTH OF TRIP IN FEET Fig. 7. Probability of trips including a period of vacillation, wandering back and forth about the point of termination. Curve based on 2,357 trips by 136 rats during their first 150 minutes in the Fergu.son Activity- Alley. These results are given here because of their bearing on the question of the proportion of time an animal is capable of responding to static compo- nents of its environment. As I have stated above, I am proceeding with this formulation, utilizing the hypothesis that directed responses can be made only at the ends of periods of diffuse activity, which are represented here by the outward termination of trips. If this responsiveness at ends of trips persists throughout the wandering about at the end of trips, then it follows that the farther a familiar type of object is from home the more likely it will be responded to in proportion to trips terminating there. This conclu- sion is subject to the (jualification that the object is so sparsely distributed in space as to require more searching than mere detection of the surround- ings at the point of terminating a trip. IV. Use of a Two-Dimensional Field A. Theoretical Origin We are here considering animals whose movements emanate from a fixed home base. For them a two-dimensional field differs from a one-dimensional 20 JoJui B. Calhoun one in that in a two-dimensional field the area available at successive radial distances from home increases with radius. Considering this fact, will the behavior exhibited by rats in a one-dimensional field lead to an equation for home range closely resembling the bivariate normal distribution [Eq. (3)]? When Casby and I originally found that the bivariate normal distribution did conform with the observed home range resulting from captures, we were merely culminating a search for a means of describing the distribution of captures about the mean coordinate point of capture. This conformity revealed nothing about the biological mechanisms involved. We shall now inquire whether the phenomena of (a) decreasing frequency of arriving at successively greater distances from home, and (b) the probability of wandering increasing with distance from home suffice to explain the origin of the bivariate normal type home range. A critical issue concerns the origin of the observation or "capture." Two types of observation are possible. First, the observer may record the physical presence of the animal at successive points independent of the activities of the individual. Second, the observation may arise as a conse- quence of the animal responding to an object placed by the investigator. Captures in traps represent this type of observation. An assumption is made regarding where responses, such as entering baited traps, will be made. This is that such responses to continuously present and unvarjdng stimuli occur only during the period of wandering at the end of trips. This assumption implies that the animal remains in a perceptually blind state during the outward and return phases of a trip. The circumstantial evidence suggesting this assumption will not be con- sidered here. Let : Pi = probability of terminating a trip at radius r. t = time spent wandering at r if it stops there. C = probability of capture at r, which equals tPi times geometry factor of two-dimensional space. Then: Pi(r) = Ae-^'-^ (19) t{r) = Br (20) These two equations, in which .4, B, and a are constants, represent the two basic assiunptions regarding use of one-dimensional space. Then considering the geometry factor: C = Kre-'i" ' rdrde (21) 1. The Social Use of Space 21 And normalizing, it is found that: C = ^ — rh'-'-'" dr (22) Where r/a = R, the cumulative probability of capture, Cum, as a func- tion of the radius R from home becomes : Cumii = 1 - f — + /? + 1 j e-« (23) Equation (23) above will be called Curve II as shown in Table III and Fig. 8. It may be compared to a similar cumulative probability curve for the bivariate normal distribution, which will be called Curve I, and which has the form: Cumi = 1 - exp (-rV2) (24) Curve II, Eci. (23), may be compared to Cui've I, Eq. (24), by con- verting R into units of r, where r, the radius from the center of the home range, is measured in the a units of the bivariate normal distribution, pro- vided the constant a. oi R = r/a is known. This conversion was arbitrarily accomplished as follows: It can be shown that the cumulative probability of "capture" of Eq. (23), when expressed in terms of a and r, has the form : Cum = 1 - ^-— (r2 + 2ar + 2a2)e-'-/a (25) 2a:- By Eq. (24), Curve I, when r = 1.2, Cum = 0.513. Therefore, by succes- sive approximations, utilizing Eq. (25), it was found that when a = 0.44, Cumii = 0.511 atr = 1.2. Therefore, 0.44 is the a conversion factor applied to ^ = r/a, so that Curves I and II may be compared in terms of the bivariate normal home range cr distance. The values for these two curves, as shown in Table III, are shown in Fig. 8. Note that up to about 2 + 3 ^ ^ + rH|N T3 a; > u ;^ 3 tn (-1 Si S O O p:; .2 lOOCOOODOJt^OGCiCO-Ht^O OOl o d o o d o o d c o o c c d d 1^ fO O O 05 '-lCCCOI>00OiO5O5O5O5O5O5Oi 005 ooooooooooooo o o lO CO o O lO iM lO QO lO 05 O C^3 t^ t^ ^ ^1 CO »C CO CO O O t'- CO COiOCO-— iOt^iCO-*0(X'C«DC2 0^00 0 0(^00050205050505 coocoooo o o o o 00 CO o i—(l>.050502CO'^lO Ttiiocofoi-oo405cocoooioooo5 '*COC0<-(I^O'30'tlt^00O5O505 O^COIOC00000050505050505 CO rt< 05 <0 CO 00 ooooooooooooo Tt- z < o o °^. I- I Ul to > K -I < UJ UJ Q: z i< "* 1 > z CD < 5 0.4 I — -• /.5tr • • » » -• • 2./— /.5ff- 0.6 1.2 1.8 2.4 o- DISTANCE FROM ANY H.R.C. 3.0 Fig. 22. Signal field produced by neighbors. If all neighbors emit signals simul- taneously at their home range centers, and these signals have the properties shown in Fig. IS, then their summated intensity will form a "topography" as here shown with reference to any particular animal moving through its home range. The value 1.0 repre- sents the intensity of a .signal at the point of emission. influence of the signal field on determination of an optimum interval be- tween home range centers. As with the sign field of neighbors, the signal field of neighbors is pre- sumed to influence interval between home range centers through the mem- bers of the community seeking that interval between home range centers which will ensure most closely attainment of both constancy of the signal field, leading to predictability and to approximation of the standard signal intensity. Judging by the three curves in Fig. 22, operation of these two criteria indicates an optimum interval between home range centers slightly less than 2.1 sigma. 50 John B. Calhoun J. Hum Field In Section VII, C it was suggested that when the emitter is between 3 and 6 sigma from the receptor the signal given by the emitter can be per- ceived by the receptor but is insufficient in strength to elicit the appropriate responses. The sum of all such signals below threshold for inducing a response is here termed "hum." When this value exceeds the standard intensity of 1.0 (see Section VII, I), the receptor will become restless even though perhaps not exhibiting a specific response to the signals. What effect this general state of restlessness may have upon the receptor is un- known, but it is logical to assume that the members of the community 3.0 I — •_ > 20 in UJ > 1.0 t- < _l LiJ 0.4 _• ■ a- /.5 a- 2.IO- 27a- \ Distance between H. R. C. 's 0.6 1.2 1.8 2.4 a DISTANCE FROM ANY H.R.C. 30 Fig. 23. Hum field refers to the sum of the intensity of all signals, any one of which is below that minimum intensity required to elicit a specific response. The value, 1.0, denotes the intensity of a signal at the point of emission. will attempt to adjust the interval between the home range centers in such a way as to reduce the likelihood of the "hum" exceeding 1.0. To do so implies that home range centers must be of the order of 2.4 sigma apart (Fig. 23). K. General Conclusion Concerning the Distance between Neighbors Effective learning of signals probably does not begin until home range centers come at least 3.0 sigma from each other, and even further shorten- ing of this interval must increase the effectiveness of learning. Several 1. The Social Use of Space 51 factors examined all suggest that the optimum interval between home range centers should be of the order of a 2 home range sigma distance. From an evolutionary standpoint, the most important of these probably is the fact that utilization of the environment becomes uniform at slightly more than 2 sigma distance between home range centers. This factor should have been the major one in the evolution of those characteristics of in- dividuals pertaining to the frequency of trips, the velocity of the individuals, and the aggressive acts elicited when two individuals meet. It is probably strictly coincidental that the properties of the sign and signal field are also likely to be such as to make an interval of about 2 sigma between home range centers optimum. It is at this distance between home range centers that both signs and signals become most constant and thus more pre- dictable. Also, the intensity of the signs and signals most nearly approxi- mate any receptor's own behavior near its home, which can serve for it as a standard in evaluating the intensity of the actions of its neighbors impinging on it. L. The Number of Neighbors Perceived When home range centers are 2.7 sigma apart, an indi\ddual at its home range center can just perceive all its six nearest neighbors. However, as it begins to move away from home it begins to lose contact with those nearest neighbors lying on the opposite side of its home range center. By the time it reaches half the distance to its nearest neighbors in the direction in which it is traveling, it can detect only three of its nearest neighbors. Toward the periphery of its home range, it can detect only two of its nearest neighbors. In addition, it can detect one, and only one, of its next-nearest neighbors, w^hich are members of the group of twelve forming the second hexagonal tier of neighbors about its home range center. Thus, with this fairly large interval between home range centers, any one individual has poor contact with its associates. When home range centers are 2.1 sigma apart, any one individual can maintain contact with all six of its nearest neighbors out to about 0.7.") sigma. Even when an individual has journeyed halfway in a direction of a nearest neighbor it is still in contact with four of its six nearest neighbors, in addition to one of the twelve neighbors lying in the next tier. As he proceeds still farther, losses of nearest neighbors are compensated for by next-nearest neighbors. Thus, at all times when home range centers are 2.1 sigma apart, an individual is in contact or po- tential contact with five or six of its neighbors. By the time home range centers are of l.o sigma apart, an individual is in potential contact with ten other indi\'iduals though not always the same 52 John B. Calhoun ten, no matter where it is in its home range. Since the dynamics of the use of space relating to uniformity of utihzation of resources and the character- istics of the sign and signal field all point to an optimum interval between home range centers of somewhere near 2 sigma, it follows that there should have been evolutionary adjustment of tolerance to simultaneous or near simultaneous communication with five to ten others. VIII. Interpretations of Observed Data Derived from Removal Trapping of Small Mammals At this stage in the development of a concept of community organiza- tion, one must resort to a certain amount of quasi circular reasoning. Regularities in observed results lead to theoretical formulations. Then these formulations can be used to reexamine the data for further insight. This is my present intent. In time, many aspects of the concept may be subjected to more rigorous study. However, for the present we must content ourselves with a search for a best approximation to a very complex set of phenomena. Section VI, "Continuous Removal Trapping of Small Mammals," presented results from several extensive studies. Specific interpretations follow\ A. The Relationship between Two Dominant Species The dominant species in the community reveals itself during removal trapping through its members having such large home ranges that every individual living near a trap has a high probability of encountering it. Thus, for them, few^r days lapse from initiation of trapping until 50% of the population is caught. As can be seen from the two Alaryland studies presented (Fig. 10 and Fig. 13B), Peromyscus fulfills this criterion. For species associated with Peromyscus, whether they be Blarina and Sorex, or Blarina and Pitymys, the dates of 509(' removal arrive much later. The later the date of 50% removal, the more subordinate a species, and the more slowly its members expand their home ranges as the dominant species is removed. In more northern forest habitats, Peromyscus rarely is found in the absence of Clethrionomys. In fact, it is as if the red-backed mouse is just superimposed upon the simpler Peromyscus-Blarina- Sorex community of more southern forests. Typical dominance of Clethrionomys over Peromyscus may be seen in Figs. 9, 11, and 13A. Although I am convinced that Clethrionomys usually can develop the ability to inhibit the home range of 1. The Social Use of Space 53 Peromyscus, there exist conditions limiting the extent to which this abihty may develop. The typically low relative density of both species (Table VI) on Alt. Desert Island, Maine, represents such a condition. As revealed in Fig. 14, both species decline at about the same rate from day 1 through day 3. This can happen only when no alteration in home range size transpu-es over time or when the survivors of each species make equivalent but slight increases in extent of home range. Appreciation of why inhibition of home range fails to develop at low densities demands knowledge of variables we lack. It demands that we know actual densities. The NACSAI census provide only relative densities. However, we can make approximations. Run long enough (30 days), the 950-foot-long B-type NACSM census procedure should take all residents wdthin 3 home range sigma on either side of the trapline and for a radius of this distance about the end of the line. If we take 50 feet as approximating the average home range sigma of small mammals, uninhibited by dominants, then approximately 8 acres are ex- posed to such a trapline. Furthermore, examination of 30-day censuses re- veals that for species with uninhibited home ranges, 25-50% of the residents are taken during the first 3 days of trapping. On this basis, there was on the average less than one Clethrionomys and less than two Peromys- cus per acre in this Maine study. Since juveniles, with as yet probably little influence on the spatial distribution of associates, comprised a portion of the catch, it is quite likely that the average distance between home range centers for each species exceeded 3 sigma. As shown in the prior theoretical sections, learning of signals would most likely be fairly ineffective here because contact between neighbors w^ould be infrequent. Under these circumstances the signals emitted by each species should have acquired little in the way of negatively stimulating characteristics for its own members. It follows that inhibition of home range size will have been negligible and thus the two species, which probably have nearly the same size home range, should encounter traps with nearly equal fre- quency, and thus the rate of decline in catch from days 1 through 3 should be nearly equal. However, in the one Mt. Desert Island, Maine, study where eight NACSM lines were run for 15 days (Fig. 13A), it is apparent that home ranges of Peromyscus were slightly contracted. Fifty per cent of the 15-day total for Clethrionomys was attained by day 6, but not until day 10 for Peromyscus. Thus, where both species regularly occur at low densities, Peromyscus is only moderately subordinate to Clethrionomys. In the Adirondacks, where Peromyscus most frequently has a low density and Clethrionomys a much higher one (Table VI), Peromyscus is markedly subordinate. Its home ranges not only are markedly contracted, but also 54 John B. Calhoun they expand immediately as Cleihrionumys are removed. The vahdity of this interpretation is revealed in Fig. 14B, which shows that during the first 3 days of trapping as the Clethrionomys population is reduced, as in- dicated by fewer numbers taken on successive days, the numbers of Pero- myscus taken increases. This increasing catch can only result from sufficient expansion of home range by survivors to bring about an increased prob- ability of encountering traps. One might argue that these latter data for Pewmyscus merely indicate that the snap-trap is initially a sufficiently strange object to elicit avoidance. As time elapses these mice become accustomed to the presence of the trap and thus later in time more individuals will enter traps. Two lines of evi- dence of reasoning suggest the fallacy of this interpretation. If it were cor- rect, we must conclude that Pewmyscus in Maine lack this strange object response but those in New York have it highly developed (see Fig. 14). There exists no logical basis for believing that such a difference character- izes the populations of these two areas. Furthermore, in the trapping of both Pewmyscus and Clethrionomys it is not an uncommon experience to find either of these mice dead in a trap with a bloody stump of one hind leg, while another trap, 2-5 feet away, is covered with fresh blood and fur. The conclusion as to what happened is clear. The mouse happened to get caught in one trap by one leg, it chewed or pulled itseh loose, then went fairly directly to another trap, bit at the bait on the treadle and was thus killed. If these mice have a strange-object reaction it must be of a suffi- ciently low order of magnitude that even the recent loss of a leg in one trap fails to increase it to the point of avoiding the next trap encountered. In the third area. Alberta, from which adequate data are available for these two genera, both are relatively abundant but Pewmyscus exceeds Clethrionomys (Table VII). Dming the fall season, nearly twice as many of each genus are trapped as during the spring. During the period of low spring densities, these genera exhibit nearly identical rates of decline (Fig. 15 A) accompanying removal trapping. As with the Maine data, such trends may be interpreted as indicating that at such densities neither species is capable of markedly inhibiting the home range of the other. However, by fall many Clethrionomys have contracted their home ranges as a response to their exposure not only to more of their own kind but also to more Peromyscus. Home ranges of Peromyscus remained unaltered, as indicated by the similarity of rate of decline during both spring and fall (Fig. 15). However, the daily catch for Clethrionomys remained nearly identical through three successive days of removal trapping. Sufficient en- largement of home ranges by surviving Clethrionomys must have taken place each day to lead to an equivalent frequency of traps being encountered on the following day bj^ red-backed mice, despite their fewer numbers 1. The Social Use of Space 55 than on the preceding day. At this Alberta site, the inhibition of Clethri- onomys home ranges by Peromyscus must have been less than the inhibition of home ranges of Peromyscus by Clethrionomys in the Adirondacks. Despite the paucity of areas from which extensive comparable data are available, it looks as though Clethrionomys has a slight advantage over Peromyscus in gaining psychological ascendency. At this point one may suspect that the characteristics of some environments will markedly favor the reproduction and survival of one of these genera. Whichever genus this happens to be will then become psychologically dominant to the other, as evinced by the contraction of home range of the less numerous genus. Consideration of other aspects of the relationship between these two genera requires familiarity with the concept of the constellation dealt with in the following sections. B. Removal Captures of Socially Dominant Species In several studies already presented (Figs. 9-13) we have seen that one species tends to be caught in large numbers during the first few days, and that the time of maximum input for the remaining species comes during a successively later period. Very frequently a secondary increase in daily catch starts near the 1 oth day of trapping for the species with initially the greatest rate of capture. Such species will henceforth be designated as the socially dominant or alpha species of the small mammal community. For example, see Cleihrionoviys in Fig. 9 and Perotnyscus in Fig. 10. Where there are several species taken, usually only one is characterized by this secondary input. Four censuses examined included one such species and a fifth included two with definite secondary inputs.^ Although several species are involved in this phenomenon, the assump- tion is here made that they all so behave because of similar properties leading to their alpha rank in the community. If this is so, we are justified in pooling the data. A table of the total catch per day of trapping was ^ The five censuses utilized in preparing Fig. 24: 1. By Dr. J. E. Moore, Sept. 1959, Edmonton, Alberta: 128 Peromyscus maniculatus borealis, 65% of 30-day total by day 14-15. 2. By Dr. A. I. Roest, Oct.-Nov. 1959, San Luis Obispo, California: 75 Dipodomys heermanni, 65% of 30-day total b}^ day 15-16. 3. By Dr. William L. Webb, Fall 1952, Rich Lake Island, Newcomb, New York: 97 Clethrionomys g. gapperi, 65% of 30-day total by day 7. 4. By Dr. Earl F. Patric, Fall 1953, Arbutus Area, Newcomb, New York: 86 Clethrionomys g. gapperi, 65% of 30-day total by day 12-13. 5. By Dr. Kyle R. Barbehenn, Nov.-Dec. 1959, Chadwick Woods, Montgomery County, Maryland: 57 Peromyscus leucopus, 65% of 30-day total by day 14; 116 Blarina brevicauda, 65% of 30-day total by day 20-21. 56 John B. Calhoun prepared. These data are shown as a three-point moving average in Fig. 24. There results a continuous decHne in catch until about the 12th day. After this, the daily rate of capture increases, reaching a second maxi- mum five to seven days later. Following this, the number of animals taken continuously declines, but it is not until about the 27th day of removal trapping that the numbers taken per day reaches the low level character- izing the 12th day. 1 1 MAINLY aa/3 1 1 1 MAINLY Y 60 1 INDIVIDUALS INDIVIDUALS g 50 q: UJ a. \ X o S 40 o - 1 • _ o \ • o 30 IT tu - \» - 1- §20 lO - \ * ^ • • 7 • *N,^ - 10 \^ •X. *v 0 1 1 1 1 1 0 5 10 15 20 25 30 DAY OF TRAPPING Fig. 24. Removal captures of 559 small mammals who are representatives of species, socially domiuant in their community. Alpha and beta represent the intraspecific domi- nant individuals with large home ranges. The gamma individuals represent the intra- specific subordinates which enlarge their home ranges following removal of the alphas and betas. If the assumption that practically all the resident population exposed to the traps is removed diu-ing 30 days of trapping is correct, then the accu- mulated catch plotted as the proportion of the 30-day total over time will reveal both the proportion of the total comprising the initial input and the time at which the secondary input begins (Fig. 25). This shows that the intersection of the two rates of input occurs on day 15 after removal of 64% of the resident population. 1. The Social Use of Space C. Constellation Formation — An Intraspecific Phenomenon 57 After the removal of 64% of the resident population of socially dominant species, whose home ranges are sufficiently large to give them a higher probability of encountering traps, there arises a secondary input. These latter individuals must have enlarged their home ranges as a response to the absence of their former associates. It follows that certain individuals _I i 1 ' ' .V"*'^ < 0.9 1 — j§ — 1- J* o yi > ym g 0.8 - V» 6 ^Z ro / ¥ 0.7 - / 1- J Ll. ^ ' o p^ Z 0.6 — ^y^ _ o jm^ 1- y^ (£ 0 O / S 0.5 _ /• - tr u Q. / < i v) 0.4 — 1 — < L X 1 o < 0.3 1 _ L _ o 1 o lU So. 1 -A - 13 / 2 A Z> ^ o 1 o 0.1 t— < n 1 1 I 1 15 DAY 20 Fig. 25. Removal capture.s of socially dominant species. Same data as in Fig. 24, but here shown as an accumulated total. have the ability to restrict the home ranges of other members of their own species. At this point in my analysis I began to wonder whether there were circumstances relating to the spatial distribution of the population which might lead to a 64:36 ratio of larger : smaller home ranges. In the previous discussion we have seen that one possible spatial equilib- rium is that in which home range centers become uniformly distributed with an inter-home range center interval of about 2.0 sigma. It was further pointed out that the mechanics of moving through space are such as to favor the evolution of a signal emitted by one individual which has the 58 John B. Calhoun potentiality of eliciting a response by another up to a maximal distance of about 3 sigma between individuals. We may then ask, "How many other individuals in such a uniformly distributed population can any one in- dividual know?" Figure 26 shows that a line connecting the home range center of any one individual's six nearest neighbors forms a hexagon. With the hypothesized communication system operating, this one individual can remain in constant communication contact with all its six nearest neighbors except under the condition when it and one of them happen to Fig. 26. Spatial distribution of home range centers during the preconstellation phase. Small open circles represent centers for individuals destined to become alpha members. Dots represent home range centers for all other individuals. Home range centers are uniformlj' distributed. move in opposite directions away from the line connecting their respective home range centers. Such actions can increase the distance between them to greater than 3 sigma. Lines connecting the home range centers of this individual's next-nearest neighbors also form a hexagon. Home range centers for all these twelve next-nearest neighbors lie nearly 4.0 sigma from the selected individual. Therefore, each of these next-nearest neighbors can be in contact with the selected individual when they approach each other, such that the distance intervening between them becomes less than 3.0 sigma. Any more-distant neighbors, those living G.O or more sigma from the selected one, will have 1. The Social Use of Space 59 such a low frequency of communication with the selected individual that mutual effects will be of little significance. Examination of the spatial distribution of home range centers in a uni- formly distributed population reveals that one-twelfth of the members each have six nearest neighbors whom they can influence without competi- tive influence being exerted by any other individuals in this one-twelfth population. Such individuals will hereafter be designated as alpha indi- viduals. Home range centers for these alpha individuals are designated by small open circles in Fig. 26. It will further be noted that two such alpha individuals, who live closest to each other, share next-nearest neighbors. Antagonistic relations, uniform utilization of the environment, and attainment of uniform sign and signal fields approximating in intensity the sign and signal intensity expressed by an individual at its own home range center, and eciualization of contact rate with all neighbors throughout any one individual range, all serve as forces leading to a uniform distribu- tion of home range centers at near 2.0 sigma between centers (Section VII, K) . Yet, we may anticipate an opposing force of attraction between members in close communication with each other. This will lead to all nearest neighbors shifting the centers of their home ranges slightly toward their single alpha associate. Such nearest neighbors will hereafter be designated as beta individuals. Now we can turn our attention to the alpha's next-nearest neighbors. It may be seen from Fig. 26 that in each group of twelve next-nearest neighbors, six are eciuidistant to two neighboring alphas. Therefore, since the probability of each of these six nearest neighbors is 0.5 of being at- tracted to either of two alpha individuals to which they are eciuidistant, each alpha on the average will have attracted to it three of these next- nearest neighbors. The remaining six next-nearest neighbors to any alpha are ecjuidistant to three alphas. It similarly follows that on the average any one alpha will have attracted to it two of six such next-nearest neigh- bors. Next-nearest neighbors w^hich so move toward an alpha associate will hereafter be designated as gamma individuals. Thus, each alpha will have attracted toward it six beta individuals and on the average five gamma individuals. This process leads to a clumping of the population into groups ranging in size from 7 to 19, with a mean of 12 (see Section VIII. D). The central alpha indi\'idual because of its more favored position in the communication network may be assumed to be dominant to both its beta and gamma associates. Gamma individuals, because of their peripheral location in the developing clump, here designated a constellation, will be subordinate to both the beta and alpha associates. Now let us consider the 60 John B. Calhoun situation where home ranges contract as individuals become more subordinate. How much beta and gamma members may be expected to contract their home ranges requires consideration of phenomena treated in Section XIV, E, titled "Velocity and Home Range." There, it is shown that in terms of o-„ units of distance, the home range sigmas for alpha, beta, and gamma individuals become, respectively, 1.0, 0.9575, and 0.6457. Since an optimum uniform utilization of the environment requires a 2a interval between home range centers, the distance between alpha and beta home range centers wall become 1.9575o-a, and 1.6032o-a between beta and gamma home range centers. The periphery of each constellation (Fig. 27) may be arbitrarily desig- nated as that radius from the center of the alpha member's home range extending to one aa beyond the center of each gamma individual's home range. This radius is 3.1478a-a. And since the home range centers of the alpha members of adjoining constellations are 6.92o-a apart, it is obvious that between constellations there lies what may be called an interconstella- tion matrix, receiving very little usage from the dominant species forming constellations. Furthermore, this interconstellation matrix must markedly reduce communication between members of adjoining constellations. How extensive this reduction becomes must be viewed against the requirement of a 2a inter-HRC interval for an optimum state. Yet, the HRC of any beta or gamma member of one constellation will lie on the average 4a units of distance away from the nearest beta or gamma members of an adjoining constellation with reference to their own reduced home ranges. On the average, such constellations will consist of twelve individuals, 1 alpha, 6 betas, and 5 gammas. Of these, the gammas with smallest home ranges form 0.417 of the population. These are the individuals who, after removal of their dominant alpha and beta associates, will enlarge their home ranges. Actually, some gammas will be trapped before the 15th day and some alphas and betas will be taken after it. Furthermore, Fig. 25 clearly shows that a few more gammas would have been taken after the 30th day of trapping. Therefore, the observed proportion of the population consisting of gamma individuals, estimated at about 36%, reasonably well approximates the theoretical expected of 41.7%- To date, this approximation stands as the only direct supporting proof (see Section XI) that populations of dominant species of small mammal communities do, in fact, tend to form such constellations. If they really do, we may anticipate that there has been evolution relative to physiology such that its optimum state is most compatible with interactions among individuals transpiring in groups with a mean size of twelve adults. In 7. The Social Use of Space 61 later sections, I shall present data which support the hypothesis that a group size of twelve has been phylogenetically retained in more highly evolved forms. For the present, let us examine fm'ther implications of constellation formation upon the structure of the small mammal community. Con- FiG. 27. The theoretical constellation phase of intraspecific community organization of dominant species. A 3-sigma radius home range for alpha individuals is z-epresented by the large circle. Small circles represent 1-sigma radius portions of all members of a constellation. Contraction of home range by beta and alpha members permits the more intensively used portion of the home ranges of all individuals to fall mostly within the 3-sigma radius home range of the dominant alpha members. Crosshatched circles represent the 1-sigma portion of the home range of alpha individuals. 62 John B. Calhoun stellatioii formation presupposes passing through a stage of uniform dis- tribution of home ranges. In the interstices between the home ranges of alpha species there is the opportunity for very subordinate species with highly contracted home ranges to establish themselves. As the constellation forms, certain members of the subordinate species will be retained within the interstices of the constellation while others will lie at its periphery. However, as constellations form, there develops an interconstellation matrix rarely frequented by members of the alpha species. We may then wonder what members of the community will live here. At this point, the Huntington Forest censuses of 1952 and 1953 (Fig. 11) are particularly instructive. The red-backed mouse, Clethrionomys, is ob- viously the alpha species. Just as obviously, the shrew Sorex is the most subordinate species, which has highly contracted home ranges lying in the interstices between those of Clethrionomys. Had all these census been run for longer than 30 days, it looks as though the 2 : 1 ratio of the alpha species to one of its most subordinate associates would have been realized. Censuses shown from other areas indicate that both Peromyscus and Blarina are dominant to Sorex in the community. And yet, in these Huntington Forest censuses, relatively few of either were caught. What I suspect has happened is that as the constellations developed, both species were relegated to the interconstellation matrix, where they existed in somewhat contracted home ranges, as indicated by the catch per day increasing from day 1 to days 4-6. In fact, for both these species it looks as though a certain portion of their members had even more markedly contracted home ranges. This is indicated by the secondary increase in catch per day starting betw^een days 8 and 10. D. Expected Variability in the Number of Individuals Forming Constellations In terms of the formulation of Section VIII, C the six nearest neighbors to any alpha individual will always be attracted toward it as the members of a population wuth a uniform distribution of home range centers begin to form diffuse clumps, termed constellations. The twelve next-nearest neighbors to any alpha individuals may be divided into two types, a and h, according to their probability of being attracted toward any given alpha neighbor. Let: a represent the six individuals who have a probability, pa = 2, of being attracted to any given alpha. h represent the six individuals who have a probability, 'Pb = k, of being attracted to any given alpha. 1. The Social Use of Space 63 The probability, Pa{i), that i number of the six a individuals will be at- tracted to the given alpha will be : Pa(i) (A /I (28) Similarly the probability, pb(i), that i number of the six b individuals will be attracted to the given alpha wdll be: Pb(i) = il \3/ \3 ' /9\^— * (29) Therefore, the probability, p{m), where m = 0 to 12, of m members of the 12 next-nearest neighbors joining any given alpha and its six nearest neighbors to form a constellation will be: p{m) = ^ Paii) ' Pbim - i) (30) For example, if m = 4 this becomes: P(4) = PaiO) ' Pbi^) + Pail) ' Pt(:i) + Pa{'2) ' p,{2) + p„(3) • P5(l) +p„(4) . PbiQ) (31) p(S)) • • • p{12) were calculated and are shown in Table VIII as p{7 + 0) Table VIII Expected ^'ARIABILITy ix the Number of Individuals Formixg a Constellation Xumbor of animals in group Prol:)abilit3' of group developing 9 10 11 12 13 14 15 16 17 18 19 0.00137200 0.01234568 0.05041152 0.12345679 0.20190329 0.23225308 0.19266546 0.11612654 0.05047582 0.01543210 0.00315072 0.00038580 0.00002143 Z 1.00000023 64 John B. Calhoun • • • p (7 + 12) since the constellation becomes composed of the addition of these next-nearest neighbors, or gamma individuals to the basic core of the one alpha and its six beta nearest neighbors. E. Social Rank and Intraspecific Associations In the 14-day removal study shown in Fig. 13B, trapping results indi- cated large home ranges for Peromyscus, moderate-sized ones for Blarina, and highly contracted home ranges for Pitymys. Estimated home range sigmas, o-, of 50, 25, and 12.5 feet, respectively, probably closely enough approximate the real values to permit their use in a study of these data. If we knew the actual home range centers of all animals trapped, a 1-sigma radius circle plotted about each on a map of the study area should pro\'ide more insight into spatial relationships. Since such centers were not known, they were approximated by making the following assumptions: 1. Peromyscus maximize inter-home-range-center distance from other Peromyscus. 2. Blarina similarly maximize distance, not only from others of theu' own kind, but also from Peromyscus. 3. Pitymys maximize distance from both Peromyscus and Blarina, as well as from others of their own kind. 4. The later an animal was trapped the farther its home range centers were located from the trapline. For Peromyscus some of the HRC's were shifted to one side of the line of capture, and the remaining to the other side, until ever}'' adjacent 3 HRC's approximated equilateral triangles. A similar procedure was ap- plied to Blarina captures except that where possible their HRC's also were placed in the center of triangles formed by the HRC's for Peromyscus. Then the HRC's for Pitymys w^ere, insofar as possible, placed in the centers of triangles connecting the HRC's of the other two species. Utilizing these assumptions, centers of home ranges for Peromyscus were plotted first, Blarina second, and Pitymys last. Originally these were all plotted on a single figure, but for the sake of greater clarity in examining intraspecific relations the home ranges, in terms of 1-sigma circles, are shown separately in Figs. 28-30. Moisture conditions in the habitat varied markedly. Steep xerophytic slopes of oak and pine covered the three sectors encompassed between the E and SW radii. The sector between the N and NW radii was quite steep and dry. A damp drainage area lay roughly along the W and NE radii. L The Social Use of Space 65 Fig. 28. Schematic home ranges for Peromyscus. The octagons represent traplines along which removal trapping was conducted. . Vng/j Aa '''"' o° ^ ° ° ° ° °o , o „ - CO I 1 I I I I I I I 1 1 I I I I I 1 1 1 5 10 15 20 NUMBER OF ADULTS IN GROUP (HOWLER MONKEYS) Fig. 32. Group dynamics of howler monkeys based upon Carpenter (1962) . Another way of looking at this problem is to ask: "What proportion of the total young are contributed by each group size?" For any group size the proportion will depend upon (a) the proportion of females in the group (Curve D, Fig. 32), (b) the number of young per female (Curve C, Fig. 32), and (c) the number of groups of each size (Curve A, Fig. 32); where such data for each group are weighed against similar data for all other group sizes. Resultant data are given in Curve B, Fig. 32. This curve clearly shows that more individuals gain their initial social experience 92 John B. Calhoun in groups of about the size anticipated by theory as most nearly optimum than they do in any smaller or larger sized groups. In fact, the mean number of adults with which the 838 young in these 136 groups had their early social experience was 12.22!, even though Curve C, Fig. 32, is flatter than predicted by the theory of Section VIII, D and Table VIII. My selection of the Norway rat and the howler monkey as examples of compact colony types is open to the criticism that I selected those species which would support my theory that group size in higher evolved types is dependent upon their evolution from species which had been characterized by the loose constellation form of social use of space. At present, this criticism cannot be avoided. I wish merely to say that my intensive study of a few groups of Norway rats, and the extensive study by Carpenter and his colleagues of a large number of howler monkey groups, are the only ones known to me that appear adeciuate for the present purpose. All we can really say at present is that available data show that optimum group size in some compact colony living species appears to approximate 12 adults and that this number is in harmony with that number antici- pated by the physics of communication characterizing more primitive and more dispersed types. C. Behavioral Sink Development by the Norway Rat IVIuch of the prior sections have been devoted to documenting theory and e\ddence supporting the hypothesis that groups of 12 individuals represent a major category of optimum density. Yet many species cus- tomarily live as aggregates much larger than this. Why such large groupings should have evolved remained a puzzle until insight developed from an unexpected phenomenon arising in the situational content of some experi- mental populations of rats I was studying (Calhoun, 1962a). The upper portion of Fig. 33 presents in diagrammatic fashion the salient aspects of the environment affecting the rats. Four 35 square-foot pens, separated by 2-foot high partitions, formed a linear communication net- work through the opportunity of access between adjoining pens via the V-shaped ramps, R, surmounting barriers between pens. F and W represent a superabundant supply of food and water in each pen. "Apartment" houses, H, connected to the floor by ramps provided ample place of retreat and rearing young by most residents. The //'s of the left-hand pens I and 11 were 3 feet from the floor, while in pens III and IV a 6-foot distance separated the i/'s from the floor. Height formed an intentional environ- mental factor designed to produce a 2:2:1:1 ratio of density across pens 1:II:III:IV as a consequence of the inverse-proportionality-to-effort usage principle. 1. The Social Use of Space 93 In addition the endedness of the environment biased movement. After some period of time every rat tended to leave the pen it was then in and go into an adjoining pen. Rats in an end pen could only go to the adjoining center pen, while a rat in one of the two center pens could go to the other center pen or to the adjoining end pen. In other words, when a rat is in an end pen it has a probability of 1.0 of going into the adjacent center pen, but if it is in a center pen it has a probability of 0.5 of going into the adja- cent end pen or 0.5 of going into the other center pen. Repetition of shifting by all members by the operation of this principle alone soon leads to a PEN I PENH PEN m PEN IS F W H 3 Ft. ==3 RC^ F W H 3 Ft. H 6 Ft H 6 Ft z> 0.5 PEN lor HI I *********** ******* *' ASONDJFMAMJJ 1958 MONTH 1959 Fig. 33. The upper portion of the figure represents in schematic fashion the environ- ment in which large social groups of albino rats were maintained. See text for details. The lower figure contrasts the amount of food consumed in the most used and the least used pen from the inception of the behavioral sink during the sixth month (August, 1958) of the study. steady state in which a 1:2:2:1 ratio will characterize the density of rats across pens I: II: III: IV. See pages 298-299 of Calhoun (1962a) for details of the mathematics involved in the origin of this ratio. Populations in four such 4-pen environments were studied from Febru- ary 1958 to July 1959. By the eighth month, September 1958, each popu- lation consisted of three generations, each artificially fixed at near 30 in- dividuals. The first and second generations were sexually adult, and the thu-d was recently weaned. Distribution of adults at this time proved to be of considerable importance in producing a phenomenon I have termed a "behavioral sink." Five surveys of place of residence gave a total count by pen of 343 for pen I, 467 for pen II, 331 for pen III, and 245 for pen IV. 94 John B. Calhoun If the two movement biasing principles described above operated inde- pendently and equally, the expected ratio of density would be 3:4:3:2 across pens I: II: III: IV, thus giving an expected distribution for the September 1958 observation of 347:462:347:232. The observed and ex- pected values are so nearly the same as to support strongly the belief that these two movement biasing principles were in fact the only effective ones operating at this time. These same factors also affected the third generation then maturing. Taking mortality into consideration, each population consisted of about 80 rats with on the average 20 living in pen I, 27 in pen II, 20 in pen III, and 13 in pen IV. Only in pen IV did the density approximate the ideal of 12. Elsewhere, particularly in pen II, density far exceeded this. From this time on a remarkable change in the differential use of space, particularly as reflected by food consumption, set in. In one pen (in three instances it was in pen II and in the fourth in pen III) food consumption increased at the expense of that in the other three pens. See the lower half of Fig. 33. By the time seven months had elapsed, most rats were eating all their food in this "favored" location and all rats were doing most of their eating there. The explanation for this change appears rather simple. Gnawing food through the wire mesh of the food hoppers required considerable time. In the one pen w^here more rats fed than in the other pens, the probability of two rats eating side by side increased. Gradually rats redefined the eating situation as requiring presence of other rats. Thus, all rats shifted most of their eating to that pen where this condition was most likely to be met. It must be kept in mind that such a system is stochastic and not deterministic, so it was not unexpected that pen III became the favored place of eating by one of the four groups. However, the likelihood of pen IV ever becoming the favored pen is extremely remote. The learned need for social proximity while engaging in an act which might have been expressed alone assumed priority over the simple original hunger drive. Food was not food without the presence of a comrade. This whole process of developing excessive aggregations in order to satisfy a secondarily acquired social drive is what I mean by a "behavioral sink." Gradually more rats also shifted residence to this favored place of eating. Such behavioral sinks result in every member encountering more associates than the ideal, and even more than necessitated by the operation of those principles of spatially structuring the environment which biases movement. In this situation marked alterations in mortality and behavior resulted. Males became pansexual in the sense that they mounted other rats ir- respective of sex or age. Nest building and maternal behavior became so disrupted in most females as to preclude the possibility of most young 1. The Social Use of Space 95 surviving. In each experimental setting the rats experienced less disturb- ance in one pen, usually pen IV, than elsewhere, since they were somewhat less trapped in the behavioral sink. And yet even here only half the young born survived to weaning and their growth was markedly retarded. In contrast, in the pen where most rats assembled only half as many young were born and only 1% of these survived to weaning. In addition, the abnormal frequency of social interaction resulted in marked disturbance to female reproductive physiology. Near-term fetuses died. Some females with such dead fetuses shortly succumbed from ap- parent toxemia. Others died from massive hemorrhaging in many organs, an accentuation of the event likely to have been associated with fetal death. Many females who survived such events later died as a conseciuence of a site of resorption of a near-term fetus becoming the focal point for the development of a large abscess. Normally death occurred by the time the abscess reached a diameter of 50 mm. As an example of this scourge, 56% of second-generation females died by a year of age, by which time only 10% of males had died. Were a species to survive for many generations in an environment fostering development of a behavioral sink, it is obvious that selection must proceed to produce individuals whose behavior and physiology were in harmony with such a heightened frequency of social interaction. Wher- ever an environmental resource which was formerly so widely distributed as to be readily available within each individual's or group's home range becomes restricted, then conditions are ripe for production of a behavioral sink. It is my belief that just such happenings have been the usual altera- tions which have forced the evolution of horde or herd type species from one previously characterized by an optimum group size of 12 adults. D. Yarding by Deer in Northern Wisconsin Characteristically since 1935 white-tailed deer (Dahlberg and Guettinger, 1956) in Northern Wisconsin assemble during the winter in a restricted area known as yards. These cover only 5-10% of their range. Conifers, which comprise the major cover in the yard, provide protection from deep snows. However, such cover provides only a secondary quality food. One or more feeding stations were established in most yards. During the 1930's food supplements represented a small amount of total food requirements. By 1953, when artificial feeding was largely terminated, most of the food reciuirements were supplied at these feeding stations in many yards. Nevertheless, many deer died of "starvation" even in yards where the most food was provided. 96 John B. Calhoun The restricted locations where food was provided and the striking ag- gregations of deer in their vicinity reaching 350 per square mile strikingly resemble my experimental populations of rats from which developed the concept of the behavioral sink. Even though many deer died in the yards, the question stands: "Is this really an instance of a behavioral sink?" Gaining insight into this question has proved to be a difficult detective job. Shiras (1921), Sanders (1939), Swift (1948), Rabat et al. (1953), Schorger (1953), and Dahlberg and Guettinger (1956) proved to be particularly helpful. Before the days of lumbering, deer were so scarce in the primeval forests of Northern Wisconsin as to contribute very little to the diet of Indians. Between 1860 and 1880 a marked increase in deer followed lumbering operations with the consequent development of openings and second growth which provided abundant food. Although the deer did not reach the den- sities of 1935 to 1953, they supported a major industry as a commercial source of meat. There is some mention during this era of herds up to 200 being seen, of aggregations about salt licks, and about concentrations in white cedar swamps during heavy snows. However, one gets the impression from Schorger's citations that it was more customary for deer to be scat- tered. After heavy snows the commercial hunters trailed the deer until they found them exhausted and trapped by the deep snow. Schorger (1953, p. 210) writes, "It is stated by Harvey Braein that about Christmas, 1857, a crust about one-half inch in thickness formed on the deep snow in Buffalo County, and that nearly every deer perished. Following the spring, their bodies were found in nearly every coulee." Unfortunately, this is the sort of data one has to rely on. Even so, it suggests a typical pattern of scattering. As early as 1920 when the Northern Wisconsin deer herd was well on its way to recovery after its prior decimation by forest fire and unrestricted hunting, private hunting clubs and the operators of tourist camps had be- gun the practice of feeding deer during the winter months. After 1935 Civilian Conservation Corps camps and the Wisconsin Conservation De- partment greatly increased this artificial feeding. However, the intensive artificial feeding characterizes only the 1943-1953 period. Swift (1948) states that yarding had not conmienced very extensively until after 1941 even though astonishingly high populations existed in many locations. It is difficult to escape the conclusion that the accentuation of yarding was a direct outgrowth of the artificial feeding. Daily movements rarely exceeded one-quarter mile from the feeding stations. Thus, available food outside the yards remained unutilized. Even with the advent of warm weather deer exhibited considerable reluctance in leaving the yard despite increasing new growth outside it. Even cessa- 1 . The Social Use of Space 97 tion of artificial feeding has not disrupted the marked yarding tendencies of Wisconsin deer. Through many generations they have developed a culture demanding an excessive frequency of contact with others during the winter season when they would otherwise be more scattered. I will freely grant that this interpretation of the origin of yarding may be oversimplified. Nevertheless, available observations warrant considera- tion of the concept of the behavioral sink as helping us understand the historical development of yarding to an excessive degree. E. Concerning Basic Numbers, Nb, for Man During the past half million years, density of Homo sapiens has exhibited a continued increase over the inhabited portions of the earth (Deevy, 1960; von Foerster et al, 1960) . Most who have concerned themselves with studying such change restrict their emphasis to changes in density accom- panying advance in extractive efficiency of natural resources. Less atten- tion, even by anthropologists, has been devoted to determining sizes of social groupings forming partially closed systems. Such partially closed systems range from a male-female pair to that of a nation such as the United States among which interactions among all members may be con- ceived of in terms of population potential (Stewart, 1948; Calhoun, 1957). It will not be my purpose here to treat the entire range. Rather, I shall merely present a few highly selected examples of some of the smaller groupings which presumably reflect evolutionary limitations to group structure. On the assumption that these group sizes represent the conse- quences of underlying basic forces, they will be used in later sections (XIII, A and B) as data for developing a general formulation of group size and social interaction. For about 98% of his history during the past half-million years, simple food gathering limited man's economy and social life. One of the earliest known settlements at the Star Carr site in east-central England of nearly 10,000 years ago consisted of five families, ten adults (Braid wood and Reed, 1957) . Thus, it appears that an adult group size not diverging greatly from my hypothesized ideal of 12 may have characterized the human species up until at least 10,000 years ago. The Australian aborigines (Birdsell, 1953, 1957) provide further insight into the basic numbers of human groups. In terms of the typical number of adults, five levels are recognizable: (a) the family with 2 adults; (b) the "horde" or extended family with 16 adults; (c) the supra-horde of 50 adults; (d) the tribe with 200 adults; and (e) the supra-tribe with 2200 adults. The horde forms the most basic social group, ranging generally 98 John B. Calhoun between 10 and 20 adults. When the group exceeds 20 adults a budding process occurs, 10 adults forming a minimal-sized horde. These approxima- tions of BirdseU's again suggest a basic group size not diverging greatly from the 12 presumably fixed by much earlier evolution. Occasionally, the horde may fragment temporarily into single family groups when scarcity of food demands such dispersal. Also, occasionally an average of five hordes, 50 adults, may temporarily assemble into a supra-horde. However, this grouping appears to be a less basic one than the other four. The third grouping, the tribe, lacks any form of authority, and only on rare occasions do the 12 or so hordes forming the typical tribe assemble. However, common bonds of culture, their cus- toms and value systems, clearly delineate the tribe as a social entity. Furthermore, marriages are primarily restricted to those between in- dividuals of different hordes within the same tribe. Only in one local region of Australia has a higher-order grouping evolved. Three supra-tribes, averaging 2200 adults, represent an assembly of tribes bound together by a more advanced type of political organization characterized by matrilineal descent. These data suggest that cultural evolution has proceeded by saltatorial steps, each characterized by some accretion to the culture. It wnll be my hypothesis, to be developed in more detail in Sections XHI, B, 2 and B, 3, that the sole function of culture is to provide a mold which enables inter- actions to transpire in a larger group such that their physiological conse- quences to the average individual closely approximate those that would result were the individuals still living in a closed social group of about 12 individuals. Hallowell (1960, pp. 345-846) states that "... a normative orientation becomes an inherent aspect of the functioning of all socio-cultural systems, since traditionally recognized standards and values are characteristic of them. Techniques are appraised as good or bad; .... Knowledge and beliefs are judged true or false. Art forms and linguistic expression are evaluated in relation to ethical values. All cultures are infused with ap- praisals that involve cognitive, appreciative, and moral \'alues," and "if the total ramifications of the normative orientation of human societies are taken into account, we have a major clue to the kind of psychological transformation that must have occurred in hominoid evolution w^hich made this level of adaptation possible and some measure of its depth and significance for an understanding of the dynamics of human social systems of social action." Culture so conceived as normative orientation in which individuals play sanctioned roles provides the structure which allows in- dividuals to reap the maximum rewards (the theta, 9, of Section XHI, A) from participation in the social system. 1. The Social Use of Space 99 If culture really does permit individuals to function in the context of a larger social group as if they were still only in the basic A^'t = 12 group com- patible with their physiology, then any disruption in the culture should reduce the group size since its unstable state would then no longer buffer the individuals from the excessive contacts with their associates. I am as- suming that, depending upon the extent of the cultural disturbance, physiological disturbances comparable to those of my rats caught in the behavioral sink (Section XII, C) would arise. In fact, Birdsell (1953) demonstrates that such a phenomenon has characterized Australian aborigines in recent times. Tribes which have recently adopted the rites of circumcision or subincision generally have a size less than one-third that of tribes which have either not been exposed to these practices or adopted them long ago. Furthermore, the historical records indicate that tribes once reduced in numbers after they first adopted these rites now after several generations have recovered their typical numbers. These data on the Australian aborigines further suggest that an in- dividual can shift his participation from one level of social organization to another, provided there are cultural means for channeling such participa- tion. Duff and Kew (1957) provide an account of the recently extinct Kunghit Haida Indians of British Columbia, which enables similar in- sights into basic group sizes in a food-gathering people. Their winter village consisted of 16 to 20 large houses (1600 sq. ft. of floor space each). From various of the accounts it appears that the tribe totaled about 500 individuals, of which slightly over 200 were adults. This means about 10-12 adults on the average per house. Each house was in- habited by a kinship group or lineage. During the warmer months of the year each lineage group left the winter village for its own hunting territory. Like the Australian aborigines, these British Columbia Indians also appear to have a basic group size not diverging far from 12 and an assembly of these into a tribe of around 200 adults. Incipient agriculture, in which plow and draft animals are absent, repre- sents an even more ad\'anced efficiency of food extraction, characterized by a permanent village. The Jarmo site in Iraq, inhabited some 6700 years ago, presumably represents a typical village at this level (Braid wood and Reed, 1957). Braidwood and Reed estimate that 150 persons (50 adults) inhabited the 25 houses located there. This type of village structure ex- tends into the present. The mean size of 185 villages in this part of Iracj is 140, which presumably represents 46-56 adults. From the scanty examination of lower-order basic group sizes in man we shall skip to the urban society of a modern nation, the United States. The social organization represented by Australian aborigines and the 100 John B. Calhoun Kunghit Haida suggests that each larger semiclosed social system includes within it all the culturally limited basic group numbers. But even if some are skipped or unrecognizable, the one group structure which must be preserved is that of 12 adults. Recent studies by Zimmerman and Broderick (1954) and Zimmerman and Cervantes (1960) confirm this suspicion. Their approach has been to focus on any given family, designated the ego family, and then to determine with how many other families its members have frequent and close associations. These latter are designated as friend families. Absence of divorce or desertion, juvenile arrest, or children not completing high school comprised criteria for judging a family as "good" or "successful." Presence of these traits were used to delimit the "bad" or "unsuccessful" families. Values held by a family were judged on the basis of their religion, region of origin, income level, and kinship bonds. The good ego families typically have five friend families with whom they have a high coincidence of values, and furthermore, if the ego family is char- acterized as good most of the friend families are likely also to be so char- acterized. On the other hand, bad ego families generally have fewer friend families and they are likely to differ from them with respect to the value traits. The fewer the values shared by the several families forming such a cluster, the smaller the cluster will be and the greater the probability that each family will be characterized by one or more of the traits denoting it as an unsuccessful family. The ideal state then appears to be six families, 12 adults, composed of an ego family and five friend families. Shared values bind such a cluster despite the dispersal of the member families through the local community. Furthermore, each friend family in a particular cluster is, as an ego family, the center of another cluster. In this way an extension of the cluster de- velops to include 26 total families. Although similar bonds between families may include a larger network, insofar as any particular family is concerned the 25 friend families and extended friend families form the limit of de- pendence and social support relationships. This approximation of 50 adults of the family-friend cluster further argues for the reality of Nb = 50 as a basic grouping revealed also in Birdsell's supra-horde of Australian abo- rigines and of the incipient agricultural village of the Jarmo type. Reduction of the size of the family cluster below the optimum of six when values held by member families diverge from each other represents another example of the principle of group fragmentation, enunciated by Birdsell, which follows a clash in values. Zimmerman and Cervantes refer to this conflict as a "confusion of values." All the information in this section, when viewed as a whole and in the context of the earlier sections concerning the evolution of a basic group size, suggests the following tentative generalization: Modern man derived 1. The Social Use of Space 101 from his primate and preprimate ancestors a physiology transpiring in groups within the range of 10-20 adults. This physiology was fixed some half a million years ago and has not significantly diverged from it since. Development of a larger social group is made possible by a culture in which a normative orientation prescribes values, and sanctions roles of behavior such that the total effect of participation in a larger group so buffers the individual that at any particular time the individual functions socially as if he were a member of a group of 12 individuals. Furthermore, genetic changes of the central nervous system making learned value systems of cultures possible must have arisen under circumstances which prevented division of the basic group size when it reached twice this level. Either an ecological-psychological trap like the behavioral sink (Section XII, C) or any isolated but very abundant source of a needed resource would be ade- quate to demand either a genetic change of physiology making life in large groups tolerable, or a genetic change endowing the central nervous system with the capacity to learn and culturally transmit values. Each increase in group size is associated with a reorientation of the value system. Such in- creases in group size are saltatory. The theoretical basis of why such changes must be saltatory and not transitional is discussed in Section XIII, B, 3. XIII. A Formulation of Group Dynamics Twelve individuals represent the approximate optimum group size for certain species (Sections VIII, C and XII, E) . Furthermore, such a sized group might be expected to have evolved from home range dynamics. Evidence could readily be assembled that other basic A^'s, NbS, characterize other mammahan species. Some typically live as pairs while others assemble in herds exceeding 100 or 1000 individuals. However, circumstances may force N to diverge markedly from A^6. Elaboration here of the model of social interaction presented in pages 349-354 of Calhoun (1957) provides insight into the consequences of such divergence of A^ from Nb. A. The Model of Social Interaction On a presumptive basis there are three variables which should determine the mechanics of contact and interaction. These are (a) the number of animals moving about and having opportunity of contacting each other, (b) the length of the refractory period following the response of one animal upon contacting another until it is again capable of exhibiting a similar 102 John B. Calhoun response, and (c) the amount of space in which the movement of A'' in- dividuals takes place. Random distribution of positions of individuals at any moment in time is assumed. We choose to ignore a small correction factor arising from the fact that all individuals move. Velocities of all in- dividuals are initially assumed to be a constant. Furthermore, we assume that all individuals are identical. Thus our concern is not which individuals meet, but rather which state, responsive or refractory, the contacting in- dividuals happen to be in. N = Number of animals forming the group. d = The diameter of interaction for each animal, that is, that distance between the centers of two individuals at which a physical or psychological collision or contact occurs. In the simplest case animals may be considered equivalent to billiard balls. Then d represents the diameter of the ball, the individual. See Section XIII A, 1 for further elaborations. Assume an animal moving in some direction on the plane in a population, A^ — 1, of other animals. Each of these other individuals presents a target of dimension d, normal to the X direction. The expectation that the incoming animal will make a collision while moving a distance A.r (in time t) is the ratio, d(N - 1)A.T of surface covered by the targets to the total surface, where A is the area available to the animals. It should be emphasized that the unit of time must be sufficiently large so that the number of collisions in that time interval is large enough to justify using the statistical law of large numbers in the derivation. For similar reasons, it must be assumed that the mean free path of the in- dividuals must be large in comparison with the target diameter. Since the velocity v may be considered ec^ual to Ax/t, the average num- ber of contacts w,-, per individual in time /. is djN - l)vt Tie = (o2j A For present purposes we are concerned only with the average ric in t and not in the variability in contacts in t. The frequency of contacts by a given individual will be : ^. . - . rf(iV-i)_. (33) { A 1. The Social Use of Space 103 Since d, v, and A will be considered constants for this presentation, we set (dv/A) = n so that /. = m(A^ - 1) ('^^i fjL reflects the ease of communication in the sense of contacts per unit ot time. Basically, d, v and A may be specified in terms of linear unit, L. Therefore, dv L • Lt~^ 1 ..,_, " = 1^-6^ = 7 ''•^' The symbol ^ is here used in the sense of ''dimensionally equivalent to." So by selecting appropriate units of time, n can be made equal to 1.0. In following discussions n will be considered equal to 1.0 in this sense whenever the basic A^, Nb, of a species is in an evolutionarily steady state. We will assume that the population of individuals can be divided into two classes: [Na], those individuals who are in a responsive state, and [Np] those individuals who are in a refractory state. We further assume that the individuals in [Na] will be rendered refractory either after a contact with a member of the same class or with a member of [Np]. After any such contact, an individual will remain in the refractory state for a length of time, a, the refractory period, and after this time has elapsed return to membership in [N^]. It is also assumed that any contact that an individual undergoes while it is in the refractory state has no influence on the duration of its refractory period. The duration of such refractory periods must be a function of the be- havior of each member of the contacting pair toward the other. It is as- sumed that the critical aspect of this behavior is its intensity. At the steady state of an Nb we shall first consider every individual to be identical with reference to the intensity of its behavior toward others. Let: la be the intensity of action of any member of [A^„] toward every associ- ate it encounters. ip be the intensity of action of any member of [Np] toward every associ- ate it encounters. It is further assumed that the most likely way that the duration of the refractory period, a, becomes a function of the behavior of two individuals toward each other is that it results from the product of the intensities of their behaviors. Furthermore, there must be some factor, which will be called B, which governs whether a refractory period will result from the interaction. 104 John B. Calhoun Let: Ba = 1.0 be the value of this factor in all members of [Na]. Bp = 0 he the value of this factor in all members of l^Np]. aaa represent the refractory period resulting in each of two members of [_Na] who meet. a,rp represent the refractory period resulting in each member of [^Na'] which encounters a member of [A^p]. aj,a represent the refractory period resulting in each member of [iVp] which encounters a member of [_Na]. app represent the refractory period resulting in each of two members of [_Np^ which meet. It follows that: iaia = oiaaBa = idp = dapBa, aud all are real values (36) and that: ^p^a ^pa-*^p ^p^p ^pp^ p V7 \*J i ) In all following discussion Ba and Bp will be omitted in discussing a, but every mention of aaa and Uap will assume the action of Ba, and likewise any mention of apa and app will assume the action of Bp. It may be objected that no distinction is being made between the two kinds of contacts, responsive-responsive, and responsive-refractory. It is perfectly feasible to introduce two refractory periods, aaa and aap, of differ- ent duration to answer this objection. At the present juncture the experi- mental data are so scanty that it does not appear to be fruitful to introduce additional complexity, and we have chosen to consider ana = cinp for the workmg model insofar as duration is concerned. An alternative model would have been to choose aap = 0, that is, the only contact inducing a refractory period being a contact between two individuals both of whom are responsive. Under such an assumption the number of contacts between responsive individuals in a unit interval of time w^ould increase asymptotically to the value 1/a, whereas, as we shall show, the model adopted provides that the number of contacts between responsive individuals passes through a maximum as A^ increases. Given sufficient proximity of an individual in the responsive state to some other indi\'iduals requisite to the usual elicitation of an interaction or response to denote a contact, evidence from certain mammals suggests a mechanism capable of blocking a social response. Such a mechanism 1. The Social Use of Space 105 which defines the probability of a contact being socially "perceived'' shall be called n'. ria == number of contacts made while the given animal is in the "re- sponsive" state. fa = (ria/t) is the frequency of responsive contacts when the animal in question is in the "responsive" state over all time. Since each contact between two individuals, at least one of whom is in the responsive state, is followed by a refractory period a, characteristic of each of the responsive individuals, and since there are ?ia such contacts in time t, then the individual is in the refractory state for a total time ana. Clearly, the total time ta in which the individual is in a responsive state is t — an'Ua. Since na = tfa then ta = t - aix'Ua = t - afx'tfa = t{l - OCuJa) (38) In this sum of refractory intervals, ta, contacts will be made at frequency /c, but all such contacts are made while the animal is responsive so that Ua = fda = fct{l — CXIl'fa) = tfa or, since /a = ria/t fa = /.(I - V/a) (39) Thus 1 — anja It will also be helpful to rearrange Eq. (39) to obtain /„ as a function of /d /. = /„ + ccn'fafc =/«(!+ an%) So /« = , / ., (41) We may also define the frequency of refractory contacts by each in- dividual over all time fp =fc-fa (42) Contacts between individuals will be of three kinds: (a) both individuals responsive; (b) both refractory; and (c) one individual responsive and the other refractory. A given individual meets fc other individuals in unit 106 John B. Calhoun time. Of these J\ contacts, fa are with individuals in a responsive state. Hence, the probabiHty pa that any given encounter will be with a responsive individual will be Pa = (fa/f.) (43) Therefore, of all the encounters /„ in unit time which the given individual makes while it is responsive, the number faa = Pa fa (44) will be with other responsive animals. Thus, /„<, may be considered the (absolute) frecjuency of responsive-responsive encounters. Substituting (43) into (44) we obtain faa = y (45) Using Eq. (41) •^'"' ^ /.(I + an%r ^ (1 + «M7e)2 ^^^^ In like manner we can define fpp as the frequency of contacts of individuals both of whom are refractory and of fap for the freciuency of contacts in which one individual is responsive and the other refractory. By an argument analogous to that given above we arrive at the formulation fr>.='^ = ^^^^-^ (47) Je Je Using Eq. (41) J pp ~ ^' Vl + V/JJ/ -^ -^ \ l+V/e / (1 -^an%y Again: (48) /.. = -^ = ?^^^I^ (49) 1. The Social Use of Space And using Eq. (41) Jap 107 2/. 1 + an% 2 1 + an'fc (1 +a/z70- •/.(I + an% - 1) 1 + an'fc f50) We can obtain an explicit relation between /„p and N and /aa and N by- substituting Eq. (34) respectively into Eqs. (50) and (46) : And Jap J aa 2aix'tx-{N 1 [1 +aMM'(iV - \)J y.{N - 1) [1 +a,x,i'{N - \)J (51) (52) The function /«« = 0 when A^ = 1 and also faa approaches 0 as A" tends to infinity. Since faa is continuous and differentiable for all positive values of A", it has a maximum A'^, for some value of fan at which the derivative of faa w'ith respect to A" is zero dfa dNr = 0 = and Hence m[1 + ann.'{N - !)][! - ann'jN - 1)] [1 +«m/(A^- 1)? 1 - auitx'{N„. - 1) = 0 Nm- \ = 1 1 afiix or ocuii Nm - 1 (53) (54) (55) Thus, the larger a, the smaller Nm. In other words, the position of the maximum shifts to the left as a increases. In order to find the maximal value of faa, faV, we may substitute Eq. (55) into (52) obtaining /i:^ = 1/4V (56) In other words, the number of responsive-responsive contacts in unit time decreases as the refractory time increases. Since the refractory time. 108 John B. Calhoun a, is assumed to increase when the intensity of interaction, i-, increases, faa decreases as intensity of interaction increases. When the A^" of a species has attained an evolutionary steady state, designated as Nb, n and ix' will each have values of 1.0. When n = 1.0 it will be designated tib. Existence of an A''^ steady state does not mean that the temporal A^ camiot fluctuate within the lifetime of a species or the history of a population. Rather, it means there is a particular A^ compatible with ixb- At this Nb, with its /X6, all contacts are perceived. That is, n' = 1.0, and whenever /jl' = 1.0 it will be designated fxb- Not only will all contacts by responsive individuals be perceived, but each member of A^6 will interact with the same average intensity and, thus, a becomes ab. Obviously Nb is the Nm toward which a species "strives." In this "striving," which may be either maturational or evolutionary in terms of units of time, A^ may vary as a function of ex, or a may vary as a function of A''. At that A^ it follows from Eqs. (55) and (56) that: a5/i:^ = 0.25 (57) This holds for all A^;,. <*b/ia^ defines the maximum satisfaction from social interaction and will hereafter be referred to as db. The usual intensity, i, of interaction, which determines a, since P = a, may be considered as basically under genetic control. Similarly, n and m' may be considered to be normal expressions of genetic factors in so long as A^6 is approximately realized and the members of N experience conditions in harmony with their genetic constitution, that is to say that the environ- mental conditions approximate those usually experienced by the species for many prior generations. However, abnormal environmental circum- stances may so alter physiology and condition behavior that i, n, and n' diverge from the u, Hb, and Mb' appropriate to A^'fe. In these circumstances n and n' no longer each equal 1.0, nor is u in harmony with A''^ in the sense that afaa will lead to maximum satisfaction from social interaction. Yet, regardless of how i, fi, and fi' have diverged during maturation, this maxi- mum may be attained if the species adjusts by attaining that A^, different from Nb, such that : a/i:^ = 0.25 = d':' (58) Theta, the maximal and also optimal satisfaction from social interaction, is here designated as d^"^ or just 6o to indicate its possible attainment at some other N than A^6. Interactions whose frequency has been designated by fap require special consideration. 1. The Social Use of Space 109 For clarification :/ap = fap + f^a And f^p = frequency with which a given responsive individual interacts with refractory individuals, while it is itself in the responsive state. And fpa = frequency with which a given refractory individual interacts with responsive individuals, while it is itself in the refractory state. It can be demonstrated that f,'^ = f^^ . Therefore Zip = 0.5/„, (59) If we let a„, represent that a appropriate to A^„, and /i™\ then from Eq. (55) 1 Similarly, for Nb with /x and /x' = 1-0 1 A^6 - 1 (60) (61) If we assign /^"^ as the fap characterizing Nm when /i^^ represents the maximal value of /„„ (e.g., see Eq. (56)), then by utilizing Eqs. (51), (52), (55), and (60) and considering the fact that /x' = 1-0, it follows that /S^ = 2/i:^ (62) And from Eq. (59) it follows that, when n and m' each equals 1.0, fT' = fa:' (63) For clarification, it is to be noted that Eqs. (62) and (63) refer to the con- dition when fjL and m' remain unchanged at the fxb and (Xb values appropriate to Nb, but a adjusts to the existing A^ according to Eq. (60) so that the existing N becomes an A^^*") differing from Nb in most instances. As already demonstrated eo = af'-' (64) where do represents the maximal, and for this special case also the optimal, amount of time an individual can remain in that refractory state denoting satisfaction from social interaction. At iV„„ where Bo is realized a/„'j"'^ 110 John B. Calhoun amount of time is spent in frustrating refractory periods. Here e'r' = af:i-' (65) And from Eqs. (63), (64), and (65) it is obvious that qCw) _ n(m) (66) Since Nb is a special, and the most important, case of Nm, Eq. (66) represents a significant consequence of evolution, as well as adjustment to current group size different from Nb. It means that when members of a group attempt to maximize satisfaction from social interaction, they will of necessity spend an equivalent amount of time experiencing frustration from social interaction. Evolution having transpired in such a system of social physics, physiology must be in harmony with this normal degree of frustration. Likewise, any marked decrease or increase of /„p from /^p"'^ should prove stressful. From Eqs. (51), (59), and (61), when mm' and a remain appropriate to Nb but A'' fluctuates, it follows that ^ MN - ly- As N approaches zero, /„p approaches zero. As N approaches infinity, lap approaches the fc characteristic of Nb, that is when/^ = Nb — I = l/ab. Yet at the same time (see discussion following Eq. (52)) /„„ approaches zero as N approaches infinity with reference to its divergence from Nb- At N's much larger than Nb the frequency of contacts resulting in refrac- tory periods (i.e., faa and f^p) comes to approximate the total contacts transpiring in Nb] however, practically all of such contacts are of the type frustrating to individuals having returned to the responsive state. 1. Terms and Equations The following assembly of definitions will facilitate understanding later discussions. Insofar as possible the N animals in the group will serve as the basis of the definitions. Some terms utilized in later sections will also be included here. N = Total niunber of individuals in the group. In the strictest sense, a group is defined by habitation of an exclusive area in which each resident member has a good chance of contacting all others. d = Target diameter of an individual. In the simplest sense, d specifies the actual physical diameter with the "animal" having no more d properties than a billiard ball. Included under d are J. The Social Use of Space ^ any characteristics such as bright color, vocalizations, odoi, or upright posture which enhance the hkelihood of an individual being perceived by its associate. Through evolution and matura- tion certain species, particularly man, acquire the capacities to utilize nonphysical characteristics to alter target diameter. These nonphysical characteristics include attitudes and values whose possession influences the likelihood of the holder being perceived and responded to by his associates. V = "Velocity" with which an individual ''moves" through its en- vironment. It includes all properties which enhance the likeli- hood of one individual approaching its associates. Thus, in addi- tion to including actual velocity, it includes all sensory mecha- nisms which extend the individual's perception of others in any direction along its travel path. Thus, where r is the radius of perception beyond the physical bounds of the individual, v be- comes rLt-\ see Eq. (35). Furthermore, v = rU-^ must actually become more complex than this. Animals further vary in the number of trips per unit time. See previous discussion in Sec- tions III, A, 1 and A, 4 which deal with how emotionality alters the frequency of trips. Therefore, if we let: D^ = r = radius of perception ^2 = number of trips per unit time; or any time or place pattern of movement which alters probability of con- tacting others v-i .-^ Lt-^ = actual velocity Then biological velocity, v, becomes: Note : Here the product is used in the sense of a function of When V is considered in later discussions it will have all these connotations. r = radius of perception as discussed above. A = area inhabited by the N individuals, each of whom has a good opportunity of contacting any other member oiN. n = (dv/A) is a communication-enhancing or contact- producing factor. By considering v in its simplest sense, n becomes (drv/A) as soon as the perception sivath 112 John B. Calhoun determined by the individual's capacity to perceive beyond its own physical bounds comes into play. n' = K communication-inhibiting or contact-blinding factor. It reflects a psychological property permitting the in- dividual to ignore a contact resulting from n. n' must derive from {d'r'v' /A') factors. See Section XIII, B, 4 for further treatment of n' . i = Intensity of action of one individual toward another upon contact. a = ^■^ the duration of the refractory period following the contact of a responsive individual with some other individual. Contacts made by an individual while it is in a refractory state have no influence upon its a. In some way the refractory period is a consequence of the intensity of interaction. It is thus the result of the interplay between the action of each individual toward the other. I have, therefore, assumed that the product of these intensities of action represents a first approxi- mation of a proportionality to the duration of the refractory period. faa = The frequency with which one individual, while in the responsive state, meets other individuals, who are also in the responsive state. /„p = The frequency with which an individual, while in the responsive state, meets nonresponsive ones (i.e., those in the a refractory state) . aaa = Refractory period produced in each individual after each of the faa interactions in which it is involved. «„« produces satisfaction. cxap = Refractory period produced in the responsive individual after each f^p interaction. a„p produces frustration at least in the sense of being a nonspecific stressor of physiology. ocaa = ocap wlth regard to duration. da or 0W = afaa, the amount of time per unit time spent in satis- fying refractory periods, da represents the consequences of positively affective interaction. Of or ^(/) = olJ'^j,, the amount of time spent in the frustrating and physiologically stressful state. df approaches zero as N approaches I.O 1. The Social Use of Space 113 df approaches 0.25 at Nb df approaches 1.0 as A^ approaches infinity with reference to Nb- Of represents the consequences of negatively affective interactions. 0<»') = amfi":^^ = maximal da = 0.25; see Eq. (57). j^(m) ^ That A^ at which S^"'^ results. In other words, at N"" satisfaction from social interaction is maximized, but at A'"^'"^ df"^ = d^"'\ that is, there is as much frustra- tion as satisfaction from social interaction. A^6 = The basic group size of a species living under those conditions to which it is most adapted. A^6 is a special case of N^'"\ 0f \ e^/\ ab, u, ixb, and Mb' represent values appropriate to Nb- Here 6^^^ and df^ always = 0.25, as may be seen from Eqs. (57) and (63). At Nb both Mb and nb must equal 1.0. d^J"\ dj'"^ represent values appropriate to A^c-) in which ^i'"> - ^f ^ and 0)'"> = However, a^"'^ i^"'\ m^""^ and m'^'"^ at A^^'") may all differ from comparable values appropriate to Nb. Q(o) _ Q{m) £q^. ^ij ^ Q^j^gj. ^j^g^j^ ^^^ although quantitatively 9^^°\ d^J"\ and da'"^ all = 0.25. No = Any A^ when da = d^°\ No may equal Nb, but when it differs from Nb, some alteration in n, ij.', or a permits attainment of the optimum 6 a, that is dj . 2. Interaction P'unctioxs Stated in Terms of A^ The number of indi\iduals inhabiting an area is more readily measured than any other function relating to this model of social interaction. There- fore, it will be helpful to state all other functions in terms of A^: /. = n{N - 1) (34) If intensity of interaction is labile to the point that 0^'"* can always be attained, then ^ (60) which means that : jlmlJ-m {N m — 1) \n,ny^n^'{Nm " 1)/ (68) JJ4 John B. Calhoun A core aspect of this thesis is that whenever ju increases above m6 there will be compensatory shifts in m' such that mm' will again eciual 1.0. There- fore, a and i will gradually become a function of N„„ or we might rather say that the members of the group attempt to adjust their intensities of interaction to make any existing A'', regardless of how much it has diverged from Nb, become A„,. Thus, Eqs. (60) and (68) become: Oim — N - 1 (69) (70) At Nb it follows from Eqs. (56) and (69) that the maximum frequency of interaction of one responsive individual with other responsive ones becomes : Hrn) ^ ^f - 1 (71) J aa A Accepting the logic above that in time all individuals will attempt to ad- just their intensity of interaction compatible with any existing N, it follows that: A — 1 fm) ^ f! i (72) Jaa ^ ^ ^ It further follows from Eqs. (02) and (69), where mm' tend to adjust to 1.0 and i adjusts to maximize dj"'\ df may be considered truly as a stressor to the extent that it exceeds d^^K As TV becomes greater than Nb, df becomes greater than the optimum value of 0.25, and as N approaches infinity df approaches 1.0. This means that nonspecific stressors in the sense of frustration from social interaction can never exceed four times the optimum level. For these reasons I choose to examine merely how df varies as a function of A^ rather than making any effort to evaluate any possible differential effect resulting from df being greater or less than the optimum. To see directly how these two stressors, dd and df, vary as N changes, a specific case for Nb = 12 is given in Part B of Table XI. Here again, as in Fig. 34, it may be seen that the fr.equency of satisfactory interactions, faa, declines following either decreases or increases in N from Nb. However, frustrating interactions, f^p decline as A^ declines below Nb, and likewise increase as N increases above Nb. There results an approximately 70% deficit in satiation when N declines to 2 or increases to about 122 from the Nb = 12. Somewhat more marked changes from the optimum frustrations follow changes in N from Nb. In order that the change in df as a function of the deviation of A^ from Nb may be visualized, they were calculated (Fig. 35) for Nb = 2 and Nb = 12, for which appropriate intensities of interaction are, respectively, 1.0 and 0.302. Only increases in df at N's above Nb are shown. As Nb in- creases from 2 to 12, the respective intervening curves for df shift to the right, that is, it takes slightly greater relative increases from Nb to produce an equivalent increase in df. For all practical purposes the df curves for all Nb above 12 are identical with that of Nb = 12. Initial increases in N 120 John B. Calhoun above Nb produce the greatest increase in 6/. Later equivalent increases in N produce less and less increments to Of, frustration. Satiation deficit, dd, increases (Fig. 35) in a somewhat similar fashion as df, but it takes somewhat larger increments in N to produce comparable increments in dd. Whereas df most likely represents a quantity of social nonspecific stressors, Od most likely reflects emotion of a kind which on the human level we call sadness, foreboding, apprehension, or home sickness. It represents the physiological consequences resulting from needed and perhaps known social interaction. 8=017424 Fig. 35. Satiation deficit and frustration at greater than optimum group size. The inset figure defines the N of ma.ximum decrease in the satiation d, per unit increase oiN. A word of explanation is in order to reveal why I selected the nonfinite Nh = 12.11 instead of 12.0 for examining Od in Fig. 35. In brief, I reasoned that there must be some Od not compatible with maintaining social life at that corresponding A". When this A^ is reached there must be some genetic change transpiring which so reduces intensity of interaction that do may be restored. On a rather arbitrary basis, I selected dd = 0.174, which is equiva- lent to a 70^f decrease in 9a from do. Reacquisition of do at this N reciuires i to decrease to 0.3 of its former level. By such criteria, successively larger Ni, starting with Nb = 2, will form a series of 2, 12.11, 124.45, etc. Any '(3) such saltatorial series of Nb's may be designated N^ \ Ny, A" ]V^"\ The dd curves for all A^6 of 12.11 and above will cross the 0.174 horizontal dd line within the small black rectangular area superimposed on I. The Social Use of Space 121 this line in Fig. 35. Further elaboration of such saltatorial series of Nb is given in Section XIII, B, 3. It must be kept in mind that a basic assumption underlying this general formulation of social interaction is that the mean free path of an individual must be large in comparison with the target diameter represented by any other individual. That is, animals must not be so crowded that one in- dividual becomes so physically hemmed in or surrounded by a few others that opportunity to contact many of its associates becomes markedly re- duced. When an experimental study violates this condition, what has been said in the above statements will not apply. 2. The Buddixg Off of Social Groups As the group size increases beyond Nb both the deficit in satiation, dd, and the amount of frustration, 9f, increase in so long as intensity of inter- action remains constant. Members of the group will find participation in it both less and less satisfactory and more and more stressful. The question arises, "At what point will members find conditions so unbearable that they will leave or at which the group will split?" Changes in da, or da, as a consequence of changes in A^, are proportional to /„„. Therefore, we would like to know if there is some N from which any given change in N brings about a greater change in faa than a similar change from any other N. The second derivative, f^'a = 0, occurs when: A^ = 1 + 2/(a6Mo) [see Eq. (81) ]. This N shall be referred to as Ni. For Nb = 12.11 this arithmetic inflection point comes &t N = 23.22. As may be seen from the inset graph in Fig. 35 this N marks the point of maximal change in da with a given change in N. At this point an increase in N produces a greater decrease in da than a similar change at any other N greater than Nb. Furthermore, at Ni, dd, as calculated by Eq. (86), for any N will always be 0.0278, which represents an 11% deficit in do. For howler monkeys and man, where the basic A'' appears to be about 12 adults, the social group size rarely exceeds 2Nb unless, as in the case with man, the next well-defined larger group is much larger. It is for this reason that I suspect that N will split or bud off another group when N approaches (2Nb — 1) , the point of maximal rate of change in satiation deficit as given by Eq. (85). In essence, this line of reasoning says that by the time a group nearly doubles in size from its basic A^, its members will begin to feel uncomfortable in the sense that they do not find participation in the group sufficiently satisfactory. This will lead to enough members leaving the former group so that within each of the two new groups interaction will produce near optimal results. 122 John B. Calhoun 3. Saltatorial Chaxges in the Basic Group Size Within most orders, and many lesser taxonomic categories, related species may be found between which there exist marked differences in the typical group size. Caribou and elk characteristically maintain large herds in contrast to the small groups or even isolated pattern of living by mule deer or moose. During the active breeding season, bats of the species Myotis lucifugus and M. yumanensis roost singly or in small clusters, whereas M. grisescens and il/. velifer maintain large assemblies even during the breeding season. Woodchucks, Marmoia monax, tend to live in isola- tion, whereas black-tailed prairie dogs, Cynomys luchviciamis, live in large colonies. Obviously these represent a select group of comparisons. Although I shall not attempt to substantiate here the typical group sizes found within any fairly closely related series of species, examination of many series suggests that there are within each series several discrete basic group sizes with an extensive range between any two nearest sizes not represented by any species. For the present purpose, this conclusion will be accepted as approximating reality. Then the question follows: "What characteristics of physiology and group interactions might lead to saltatorial steps in group size which become fixed by natural selection or cultural evolution?" In the first place, there must be some condition which induces animals to assemble in far greater group sizes than their Nb, and this condition must remain sufficiently strong to prevent splitting of the group as it approaches 2Nb — 1 [see Eq. (85)]. Any spatially restricted but locally abundant resource might well so act, particularly if response at the source favored the establishment of a behavioral sink as described in Section XII, C. In- crease in group size beyond 2A^6 — 1 would accentuate social discomfort and stress in the sense of increasing 6d and 6/ (Fig. 3o) . At some point these factors must become so intense as to produce sufficient decrements in re- production and survival to threaten the survival of the species. There is no a priori basis for judging what this threshold might be. Beyond 2A^6 — 1 each increment in N produces a smaller increment of 9d and df. Examination of the curves in Fig. 35 reveals that when dd is about 0.70 of its maximum and df is slightly over twice its optimum level, any further increments to N produce little further change in dd and 6/. The horizontal line through all curves defines this point on each curve and shall be considered empirically as a limit beyond which further increases in A'^ cannot be tolerated. If Ni'^ = 12, the limit is Ni^^ = 82 for Of and A^f ^ = 123 for dd. It will be recalled from Section XII, A that Nb for the Norway rat appeared to be about 12. Although local colonies approximated this number, all mem- bers of all colonies were forced to interact at the single source of food and 1. The Social Use of Space 123 • water. Furthermore, the entire population in the quarter-acre pen sur- rounded by a rat-proof fence made a closed system out of the entire popu- lation. At 123 adults (Table X), marked disturbance was in evidence, witli only a minority of the females reproducing successfully. In the closed systems contained within a smaller area, described in Section XII, C, severe reproductive disturbance characterized an A'' of slightly less than 80 adults. Therefore, for the Norway rat at least, when the actual A'' ap- proaches the increase above Nb presumed to represent the tolerance limit, a degree of physiological disturbance of sufficient magnitude arise as to indicate a necessity for some evolutionary adaptation to the increase in group size for continued survival. Parenthetically, I might add that this tolerance limit for dd and 6/ was arbitrarily assigned simply with reference to the slope of the curve, and without prior knowledge that this level would lead to tolerance limit A^'s so closely approximating those observed in my experimental studies. One type of evolutionary change which will reinstate 6 to its optimum level, that will eliminate dd, involves reducing intensity, i, of interaction. It will be recalled that i- = a, the refractory period following interaction. Now if Nb = 12, and the tolerance limit A^ is 123, a reduction of a from 0.091, the a appropriate to Nb = 12, to 0.0082, the a appropriate to Nb = 123, will return d to its optimum value of 0.25. The change in i is 0.3 of its level at the former A^'b, that is, from i = 0.3 to i = 0.09. With a hereditary change in behavior amounting to a reduction of i to 0.3 its former level, A^6 changes from 12 to 123. These would then represent two species, the stem one having an A^^^^ = 12 and residing under those environmental conditions not necessitating an evolutionary change in physiology and behavior, and the derived one having an A^^^^ = 123 and residing in the presence of those environmental conditions forcing the maintenance of group size far above that of the stem species. If this process is repeated each time 9d reaches a tolerance limit of approximately 0.607 of the minimum dd possible, there arises what might be termed a "satiation deficit saltatorial series of basic N's" which are as follows, starting with A^,^^^ = 12. Ni' 12 Ni' 123 Ni' 1,359 Ni' 15,088 Ni' 167,645 Ni' 1,862,544 Ni' 20,695,365 A^r 229,937,917 124 John B. Calhoun Each successive Nh will have an intensity of interaction approximating 0.3 that of the preceding. At the 8th and last listed Nb, intensity of inter- action would be only 0.0002 that when Nh = 12. It seems rather patent that no meaningful behavior could transpire with such a reduced intensity (duration) of interaction. Two-hundred thirty million adults in a semi- closed social system can only apply to the world as a whole for the human species. Reduction of intensity of activity as a means of recovering satia- tion from social interaction could, in evolutionary terms, likely suffice in mammals to the third stage of 15,000 adults which entails a reduction of i to 0.09 of that appropriate to A''^ = 12. A similar series of Nb can be calculated with reference to Of = 0.775 or the tolerance limit involved in shifting Nb from 12 to 82. Optimum df = 0.25 can be regained if at this limit i is reduced to about 0.36 of its intensity at the former Nb. Such a "frustration saltatorial Nb series" becomes: Nt'^ 12 Ni'^ 82 ^(3) 597 m^^ 4,491 ^(5) 32,343 Nr 238,153 iV^' 1,753,772 ^(8) 12,914,892 Again this series becomes rather absurd at the upper limit because of the great demand for reducing intensity of interaction. Since semiclosed systems, at least on the human level, and occasionally with other mammals do approach some of these A^6, we must ask what other avenues of evolu- tion exist. For this we must assume that intensity of interaction remains constant at some level approximating that for Nb = 12, but that a tolerance limit for dd and df exists. At the A^ of these limits a change in behavior may take place which insulates the individual by producing subaggregates in which, for all practical purposes, the individual at any particular time is a mem- ber of a subgroup in which Nb = 12, even though many other subgroups exist in the environs. The individual may be a member of several such groups but participates in only one at a time. Such changes in behavior can be considered to be of either genetic or cultural origin. In either case, so long as any tolerance limit for 6/ and/or 6d exists, there must be salta- torial steps between successive Nb, and only a few such steps are possible even if the tolerance limit arises at a somewhat lower level than hypothe- sized above. If later research supports this hypothesis it will haxe considerable 7. The Social Use of Space 125 bearing on our understanding of the course of evolution involving change in group size. It will mean that gradual changes in heredity or culture will rarely have transpired. Rather, from the pool of gene variability accumu- lated in the species, there will be rapid shifts in gene frequencies of many genes, thus resulting in a new phenotype. In so long as environmental conditions facilitate maintenance of its Nb by a species, its gene pool may become quite diverse through the accumulation of mutant genes. Then, once environmental circumstances force the species to maintain an ele- vated A'' near its tolerance level for dd or 9/, an extreme selection pressure will arise for reducing the frequency of all genes except those which adapt the species to its new N. A genetically variable A^^^^ species will thus rapidly be transformed into a genetically rigid Nl"^^ species. On the cultural level such a process of saltatorial change in basic group size demands that the value system which dictates acceptable roles of action and communication be preserved even after the usual group size has far exceeded the Nb appropriate for that value system. At the same time, under the pressure of increases in 6d and 6/, small segments of the closed system will develop values divergent from the main group. At the tolerance limit of dd and 6/, when A^ has so diverged from Nl^\ there will arise a marked and rapid shift to the prevalence of those newer values appropriate to d^'"^ and 9f"'^ at N^'^K Value frequencies and gene frequencies become isomorphic in these two avenues through which there can be a saltatorial evolution from one basic group size to another. Basic group size for adults only in the primary steps of human cultural evolution seem to include the 10-16 range, 50, 200, and 2,000. This series resembles neither of the hypothetical saltatorial group size series except in its saltatorial character. The hypothetical series merely demonstrated the kind of changes following from stated assumptions. The exact series followed by any line of change depends upon the threshold tolerance limit for dd and 6/ as well as three factors ignored in our discussion up to the present. Discussion up to this point assumes /x = (dv/A) = 1.0, where d represented the target diameter of other individuals, A the area inhabited by the N individuals, and v the velocity of movement of individuals. In essence, m represented the likelihood in time t of one individual encounter- ing another. It can readily be shown from Eqs. (52) and (60) that da, the satiation from social interaction, i.e., afaa, can remain constant regardless of changes in fjL. At least this is so if the physiology and behavior of the species is com- pletely adjustive. From the general form of Eq. (60) where n' = 1.0, a = 1/[m(A^ — 1 ) ], it follows that each doubling of /x, that is doubling the likelihood of one indi\'idual meeting another, necessitates a halving of a, and thus reduces intensity of interaction from (a)^'^ to (a)^/-/2. If we 126 John B. Calhoun follow the prior assumption that each species has an optimum intensity of interaction, then each increase in n will have an analogous effect to in- creasing group size. In other words, increasing n above 1.0 will increase dd and df. When we are concerned with the effects of changes in m but as- sume a remains static at the value appropriate to m = 1-0, then a must be calculated from Eci. (60) with /x' = 1-0 and faa calculated with this a by using Eq. (52) above and some value of n different from (Xb = 1.0. For example, consider Nb = 12. Then ab = 0.091, and db = 0.25 (see Table XI). If A'' doubles and /x remains 1.0, d„ becomes 0.219, but if A^ remains constant at Nb but m doubles to 2.0, 6 becomes 0.195. Thus, a comparable increase in ^ produces a greater deficit in satiation, 6^, from social interaction, than does a double of A^. Thus, saltatorial evolution of A^^^^^ to A^^"^ may be necessitated either by an increase in A^ or an increase in m- The rate of change in N and ijl may well offset the tolerance limit of da or 6/ and thus affect the magnitude of the shift from A''^^^ to N^^^K dv essentially measures the rate of com- munication and A the space within which this communication takes place. Thus, n will increase if A remains constant and dv increases, or if dv re- mains constant and A decreases. If both the rate, that is means, of com- munication increases and the distance over which communication must take place decreases, m will increase very rapidly. Detailed consideration of communication is given in the following section. 4. The m Communication Function We have already seen that n = (dv/A), as defined by the previous Eqs. (35) and (80), is a communication-enhancing or contact-producing factor. (See prior discussion under Terms and Equations, Section XIII, A, 1.) Other than for pointing out in the latter part of Section XIII, B, 3 that altering /x has much the same consequences as altering N, we have been content to consider consequences of variability in other functions when IX remains constant at that value /X6 = 1.0 appropriate to A^6. I was led to examine the question of the consequences of varying /x as a result of the observation by Birdsell and by Zimmerman and Cervantes, cited in Section XII, E. They observed that where a conflict of values arises in a group there results a reduction in group size. Here, we are con- cerned with the special case where attitudes or values comprise a major aspect of the target diameter d. Each member of the group holds some n number of values by which others recognize it as an appropriate object for interacting. When some particular ^-aIue is shared by all members, it may be said to possess a unitary value in contributing to target diameter. In other words, under this circumstance all individuals possess the same 7. Tlw Social Use of Space 127 target diameter, d = 1.0. With reference to Eq. (:i5), a unity value for target diameter merely means that there has been genetic or cultural adaptation to the actual magnitude of d, such that ju = dv/A = 1.0. How- ever, if an individual expresses a value shared by only a few of his associ- ates, he will by this fact be much more likely to be perceived by his as- sociates, and thus more likely to be reacted to by them. His target diam- eter will be increased. Furthermore, it is logical to assume that the larger an individual's target diameter, the greater will be the response evoked from associates. In so long as all other d xqXwq characteristics remain identical among the members of the group, the one which does vary among members will assume the sole role of influencing target diameter. As a first approximation this response-evoking capacity, which I will call S, of a particular d value can be taken as being inversely proportional to the probability j) of its being encountered among the members of the group of N individuals. Therefore : S = l/v (87) Where only one component of d varies, and since those shared compo- nents of d may be ignored, d ^ S. For the special case where all members have the same d: M = {dv)/A = {Sv)/A = 1.0 (88) Furthermore, where area. A, remains unchanged at the value appropri- ate to Nb it has the relative value of 1.0. Therefore: Sv = 1.0 S = l/v (89) And considering Eqs. (87) and (89) V ^ p (90) Lastly: V = l/S (91) A'ariability of the target diameter d among individuals means that d comprises an assembly of traits, physical size, color, vocalizations, behavior, and attitudes or values, d is the total complex. Components shared by all members will be referred to as {d) . Those remaining traits, through which an individual differs from its associates, represent a genetically and cul- turally determined phenotype to which the response evoked from associ- ates is a function. By response I here refer solely to actions reflecting the choosing or rejecting of an associate. Such a response may be a function 128 John B. Calhoun of the trait itself or may be a function of a recognizable degree of differ- ence between one individual and its most similar associate. 1 believe that such degrees of difference form the primary basis for the maturation of social behavior and social organization within a group. Further treatment of this topic follows in Sections XIII, B, 5, a and b; XIV, A and B. Such traits or degrees of difference comprise the units influencing social behavior. These units will here be called rf-genes. As stated above they may be of either hereditary, or cultural origin. Any rf-gene, g^^\ may develop an allelic series of differing or "mutant" forms ^i^' • • • gl^K When degrees of difference, and not the absolute amount or kind of difference, forms a (/-gene there can only be two forms of a particular t/-gene, g]l^ and g^^\ where g\]^^ represents a degree of difference from the ideal type, the ideal d, and g^2^ represents the retention of the ideal traits for which g'^^^ represents the divergence. c?-genes of the type g*"^ will be called dominant c?-genes, while those of the type g]p will be called recessive c?-genes. d- genes of the latter type are treated in detail in Sections XIII, B, 5, a and b. Without specifying the allelic nature of any rf-gene it is obvious that the target diameter d is a function of (rf), g^^\ g^-\ • • •, ^^"\ Let Si^ represent the response-evoking capacity of any ith. individual with reference to the probability of its being chosen by associates as an object of affection. S'"^^ is related to Schaeffer's love-acceptance referred to in Section XIY, C. aS,^"^ represent the response-evoking capacity of any zth individual affecting the probability of his being rejected by associates. *S^"^ is related to Schaeffer's hostility-rejection referred to in Section XIV C. 1.0. As originally formulated in the discussion before Ec^. (38), n' simply operated as a probability of an actual contact being perceived. However, the above and following discussion indicate that m' can exceed 1.0. By imagining contacts, which actually do not occur, through a de- crease of the A' component of /i', n' can exceed 1.0. In terms of the model proposed in Section III, A, whenever A decreases, the rate of firing of the neuronal net of the governor will increase. Thus, an increase in A' represents an increased rate of firing of the neuronal net of the governor. Previously I pointed out that a decrease in A' to compensate for an in- crease in A might be visualized as an hallucinatory process. There is no reason why A' camiot equally involve the governor of intensity of activity when A increases above .-l^ normally appropriate to Nb', a decrease in A' would represent a slowing of the firing of the neuronal net of the governor, which change would then permit a longer duration of interaction. This longer duration of interaction would compensate for the fewer /«« interac- tions possible in a larger A. The concept of social perception of contacts subsumed under n' thus includes a wdde variety of processes. It includes (1) selective acceptance of stimuli to be integrated in the central nervous system; (2) impedance or facilitation of passage of signals across neuronal synapses; (3) alteration in the length of a neuronal circuit; (4) hallucinating a contact; and (5) governing the intensity of interaction. These m' capacities for adjustment are most likely to be found farthest advanced in those species in which d, V, and A fluctuate most markedly with reference to all members of a group within the life span of every individual. However, over long spans of time encompassing many generations, a gradual increase in d, v, and A should increase the complexity of social life possible. At least this conclusion holds to the extent that enhanced synaptic transmission, increased dura- tion and intensity of behavior, and increased discriminatory capacity foster more effective social behavior. 1. The Social Use of Space 137 The following summary of presumed relationships may serve as a basis for evaluating the consequences of change in the components of ju and m'- External Internal change change Increase in Decrease in d d' V v' A A' = Increase in discriminatory capacity = Impeded synaptic transmission = Increased duration and intensity of be- haviors, or Increased memory storage of social stimuli permitting hallucinated interactions which indicate increase in cortical mass Decrease in Increase in d d' = Decreased discriminatory capacity (i.e., less selection of stimuli passing the "filter") V v' = Enhanced synaptic transmission A A' = Decreased duration and intensity of be- havior, or decreased memory storage of stimuli which are available for producing hallucinated social interactions which in- dicates decrease in cortical mass These relationships represent intuitive logical deductions, d' and A' serve as fairly satisfactory first approximations. With progressive social evolution, d and A generally increase. Along with this trend, discriminatory capacity increases, cortical mass increases, and ability to maintain a be- havior for longer periods of time increases, all of which tend to harmonize with the model. However, I am less satisfied with my formulation of v' (Section XIII, A, 1). The reason for this opinion is that with advancing social evolution there presumably arises an increase in Vi, that sensory ex- tension of the seK to produce psychological contact before bodily contact. This should produce the opposing phenomenon of impeded synaptic trans- mission. For the present, I can see no rational basis for reconciling impeded synaptic transmission with social advances. v' merely connotes alteration of sensory perceptions of others involving some distance between the two individuals concerned. My supposition that alteration of synaptic transmission subserves v' may well be wrong. The important point for the present is simply recognition of the likelihood of some such mechanism whose evolution is influenced by social conditions. 138 John B. Calhoun I have pointed out that since fx can change as a result of independent change in d, v, and A, conseciuently there must be discrete phenomena in the individual representing what I call d', v' , and A' , which can change independent of each other. Nevertheless, it is ciuite likely that the compo- nents of n and /x' do have interactions. The concept of intensity (duration) , i, of social action includes control of i by both internal and external factors. The internal factor is A', the "governor" previously discussed. The ex- ternal factor is the d of the other. The greater d, the greater i. Thus, d can influence the governor. This means that an increase in the d of associ- ates can decrease the A' of self. In studies with rats recently completed (Calhoun, 1962b) some rats develop a high v while others develop a low v. Those with a very high v exhibit high i in terms of both intensity and duration. This suggests that in some way an increase in v leads to a decrease in A' . Furthermore, male rats with very low v commonly respond as though they did not make ade- quate discrimination of the cues emanating from associates. They sexually mount associates without regard to their age, sex, or sexual receptivity. These observations suggest that lowering of the motor components of self's V increases self's d' , which suggests that somehow when an animal decreases its velocity its ability to discriminate among available social stimuli also becomes reduced. All I have attempted to do in the preceding paragraphs is to lay the groundwork for understanding the meaning of the contact- modifying factor jj.' . Decreases of n re increase in N : We are here concerned with the special case where the area. A, remains constant as numbers of individuals, N, increase. This means that density increases. We have already seen that an increase in A^ with ^ held constant leads to a deficit, da, in satisfaction from social interaction as well as an increase above optimum of the frustration, df, from such interaction. As density increases one should anticipate n changing before y.' . Therefore we shall consider ix' as remaining constant at the 1.0 value appropriate to Nb but let N increase. In each instance we wish A^ to become No, which means that do and 6/"'^ will be optimum. Con- sider the case where A^b = 12 and intensity of interaction remains at u, it may be seen from Eq. (80) that successive doublings of No demands suc- cessively slightly more than halving of jXo'- No IJ'O 12 1.0 24 0.478 48 0.234 96 0.116 192 0.057 384 0.028 1. The Social Use of Space 139 Where fx = Ho and N = No it may be seen by substituting Eq. (80) into Eq. i'-U) that the frequency of contacts will remain constant at (Nb — 1) regardless of the increase in density. Since we are considering the special case where area, A, remains constant, the constancy in the absolute num- ber of contacts despite increases in density can only derive from decreases in the d or the v component of ju = dv/A. Where decreases in ju transpire within the lifetime of an individual as an adjustive change to increase in density, and where this decrease in m results solely from a decrease in the target diameter, d, this change must be re- flected through reductions in the frequency of usage of signahng mechanisms or of the intensity of such signals. Vocalizations should occur less frequently, be less complex, and of reduced intensity. Bodily display characteristics under voluntary control should similarly be reduced, as should also the use of chemical signals. Similarly, when a species, A, now exhibits an Nb of 80-120 or 800-1400 (see Section XIII, B, 3) but there is reason to sus- pect that at some earlier era it had had an Nb of 2 or 12, such as is still expressed by a related species (or genus), B, then a comparative examina- tion of species of types A and B should reveal that members of species B more frequently resort to the utilization of vocal, display, and chemical signals and that these are of greater complexity and intensity than in species A. In making any such comparisons it is well to keep in mind the earlier hypothesis that the change of an Nb = 2 to an Nb = 12 may lead to an increase in complexity of the signal. For this reason, it is more ap- propriate to compare a species w^hose A^6 has a typical range of 7-19 with one which rarely falls below 80. Such comparisons will provide critical tests of the general formulation. In like fashion, velocity, v, may be the factor which becomes reduced as density increases. This reduction may be expressed in any of the three aspects of v listed in Section XIII, A, 1. Sense organs may become less effective with reference to the animals' perception. This reduces ^i. Such a tactic must be effective only through genetic changes and so can serve only as a long-term adaptive mechanism. The animal may also reduce its V2 by w^ay of reducing the number of trips it makes, or by altering the time and place of its activities. This strategy includes initiating activity while others are resting, or by becoming cryptic in the sense of becoming arboreal or subterranean. Finally, the animal may reduce its Vs, its actual rate of movement. Although such reductions in d and v will lead to a reduction in m which will compensate for increase in density, it is obvious that n must decline so markedly as to present biological limits of effectiveness. Further accom- modation to increases in density must require m' to decrease also. Reduc- tion in this communication-inhibiting or contact-blinding factor means (a) decreased duration or intensity of behaviors or decreased memory 140 John B. Calhoun storage (i.e., increase in A'); (b) increase in discriminatory power in the sense of screening out portions of those stimuli of the d of others requisite for ehciting responses (i.e., decreasing d'); or (c) impeded synaptic trans- mission (i.e., decreasing v'). 5. Behavioral Origin of Response-Evoking Capacity, S a. The target diameter genotype as determined by varibility of behavioral traits. I now wish to present the logic of why variabiHty of behavioral traits becomes inevitable. In fact, as aminals become more social, varia- bility in physical traits must become of less importance in determining the kind and intensities of interaction. So let us start with the case where all indi\'iduals possess identical heredity and therefore identical physical characteristics. Even for so simple an organism as the house mouse, marked differences in capacities for social involvement develop despite the fact that the members of the group come from a stock made genetically homo- zygous by nearly a hundred generations of brother-to-sister inbreeding (Calhoun, 1956). The initial formulation of social interaction dealt with a deterministic model in which all individuals w^ere identical. It showed that half the time an individual was in the responsive state it would meet another responsive individual and half the time it would meet another in the refractory state. Thus, even under ideal conditions, an individual would be frustrated as frequently as it would be satisfied from social interaction. But satisfaction will not hkely precisely alternate with frustration. Furthermore, if we consider some arbitrary relatively short span of time when the group first forms, determined by the average individual having, for example, a total pool of interactions equivalent to 2-5 times the number of individuals in the group, then something like the following will have transpired : Each individual's behavior toward another may be characterized by its form or pattern and by its timing with regard to whether the other in- dividual involved in the interaction is also in the responsive state (the a state) or whether it is in the opposite or nonresponsive state (the p state) . Initially the form of the behavior of all individuals in the responsive state will be identical. Identical form denotes possession of the entire assembly of traits, d, by every individual. With each individual contacting its as- sociates in a random sequence over time, it is inevitable that some, who are in the responsive a state, will purely by chance more frequently en- counter others who happen to be in the nonresponsive p state. Each such encounter will throw the responsive individual into an a^^ frustrating type refractory period. Thus, the appropriate behavior of this individual will not only not be rewarded, it w^ill actually be punished. After this individual 1. The Social Use of Space 141 passes through its a^p refractory period and again enters the responsive state, some random change may typify its behavior. The more freciuently it is frustrated, the more hkely will its behavior become deviant simply because there has been so infrequent reinforcement of its original appropri- ate form. Conversely, those individuals which, when they are in the re- sponsive state, have met another also in the responsive state, will have the original appropriate behavior rewarded or reinforced. The behavior of such individuals will remain much in its original form. In this way the members of a group may be rank ordered according to the degree to which their behavior has deviated from the original. Each recognizable unit of deviation represents a recessive d-gene. Each unit of retention of the original behavior pattern from which theirs has been a deviation represents a dominant c?-gene. The more dominant c?-genes an individual possesses, the more intensely will associates respond to him in a positive affective manner, and the more likely will he be chosen as a partner or leader. Conversely, the more recessive c?-genes an individual possesses, the more intensely will associates impose restraints or sanctions on him, and the more likely will they reject him. It is useful to borrow terminology from genetics which deals with he- redity. Let upper case letters represent dominant d-genes, and lowercase letters represent recessive d-genes. Such a system for an A^ = 11 is shown in Table XIII. Here (d) represents the common traits shared by all mem- bers of N. (d) plus the remaining dominant and recessive genes specify an individual's rf-genotype. That individual which has been exposed to the least number of circumstances producing changes in its c?-genotype may be said to possess the "ideal" d-genotype. All other individuals will diverge more or less from this ideal. They may be rank ordered from the alpha in- dividual with the ideal d-genotype to the omega nth ranked individual, which differs most from the alpha one. Each can then be assigned a simi- larity rank, R. The alpha individual is represented by Ri; the one who differs least from the alpha has R2; while the individual who differs most from the alpha has Rn. In Eqs. (92) and (93) i = R (Tables XIII to XV). Consider R4. By utilizing Eq. (93) its c?-genotype, by which we simply mean its d, becomes: d = (d) + gi'^ + r/r- + r/;^ + g\,'' + g'/' + g'o'' + gk'' + g'l'' + g'^ (104) Obviously the d for each similarity rank, R, will be different for every other one. Therefore S for each individual will be unique. This response- evoking capacity, S, represents the d-phenotype. 142 John B. Calhoun Table XIII Trait, d-GENE, Differentiation in a Similarity Rank Hierarchy Common Similarity N^ Nj traits rank, R {d) Differentiating traits, d-genes 10 11 11 1 2 10 id) Dominant d-genes ABCDEFGHI J 10 2 (d) a B CDEFGHI J 9 3 (d) a b CDEFGHI J S 4 (rf) a b c D E F G H I J 7 5 {(}) abed E F G H I J G 6 ((/) a I) c d e F G H I J id) a b c d e f G H I J 4 8 id') a b c d e f g H I J 3 9 {d) a b c d e f g h I J (d) a b c d e f g h i I J 1 11 {d) a b c d e f g h i j Recessive d-genes 1. The Social Use of Space 143 b. Response-evoking capacities. Prior formulations regarding the typing of behavior and personality, exemplified by Schaefer (19r)9, 1961), suggest that the nature of one's own S and the nature of the response evoked from others is influenced by the mood or attitude of the other individual involved. This mood or attitude determines how one views the target diameters of others. It determines whether one focuses on the dominant rf-genes or the recessive <:/-genes of others. That is, when an individual responds to another does he look at the other's desirable or undesirable characteristics. It will be a prime premise of my formulation that one can be afTected only by the good or by the bad side of another at a particular moment in time, but not by both simultaneously. Furthermore, I shall show that there are two ways of assessing the good qualities, the dominant d-genes, of another. Likewise, there are two ways of assessing the undesirable finalities, the recessive rf-genes, of another. Any individual's (/-genotype in a social setting produces four types of r/-phcnotypos, that is four kinds of S. Let *S(-^> represent the response-e\-oking capacity of an individual affecting the probability of his being chosen by associates as an object of affection. Sa is related to Schaefer's love-acceptance. Sa depends upon both the common target diameter, (d) , and on dominant d-genes. gia) represent the response-evoking capacity of an individual affecting the probability of his being rejected by associates. S'^"^ is related to Schaefer's hostility-rejection. S'-"^ depends solely on recessive rf-genes. It is dependent in no way upon the common traits, (d) . S'^^^ represent the response-evoking capacity of an individual affecting how intensely he will be loved or approved of by associates. Love here implies intensity of positive response and thus connotes increase in probability of an individual realizing the objective of his behavior. *S'^'^ determines the extent to which an individual's desires will be facilitated by associates. In this sense, S'-^^ is related to Schaefer's autonomy. S'-^^ depends upon both the common target channels, (d), and on dominant rf-genes. *§(") represent the response-evoking capacity of an individual affecting the degree to which its velocity is altered. S'-'^ is related to Schaefer's control. *S^''^ is dependent solely upon recessive d- genes. It influences the intensity of negative sanctions imposed by associates. Equations for ;S^^' and S'f'' have already been given; i.e., Eqs. (92) and (93) subject to the restrictions there stated. 144 John B. Calhoun Let: Pi^^ = the probability of choosing any ith individual. Pi"^ = the probability of rejecting any zth individual. Then Vr = -W^ (105) Vr = -W^— (106) i here, and in Eqs. (92) and (93) and (105) to (113), refers to specifica- tion of individuals by similarity rank, R. See discussion before Eq. (104). Equations (105) and (106) in essence state that the probability of any other individual choosing or rejecting the ith. individual depends upon what proportion of the total dominant d-gene pool, or recessive c?-gene pool, of the entire N individuals is encompassed by this ith. individual. Note that these equations include evaluation of one's entire experience with members of the group, including awareness of one's own traits. This topic of self-awareness will be discussed later. Conceptually, it is somewhat more difficult to understand S^^^ and S^''\ although the equations for their calculation are rather simple. Let us con- sider iS^"^ first, since earlier reference simply to S was usually in the re- stricted sense of ^S'^''^ Consider the individual in Table XIII with similarity rank 6, Re. When individuals Ri to R^ are in that state where they tend to impose restraints or sanctions on others, they will view Re as being more different from the ideal type than they themselves are. In this sense, Ri to ^5 are type 1 individuals, in the sense of Eq. (94). Similarly, R^ to Rn will perceive ^7 as being like themselves in that they all share the recessive rf-gene, g[^K Thus, they along with Re may be considered as type 2 individuals, in the sense of Eq. (95), with reference to calculating the S^"^ of Re by Eq. (97). Nj for Re is 6. By a similar logic the S'^'"'> of each individual may be calcu- lated. See Table XV for S'^"^ calculated for every member of an A^ = 11 as depicted in Table XIII. Each individual will belong to a different-sized A'' of type 2 indi^nduals. This N will hereafter be referred to as Nj to differentiate it from the A^2 given in Eq. (97) . By analogy to Eq. (97) : ^(.-) = N/Ni (107) 1. The Social Use of Space 145 And from Eq. (91) it follows that Vi = N-JN (108) Equation (108) has proved a most useful one in the study of social groups of experimental animals because it leads to predicting the degrees of social withdrawal expected among any group of known size. In the dis- cussion following Eq. (99) I pointed out that where /x increases as a result of S^"^ becoming greater than 1.0, acconmiodation might be through ejection of those members with the largest ^S^"^ or by a splitting of the group. Each of these possibilities presumes unused area A into which the appropriate individuals may immigrate. However, when surrounding groups maintain territories, or other circmnstances preclude emigration, then the A component of m = {Sv/A) remains constant. Thus, reduction in velocity, v, becomes the only avenue for reducing /x back to the 1.0 value appropriate to No. By a similar line of reasoning to that leading to Eci. (107), A''j represents the number of individuals with which the individual in question possesses a given uniqueness of dominant c?-genes. Reference to Table XIII will clarify the meaning of Nj. For example, Rh belongs to an iVj = 5 since it may be recognized by sharing the domi- nant c?-gene, E, wdth four other individuals. A^j and the similarity rank, R, will always have identical numerical values. By analogy to Eq. (107) S^P = N/Nj (109) And although I do not for the present see how one identifies T' in biological or social terms, although it may represent the seeking for positive affec- tion, it is obvious that Vi = Nj/N (110) In this sense behavioral c?-genes do not represent retention or deviation from specific behaviors. Characterization by two individuals of possessing at least three degrees of deviation does not mean that these degrees of deviation are identical. Now consider a group consisting of four individuals, the pertinent data and calculations for which are given in Table XIV. The probabilities of the dominant and recessive c?-genes are: Pa = 1/4 Pa = 3/4 Pb = 2/4 p, - 2/4 PC = 3/4 p. = 1/4 Pid) = 4/4 146 John B. Calhoun o f^ . tc fa z ° S CU ID ^ J O C « o O ^ w -< > z 9 H-c n z ^ O tc > K a H '^ z ^ H ►J s >■ -< <; t— t PS CL, >A o pa (-1 K, > 5 -!; K to a « '-^ a C Ch £-1 ei- z< 2 M H Z < O z - fi K H t S o ■» >. a K H o u . t3 o ^ "OQ* S:^ < ^ o o m « < 33 o Pi o 1. The Social Use of Space 147 The pool of shared behaviors, (d), acts as a single dominant d-gene. Where R represents the rank of the animal in terms of the degree of reten- tion of dominant d-genes, that is how closely it expresses the ideal proto- type manner of behaving, S'-'^^ and S'-"^ may be calculated by Eqs. (92) and (93) utilizing the above probabilities of dominant and recessive d-genes. (4/1 + 4/2 + 4/3 + 4/4) = 8.33 (4/2 + 4/3 + 4/4) = 4.33 (4/3 + 4/4) = 2.33 (4/4) = 1.00 Then ^R=4 16.00 = 4A^ Restatement of the concept of behavioral c?-genes in the context of a hypothetical example of their relationship to the origin of the various stimulus-evoking capacities and of velocity, v, will assist in clarifying the relationships. As described in Section XIII, B, 5, a the members of an es- tablished group may be ranked in terms of the degree to which deviation has developed from the ideal prototype. This ideal prototype will always be that individual characterized by the least absolute deviation. There will be A^ — 1 degrees of deviation in a group of N individuals. Let: Ai, Then: S2, •••, Sn-1 represent the characterization of an individual by 1, 2, ■ ■ • , N — 1 degrees of deviation A2, • • • , A.v_i represent the absence of de\'iations 5i, 82, • • • , 5.v_i 5i = recessive d-gene a 82 — di = recessive d-gene b 8;i — 82 = recessive rf-gene c etc. And Then Ai = dominant d-gene A A2 — Ai = dominant d-gene B A3 — A2 = dominant c?-gene C etc. ^R=l = 0 C(a) _ (4/3) = 1.33 C(n) _ ^R=i — (4/3 -h 4/2) = 2.33 S'r% = (4/3 + 4/2 -K 4/1) = 6.33 j: .s,^«) 10.00 = 3A^ - ff=i (A^/2) 148 John B. Calhoun N.1 and A^j in the sense of type one and type two individuals discussed in relation to Eqs. (94) and (95) and (107) are given in Table XIV. When A^j = 2 it means that the second ranked, R = 2, individual is a member of a subgroup of two individuals which share the dominant d-gene B. Like- wise when N j = 2 it means that the third ranked, R = 3, individual be- longs to a subgroup of two individuals each of whom possesses recessive d-gene b. Every individual belongs to a unique A^j and N,. Given these uniquenesses of A^'j and A^j as shown in Table XIV, the respective S^^\ Sl"^ and Vi were calculated respectively by Eqs. (109), (107), and (108) and presented in Table XIV. Up to the present I have intentionally maintained the discussion of response-evoking capacity, S, on a nearly strictly theoretical plane for the purpose of clarifying concepts. Even though such theoretical formula- tions may be justified in their own right, regardless of how well they ap- proximate reality, still it is desirable to ascertain whether they are in harmony with observed data. To this end I selected two sets of empirically obtained data. One involves measurements for mice from which velocity, V, may be derived. The second involves the choosing of table partners among groups of delinquent girls. These latter data permit determination of how well the observed choosing can be predicted by Eq. (105). XIV. Consequences and Examples of Social Interaction Systems A, Velocity Reduction in a Hierarchy of Mice I have previously described (Calhoun, 1956) the patterns of social rela- tionships which develop among members of small groups of inbred domes- ticated mice. Whenever two mice passed within a few inches of each other they were recorded as having a contact, regardless of whether or not a detectable social interaction could be detected. During a "contact" two mice merely came within that range of each other for which contentions for status did at times develop. We shall consider the example provided by a group of eleven C57 black, inbred male mice which had developed a stable hierarchy prior to recording the frequency and kind of associations of each individual with his associates. Some pairs of mice contacted each other much more frequently than anticipated on a chance basis, while members of other pairs very infrequently met. These mice are rank ordered in Table XV according to the number of contacts each had with associates. For all practical purposes this order also represents the observed ability to dominate an encounter which precipitated in a fight or flight. That is. 1. The Sdicial Use of Space 149 the most active mouse was the most dominant one and the least active one the most subordinate. It can readily be shown that with N's as large as eleven, the number of contacts, ric, is so nearly proportional to velocity, v, as to justify utilizing number of contacts as a measure of velocity in the present example. From Eq. (91) it is seen that S^i'''> varies inversely with Vi, and therefore on a theoretical basis mice with few contacts should be those wdth large response- evoking capacities. Table XV Velocity in a Hierarchy of Mice 1 2 3 4 5 6 7 Rank R iVi Number of contacts, ric, expected Mouse's number Obs. Exp. V Eq. (113) Eq. (108) Eq. (107) 315 1 11 123 128.17 1.000 1.00 311 2 10 116 116.63 0.910 1.10 282 3 9 109 104.84 0.818 1.22 286 4 8 93 93.18 0.727 1.38 319 5 7 85 81.52 0.636 1.57 303 6 6 65 69.85 0.545 1.83 321 7 5 51 58.19 0.454 2.20 317 8 4 46 46.65 0.364 2.75 290 9 3 35 34.99 0.273 3.67 288 10 2 26 23.33 0.182 5.50 301 11 1 20 769 11.66 0.091 11.00 2 2 = 6.001 = (N + l)/2 Where v represents relative velocity as calculated by Eq. (108) for any A^, empirical calculation will show that: Then where wj°^^) and 7ilf-p^ represent respectively, observed and ex- pected number of contacts in any arbitrary period of time, the number of 150 John B. Calhoun contacts, Hd, for any ith animal l)ecomes: Vi n (exp) _ {N + 1)/2J t^ Zn^ bs) = Vi 2 E n(f «) iV + 1 (112) And by substituting Eq. (108) into Eq. (112) we obtain an equation more convenient for calculation: „(exp) _ "'ci ~ N 2 E nT' t=i N + 1 (113) nfl^\ so calculated, are given in Table XV. Where i2=l , (exp) X" = 8.001, which with 10 degrees of freedom has a p of 0.629. On this basis the observed certainly does not deviate significantly from the expected. 1. Awareness of Self Three-fourths of the contribution to the above x" come from the single omega, nth. ranked indi^'idual. Considering only the highest ten ranked individuals, x" = 2.006 which with 9 degrees of freedom has a p of 0.99! I have already shown (Calhoun, 1956) that the paired contacts in this group diverged markedly from randomness, and so the divergence must reflect some fixed social system such as elaborated here with regard to reduction in velocity. Therefore, the marked divergence of this single omega individual is likely to reflect a basic process, not just a random variation; so I asked, "How would self-awareness afTect the present formu- lation?" By self-awareness I mean that an individual recognizes and im- poses self-sanctions which are of sufficient intensity to reduce his velocity just as much as do the sanctions imposed upon him by his associates. For this to happen it means that an individual can "meet" himself. Equations (96), (97), (107), and (109) imply that an animal can meet itself. That an individual meets himself means that he must recognize himself. This raises the question of how an individual recognizes himself. One way is by comparison. Considering degrees of difference depicted by Table XIII, an individual can say, "I am at least as different as those 1. The Social Use of Space 151 which possess certain recessive c?-genes that I possess." By this method of comparison with individuals who differ more than he does, an individual can know the entire extent of his difference. This is true for all except the 7iih. ranked omega individual. As may plainly be seen from Table XIII, 7?ii has no basis for comparing his d-gene ^"^j"^ since no other individual shares it. He can only be aware of his divergence including gi^^---g\^^ shared in entirety by Rw. Therefore, by Eq. (107) his SM = 11/2 = 5.50 andby Eq. (108) his V = 2/11 = 0.182 Therefore, by Eq. (113) his n^;-p) = 2.3.33 Using this \'alue in Table XX the x" for the entire group of 11 mice becomes 2.522, which with 10 degrees of freedom has p = 0.99. I realize that this is only one case and I may justifiably be accused of making a "conceptual mammoth out of a mouse." Yet if animals do recognize their individuality, the only confirmation of such recognition can come through observing that the omega individual in an Nh group exhibits twice the velocity or twice the number of contacts he would otherwise be expected to have. It is realized that if the iVj of the iVth ranked animal, the omega in- dividual, is equivalent to that of the (iV — l)th ranked animal, the n^®^^^ for the omega animal will actually be slightly less than 23.33. Likewise the n^^^^^ for all higher ranked animals would be slightly less than stated in Table XV, since N N R=l S=l 2. Sanctions and Facilitations When the target diameters of all members of N are identical, then the S, in the sense of S'^''\ is identical for all individuals and is equal to 1.0. As target diameters vary in accordance with the system illustrated in Table XIII, S increases except for the alpha first-ranked individual. Such in- creases in S mean that the intensity (duration) of the response evoked from others will be greater. Therefore, intensity of response, the i of the prior formulation, will increase by a factor = aS*"'. Let 2^'' represent the intensity of response evoked from every member, 152 John B. Calhoun e, of A^ compatible with one's own »S'''\ Then it follows from Eq. (70) that for the iih individual ,■(«) _ C'C'') S 1 N - 1 1/2 (114) {(V) represents the imposed restraint or sanction. Sanctions in this sense lead to velocity reduction as exemplified by the mice, i^"^ = i'f^ with reference to self action. Where the target diameters of all individuals are identical, Eq. (70) with an AT" of 11 gives an i = 0.316. However, where target diameters differ as given in Table XIII, it may be seen from column 7 in Table XV that S''"^ increases from 1.0 to 5.5. (Here, I am also assuming that the A^'th ranked individual has the same S as the (N — l)th ranked individual for reasons discussed in Section XIV, A, 1.) The mean *S^"^ will be 2.52. There fore, the mean i^"^ becomes 2.52 X 0.316 = 0.816. We are considering intensities of interaction involved during imposition of sanctions in the sense of restraints. Therefore, when we consider any individual in the a responsive state, the other individuals from which it evokes an {'-'"'> sanction-type interaction must be considered to be in the p nonresponsive state since the resulting interaction will not contribute to this individual's satiation from social interaction. Every member, e, of A'', which is in the responsive state, a, will exhibit an i^'f intensity of response toward any ith individual, also in the a responsive state, where iiV = S)'' 1 N - \ (115) i^^^ represents the intensity of interaction of the individual searching for satisfaction. Similarly the mean z^^^ will also be 0.816 instead of the 0.316 which exists when all individuals in an A^ of 11 have the same target diameter. = 0.666 This a^j, represents the mean frustration-type refractory period resulting from the imposition of sanctions in an A^ = 11. Since when all individuals have the same target diameter, z^ = (0.3 1 6) ^ = 0.1, hierarchy formation increases the average amount of stress more than sixfold. No wonder that the i^gi elicited from others became so eflFective in reducing velocity so that each individual's m again equals 1.0. That is, r^S" = 1.0. Although 1. The Social Use of Space 153 intermittent application of sanction, t^''^ may be required to reinforce the V behavior, sanctions still must be primarily a phenomenon of hierarchy formation or role assumption. When two individuals, x and y, are both in the a responsive state, their resulting interaction, ii^H^^^ will lead to a satisfying aaa refractory period. Being in the responsive state implies a need for satisfaction from social interaction. Furthermore, during such interactions each must be focusing its attention on the S^'^^ aspects of the other's target diameter. In like fashion, when individual x in the responsive state approaches 2j in the non- responsive state, X exhibits behavior appropriate to ys *S^^\ while y retaliates with a response appropriate to x's *S^"\ One individual which is in the responsive phase will have its behavior toward another judged by the latter as appropriate or inappropriate, de- pending upon whether or not the individual approached is also in the re- sponsive state. Appropriate social behavior becomes synonymous with what I have termed "dominant (/-genes." These behaviors must be ap- propriate both in form and in timing, such that the approached individual will be in a similar need state for obtaining satisfaction from social inter- action. Even though a social behavior may seem appropriate with regard to form, if the timing of its expression is not harmonious with the refractory nonresponse state of the individual approached, then the approached in- dividual will judge this behavior as being inappropriate. Inappropriate- ness in this sense becomes what I term a "recessive c?-gene." In a perfectly random system, with all individuals exhibiting identical behavior with regard to its form, some individuals will by chance more frequently encounter others who are in a refractory nonresponsive state. Thus, such individuals will be responded to by their associates in identical fashion as they would have been if the form of their behavior were actually inappropriate. To the degree that such structurally appropriate behaviors fail to be reinforced by similar behavior from associates, they may be ex- pected to vary in some random fashion until their form becomes relatively distinct from the original. To the extent that these alterations in behavior become established, they represent clearly recognizable recessive d-genes. Due to this modification of behavior S^''^ will increase and S^^'^ decrease, so even when the approached individual is also in the responsive state the approaching individual will experience less satisfaction from the inter- action than it would have had these random processes not transpired. Once M becomes restabilized to 1.0 following the reductions in velocity accompanying hierarchy formation, it will then be possible for two in- dividuals, each in the socially receptive a state, to encounter each other and mutually contribute to each other's need state by an i^^H^^^ - ««» interaction. In this case, each individual's own i^^^ represents its searching 154 John B. Calhoun for social satiation, while the other's i'^^ represents a social facilitation, the opposite of a social sanction. I shall leave the concept of social facilitation at this theoretical level without seeking empirical confirmation. However, excellent data have been presented by Aloreno (195o; Moreno and Jennings, 1960) which permit an exploration of the probable validity of *Sj-'^', Eq. (92). B. The Choosing of a Partner We have already seen that >S.^"), Eq. (107), and Si^\ Eq. (109), relate to those response-evoking capacities of an individual's target diameter which determine the intensity with which associates will respectively im- pose sanctions or facilitations. S\-'^\ Eq. (92), and S^^^ Eq. (93), like- wise represent aspects of one's target diameter influencing the response of others. One's own S'-'^^ determines the probability of being chosen by others as an appropriate object for social response, while one's own S'^"^ similarly determines the probability of being rejected. No doubt there are excellent empirical data for testing the validity of S'-'^K However, I shall confine myself to S'-'^''. If I can show the likelihood of aS^^^ being an approximation of reality, it follows that «S^°^ can be similarly justified as a concept. Moreno (1953, 1960) presents a set of data for which there has been no adequate formulation of their origin. In seven cottages each containing exactly 26 delinquent girls, he asked each girl to choose three others in their own cottage whom they would most like to sit close to at the dining table. This instruction presents marked complications in determining whether Eq. (105) wall account for the observed results. However, Eq. (105) includes the possibility that one wdll choose oneself as a partner; that is, one will choose to eat alone. Moreno by his instructions excluded this possibility. Further, Moreno's instructions precluded the possibility of choosing the same person two or three times, which Eq. (105) permits on successive independent choices. Dr. Clifford Patlak worked out for me the full set of equations required to determine how many times each in- dividual would be chosen, considering Moreno's restrictions, after the probability, p, of being chosen was calculated by Eq. (105) for each iih individual in an N = 26. Moreno's restrictions so complicated the calcula- tions that it was concluded that a simple lottery would adequately test the applicability of the present theory, and at the same time avoid the time-consuming job of developing a computer program to the same end. This was done as follows: 1. Sl''^^ was calculated by Eq. (92) for each of the 26 members of N, from Si'^'> for the alpha-ranked individual to Sii^ for the omega- ranked individual. 1. The Social Use of Space 1^5 2. Then the p of being chosen was calculated for each individual by Eq. (105). For example: p(-4) = 0.152, Pi'^ = 0.121 p1^^ = 0.092, p[V = 0.039 pir = 0.012 3. We then prepared 1000 -pi tokens for each individual. 4. All these 1014 tokens were placed in a large glass jar. For any "in- dividual" to make three choices, three squares at random were picked out. If an "individual" picked himself, the token was returned to the jar and another "choice" made at random. Similarly, if another individual was chosen twice, one of the two tokens was returned to the jar and another selection made until each "individual" had chosen three different "others." Between drawings all tokens were returned to the jar and the contents mixed. Each such test consisted of 78 "choices." At the end of each test it was possible to tally how many of the 26 "individuals" had never been chosen, chosen once, chosen twice, etc. 5. Fourteen such independent tests were performed and the mean number of individuals in each choice category was calculated. This mean represents an estimate of the expected. These data in Table XVI are plotted in Fig. 36. A smoothed curve ap- proximating the means of the observed and the lottery presumably ap- proximates that conforming to Eq. (105), considering the restrictions im- posed by Moreno. This smoothed curve is called "theoretical" in Fig. 36. Each of the two sets of points varies so closely about this curve as to pro- vide confirmation that my formulation is adequate to account for the ob- served sociometric phenomenon of choice. IMoreno and his associates make much of the chains, triangles, etc. of reciprocal or nonreciprocal choices that became apparent in such a socio- metric system. While such patterns may become fixed realities, there is no reason to attribute any condition other than chance to their origin. C. The Response-Evoking Capacity Circuraplex Schaefer (1959, 1961) presents a conceptual model capable of describing the attitudes, personality or behavior of an individual in a two-dimensional space. This latter is determined by two orthogonal axes of polar opposites. As may be seen in Fig. 37, one axis consists of the polar opposites love and hostility, while the other is represented by control and autonomy. About 156 John B. Calhoun Table XVI Empirical and Theoretical Data Regarding the Choosing of a Partner Mean number of individuals "Theoretical" mean of Times chosen A B Moreno (1953, Present Lottery A and B 1960) based on S^"^' 0 5.00 5.36 5.18 1 4.15 5.36 4.76 2 4.29 3.82 4.06 3 3.72 2.29 3.01 4 2.29 2.50 2.40 5 2.00 1.79 1.90 6 1.14 1.50 1.32 7 1.43 0.86 1.15 8 0.86 0.72 0.79 9 0.57 0.57 0.57 10 0.14 0.50 0.32 11 0.43 0.36 0.40 12 0.00 0.29 0.15 13 0.00 0.07 0.04 (5 k 1 A 1 1 ' 1 1 1 1 { 1 1 "Theoretical " 1 1 5 ^.^ • ▲ Moreno 1953 Lottery — CO ^ 4 • x! o > \ • \ ^ 3 u. o CE LU OD i 2 N 1 - \ 1^ • V5 ^^^^^ • — n 1 1 1 1 1 1 1 1 1 Vl^-i- i 0 5 10 T TIMES CHOSEN Fig. 36. The choosing of a partner. Moreno's empirical data are compared with a lottery conforming both to Moreno's procedure and the probabilities of being chosen as predicted by Eq. (105) in the present paper. 1. The Social Use of Space 157 or within the circle determined by the extremes of these polar opposites, the typical characteristic of an individual may be oriented. There exist remarkable similarities between Schaefer's model and that implied so far by my concept of response-evoking capacity, S, and the resultant or concomitant change in the behavior of the individual, such as reflected by change in velocity. *§<'■', S^^\ S^"^', and S^"'' represent factors not specifically treated by TM. QUADRANT Choleric " Ouorrelsomness Irritability Impulsive Aggressiveness Delinquent I SJ- QUADRANT Songume " Intellectual efficiency Social participation Friendliness Leodership (HOSTILITY ) REJECTION (ii)s'°> (LOVE) ACCEPTANCE Ego strengtit Sympathetic Trusting 3 RD. QUADRANT ' Melancholic " Schizophrenio Psychosthenia Social withdrawal CONTROL Introversion Repressed anxiety Social opprehensiveness Neuroticism 2 ND. QUADRANT Phlegmatic" Obedient Conscientious Fig. 37. The circumplex depiction of behavior and personality superimposed upon the coordinates of response-evoking capacity, S. Schaefer. They relate to his formulation as follows: They represent those characteristics of the individual that determine the probability of accept- ance or rejection as a social object and that determine the kind and in- tensity of response elicited. Schaefer considers the second logical step, the evoked response, such as the mother's response toward her children. He also considers the third-order phenomenon, that of the personality de- veloped as a result of being the target of such responses. I shall now attempt to place these throe orders of phenomena in perspec- tive. For an A^ = 11, S^'-'\ S^^\ S^^\ and S^"^ were calculated by the 0.091 1.000 1.000 0.000 0.166 0.166 0.244 0.220 1.000 0.000 0.030 1.000 158 John B. Calhoun above equations. These values were then recalculated as proportion of the maximum value. For examples, see tabulation. Similarity rank S'"' S^^ S^^'> S(«) 1 6 11 /S*"^ and iS^^^ with values of 1.0 form polar opposites, as likewise do ^S^-^^ and aS^"\ These polar opposites are shown as a two-dimensional co- ordinate system in Fig. 37. The four "response-evoking capacity" coordi- nate points for each individual are connected by lines. Thus, a square may be delineated for each ranked individual which represents its "life-space" with regard to eliciting responses from associates. Schaefer's two-dimensional circumplex description of behavior and personality replaces the relative intensity values of my axis of correlation coefficients. In most comprehensive sets of measures of behavior or per- sonality, he regularly found that two measures which can be equated with the terms love (acceptance) and hostility (rejection) are highly negatively correlated and so form polar opposites which may thus be plotted as polar coordinates at 180 degrees from each other. Similarly, concepts identified by the terms "control" and "autonomy" form polar coordinates opposite each other. Control and autonomy have zero correlation with acceptance and rejection and so the control-autonomy axis lies at right angles to the acceptance-rejection axis. From the center zero point each of the four axes extend outward to represent a maximum correlation coefficient of 1.0 at its extremity. Every other concept in the set is then correlated with each of the four "key" concepts. It is regularly observed that every other con- cept in the set has positive correlations with two of the neighboring polar concepts, and so each may be plotted in this two-dimensional behavior- personality field. Such points approximately fall on the circumference of a circle inter- secting the polar coordinates. Schafer calls such a set of points a circumplex. His schematic representation of types of maternal behavior is shown by dots in Fig. 37. Terms connected by arrows to these points denote various kinds of maternal behavior. These maternal behaviors are the types I would anticipate as being directed toward, and derived from, the response- evoking-capacity circumplex determined by *S^^\ ^S^^^ S^^^, and >S^"\ Schaefer also reviews many studies by others which harmonize with this conceptualization of behavior and personality. I have included selected 1. The Social Use of Space 159 terms in boxes which carry the "flavor" of what each pole or each t^uadrant represents. It will be noted that the response-evoking-capacity life-spaces of the members of any group, as I have described their origin, mainly fall in the first and third quadrant of this two-dimensional space. I shall, therefore, call these two quadrants the "primary life-space." We may inquire how individuals become identified with the other two quadrants, the second and the fourth, which may be called the secondary life-space. INIy colleague. Dr. Kyle Barbehenn provided the solution. In examining Table XIII he noted its bilateral symmetry with reference to dominant and recessive c?-genes. In any group recessive d-genes merely represent degrees of divergence from some ideal prototype. The alpha-ranked in- dividual possesses only dominant prototype characteristics, whereas the omega-ranked individual, except for commonly held (d) traits, possesses only divergent and therefore recessive d-genes. But suppose in the history of the group some circumstance led the omega's associates to consider his characteristics as being more desirable than the alpha's. Such a change in attitude would reverse the roles of all individuals, except for the median- ranked individual. The individual who formerly was socially withdrawn and had a low velocity would immediately become a high velocity in- dividual, participating in many social interactions. Likewise, the former alpha individual would become the omega one, losing his "leadership'' role and becoming socially withdrawn. This transformation of recessive rf-genes into dominant ones, and vice versa, will still place most of the individuals again within the first and third quadrants of the circumplex life-space. The critical question involves the transition period. In this transition Eqs. (92) and (93) change roles with reference to their application to dominant and recessive c?-genes, as like- wise do Eqs. (107) and (109). There arises the hkelihood that previous to this transition choosing and rejecting will be a more predominant activity than controlling or granting autonomy. If so, S'-^'' will switch to pertain to recessive rf-genes and /S^"^ to dominant d-genes while *S^^^ and S^"'' will retain their orientation toward dominant and recessive c?-genes, re- spectively. Or the reverse could happen if the group were primarily oriented toward the control-autonomy axis. The consequence of these changes are summarized in Table XVII. 1. Shifts into the Second and Fourth Life-Space Quadrants BY Rats No intent is here implied of proving the validity of the general formula- tions. All I have hoped for is to evolve a logical and reasonable formula- tion that may later pro^'e to be a fair first approximation of processes that 160 John B. Calhoun do in fact exist. This elaboration of Schaefer's circumplex life-space im- mediately brought recall of a striking transitory change in behavior which regularly occurs in structured, dense, socially closed systems of domesti- cated Norway rat populations. When these populations have been permitted to attain a density of 60 to 100 adults in a space ideal for 40 or fewer adults, an extremely rigid social structure develops. All rats "know" their place and aggressive ac- tions terminating in some individuals receiving even moderate-sized wounds become markedly reduced. Threat and avoidance becomes the predominant pattern where aggression and imposition of sanctions di- Table XVII Change of "Attitude" toward d-GENEs Affecting Shifts into the Secondary Life-Space of the 2nd and 4th Quadrants Initial change cZ-Gene Interaction of involved neighboring poles Quadrant 5'"*^ oriented to recessive Recessive Control-acceptance 2nd involves dominant d-genes. Their low velocity indicates that now as adults S^^'> also involves dominant d- genes. They are rats for whom we may infer that their associates have always been "overindulgent" and "overprotective." Such rats are quite fat and have relatively small adrenals, ventricles, and kidneys. Though they exhibit some displaced sexual behavior, their "personality type" is one most characteristically involving failure either to elicit or initiate social interaction. They are types lacking social involvement. This brief discourse on rat types suggests that my elaboration of Schaefer's (1959, 1961) circumplex behavior-personality complex may prove to be a fruitful framework for pursuing studies in comparative social psychology. D. Conformity, Withdrawal, and Creativity When N increases above Nb or n increases above jU6 it has been shown that fragmentation of N to appropriately sized discrete subgroups may lead to reacquisition of 6^°^ and 6j°\ Even when A^ remains at Nb, the unavoid- able variability in the four types of S leads to yu differing among members of the group. Reduction of v as S'-''^ increases enables the individuals to prevent excessive increments of 6/ above d'/\ Even so, many individuals with reduced v must experience either reduced da or excessive Of. We may inquire as to possible avenues for escaping these deviations from dj^"'' and 6^/'> without leaving the group. 1. The Social Use of Space 163 For those individuals who in their behavior do not differ markedly from the alpha-ranked, Ri, member, there exists the possibility of adopting the outward behavior of Ri. Such acquired conformity should permit eleva- tion of velocity to basic levels and should produce a discontinuity in the range of velocities observed among members of the group. Whyte (1956) in his "The Organization Man" has emphasized the role of conformity as an adjustive mechanism accompanying increases in A''. At the opposite extreme of original behavioral divergence there exist individuals with such reduced velocity that their contacts with higher- ranked individuals proves insufficient to permit their developing conformity through emulating the behavior of their superiors. Recently I have had the opportunity of studying the behavior of all members of three populations of domesticated Norway rats for every member of which assessments of velocity had been made. Low-velocity rats develop the capacity to move about without engaging in interactions with their associates. They rarely initiate interactions nor do they elicit actions from associates. This social withdrawal becomes so complete that, despite being in the presence of many associates, they are characterized by small adrenals and small ventricles, just as are rats which have lived all their lives as members of A'''s of 3. David Riesman et al. (1953) has movingly described such isolation and oblivion of surroundings among humans in his "The Lonely Crowd." In between the velocity levels producing conformity and withdrawal, there lies a narrow but important range of velocity permitting a process which can terminate in creativity. Why this is so requires recall that ac- cording to my model or social interaction, interaction with self must be included along with interaction of self with others. One can choose oneself, one can reject oneself, one can facilitate one's own behavior, or one can restrain or impose sanctions on one's own behavior. All are possible. Consider sanctions. These are mostly the i['i' , Eq. (114), of others directed against oneself. Let i^"'^ represent self-sanctions. The self-inter- action becomes: N - 1 l/2\2 = ^ ' ^ (116) N - 1 The lil"'^y, which initially solely represents self-control but may evolve into creativity, is proportional to [ij^"'^]-. As may be seen from column 7 in Table XV, the intensity of this self-control mounts ever more rapidly as lower ranks in the hierarchy are approached. In so long as self-interac- 164 John B. Calhoun tion only represents self-control, there can be no creativity. However, in this system what were recessi^•e c?-genes can become considered as dominant d-genes. When this happens for the whole group, a complete reversal of the social rank ordering develops. But such reversal can also take place within a single individual. In essence, this means that [ij-"'^]", which is equivalent to an a'^p frustrating experience, became transformed into an [^i^'^]"; which is equivalent to an aaa satisfying experience, without losing any intensity in the process. There need not be any outward manifestation of this transformed self- control. \_i\^'^^ only implies cortical associations among stored traces of external events lacking any aura of negativism. Other than this, there are no limits to the kinds of traces which may by chance attain a high condi- tional probability of association. External manifestation of p,-^'^]", that is creativity, implies sufficient contact or awareness of external events to permit symbolic or behavioristic alteration of the enivornment in harmony with these heightened conditional probabilities of association, [z'i^'^]- must not be confused with learning. I shall not attempt to go into the ques- tion of learning here other than to say that it should be most effective in high velocity individuals. It is well recognized that a feeling of ecstasy, of extreme well being, ac- companies any instance of creativity. A unit of ^^°^ arising from a single interaction represents such ecstasy. Recall that di°'> = 0.25. Examination of Table XV reveals that not until R^. is reached in the descent through such a hierarchy of A^ = 11 individuals will li^-'^J = IS^/^J/iN- 1) exceed 0.025. It will exceed 0.25 for Rs • • - Rn in an A^b = 11. And yet I have already indicated that some of these, probably at least the last two, will be so withdrawn from reality as to preclude any opportunity of creativity. At most, we can therefore anticipate only 2/11 or 18% of the group to possess potentialities of creativity. As N increases, proportionately more individuals will accommodate by social withdrawal and relatively fewer will possess potentialities of creativity. Realization of these potentialities requires another set of conditions, opportunity for having made many satisfactory accommodations to new configurations of stimuli. As discussed in the later Sections XIV, G, 1 to 3, this means that there must have transpired an increase in one's psycho- logical area. A", as a compensation for the reduced A associated with a lowered v. E. Velocity and Home Range In my search for adequate formulations of the social use of space and time I have been guided by several competent mathematicians. With 1. The Social Use of Space 165 regard to home range, Mr. James U. Casby (see Calhoun and Casby, 1958, pp. 16-17) derived a function, K/'Iira^-. He called this term "visita- tion frequency." It describes the relative frequency of visiting a particular place in the environment. Later, though published earlier (Calhoun, 1957), Dr. Murray Eden derived the function, ^l = dv/A to represent a communi- cation function defining the relative probability of one individual meeting another. K/2Ta~ concerns arrival at a stationary point, while dv/A con- cerns arrival at a moving point. It was only after I began this elaboration of concepts concerning social use of space that I realized the isomorphism of these two functions. A and 2ira^ become equivalent expressions as like- wise do K and dv. d here is used in the sense of S'~''\ Eq. (107). I have already pointed out in the discussion pertaining to Eqs. (35), (80), and (88) to (91) that when a group is in a steady state in harmony with its heredity and environment, m = 1.0, provided appropriate units of time are considered. It followed that v, S^'^ and A also have relative values of 1.0 at Nb, the harmonious steady state TV. Therefore t;*S(^V27rc72 = 1.0 (117) Given this relationship, can it assist us in determining relative home range 0-? We have already seen in Sections VI-VIII that contractions and ex- pansions result from both intraspecific and interspecific interactions. Let us consider home range of members of a constellation as discussed in Sec- tion VIII, C. On the average the constellation consists of one alpha, 6 beta, and 5 gamma individuals, ranked in this order: Nb = N. + N0^ Ny, where N^ = 1, N^ = Q, Ny = o. The a individual represents the ideal prototype. Each beta diverges an equivalent amount from the alpha. Like- wise, each gamma also diverges from the alpha, but more so than the beta. By analogy to the discussion pertaining to Table XIII, the rf-genotypes of the 12 individuals in a constellation will be represented as shown in Table XVIII. as in the table denotes alteration in the home range a resulting from the individual's S'-''\ The Ni for the alphas, betas, and gammas, according to the formula- tion of Section XIII, B, 5 become respectively 12, 11, and 5. From Eq. (107) it follows that their S^''^ are, respectively, 1.0, 1.091, and 2.40. This increase in response-evoking capacity, S^''\ among beta and gamma individuals will lead to their reduction of velocity, v, respectively to 0.9167 and 0.4167, as given by Eq. (108), when compared with v = 1.0 for the alpha member. 166 John B. Calhoun In terms of home range the aS'^'^ function in Eq. (117) may be ignored, which means that: l^/27rc72 = 1.0 (118) For this relationship to maintain in the face of reduced v for beta and gamma individuals, a must correspondingly decrease, such that a = (y/27r)i/2 (119) Since 2t is a constant we may ignore it for the purpose of determining Table XVIII Relative Home Ranges of Constellation Members Constellation member d-Genotype N-, v (Eq. (lOS)) been calculated, as would have been represented by a straight line connecting these extremes on Fig. 38, it is quite obvious that the observed w^ould differ significantly from the ex- pected. One could drop the inquiry at this point and conclude that veloci- ties for rats do not accord with theory as for the mice cited in Section XIV, A. However, there are two reasons for not dropping the inquiry at this stage. First, 32 males represent an V almost three times the theoretical basic N, Nb = 12 while the A" = 11 for the mice closely approximated this Nb. Second, the regression curve of velocity for the lA and 2A males con- verge at the omega-ranked individual. Furthermore, this convergence is at a velocity 6 to 8 times that anticipated by Eq. (113) . This fact suggests a minimum velocity, Vm, below which rats cannot reduce their velocity and long survive. Two such individuals with excessively reduced velocity are shown on Fig. 38. I can only say that, on the basis of the very few individ- uals which did develop such unusually low velocities, such individuals usually become bloated and usually shortly died. Accepting the indication of the reality of Vm, is there a logical basis for recognizing its relative value? In the course of evolution, where the group becomes adjusted to an Nb, there will in any stabilized group be an Nb- ranked omega individual. In terms of Eq. (107) it is readily apparent that, where R = rank in the sense used in Table XIII: Ni = 1 -\- (N - R) (121) Therefore, for any ith. individual where i is equivalent to its rank R, Kq. (108) becomes Z. The Social Use of Space 171 Since the rank, Ra, of the omega individual is A^;,: Va = Nt (123) Since Vn is the lowest velocity achieved in the normal Nb selected by evolu- tion, Vq most likely also represents v,n. Given a v,„ observed, y£°^^ we may calculate a v^J^'p^ appropriate to Nb. Recall that from Eq. (108) v^'^^^ in relative terms = 1.0 and the relative velocity, v^'^^\ of any other ranked individual is by this equation represented as proportions of the alpha's velocity, v^^^^^ or v^^^''^ from Fig. 38 is 12. Therefore 12 = v^'^^^ i(exp) And thus at Nb, and utilizing Eq. (123) : yCexpat.Vft) = ^(obs) /y (rel) — y(obs) ^ jy^ (124) However, solving Eq. (124) requires that Nb be known. The rats used were a domesticated albino strain, Osborne-Mendel. Nb still might be 12, as we can expect it to be for the wild type, but we have no way of knowing directly how domestication has altered Nb. Furthermore, the artificial environment imposed possible changes on the area. A, factor in fj. = dv/A. So all that can be expected is that there is some optimum A^, No, har- monious with the existing spatial structure of the environment and any changes arising through domestication. Now, using Nb in the sense of A'',,, values in relative (rel) terms become: For N ^ Nb, R = l:v„ = 1 For A^ = A^6 or iV < or > Nb, R = Nb or A^: vq = Vm = l/Nb 'N - Nb For N > Nb, R = I: vj'^^^ = 1 - A^ (1 - v„,) (125) When A^ = oo : y„ = t;^ = 1/A^6 The general equation for v, where v„ = 1/A^6, and R = velocity rank becomes: _ {1 _ [(jV - A^,)/A^](l - vj] A^ - 1 ,(rel) R - N + v„, (126) 172 John B. Calhoun Assuming the validity of all assumptions inherent in Eqs. (124) to ( 126) we can now approximate the No of the lA society of rats. The regres- sion curve for lA shown in Fig. 38 gives v^°^^^ = 38. Insertion of successive values of Nb in Eqs. (124) and (125) shows that when No = 9, yjexpatA-6) = 1Q8 and z'i-^^" = 0.36. Since 0.36 X 108 = 38.9, it follows that, for the strain of rat under the existing environmental conditions, 9 individuals approximate No for male rats. Now we may return to the "tranquilizing" effect by which vitamin A "buffered" the 2A males from the velocity-inhibiting consequences of A'' > Nb. There needs to be a correction factor in Eq. (126) which, as a "tranquilizing" factor, Z, increases the slope of the velocity — velocity rank curve also increases, "pivoting" about Vm. At present there is no r\ IBJ \ /V--/^ N Varies / -- 0 0 "^^A^-'i"* 1 1 N'48 I 1 I Z v-0.5 Fig. 39. Hj^jothetical effect of group size, A^, and tranquilizer, Z, on velocity, v, when A'^6 = 12. a -priori basis for determining this Z factor, which can draw upon empirical evidence. However, one can visualize a likely formulation of Z. Z implies a factor "blinding" awareness of the d or ^("^ of associates. Such perceptual blinding conforms with the cV factor of ix' = d'v'/A', previously alluded to. The critical issue concerns the influence of Z upon r„. If the velocity of the first-ranked alpha individual never exceeds that appropriate at Nb, that is, if : = I'M = 1.0, (A' 6) = then we would have a partial basis for understanding how Z alters v. In the absence of adequate empirical data regarding the function of Z on V, consideration of hypothetical relationships (Fig. 39) will facilitate our understanding to the point of enabling the design of critical experi- 1. The Social Use of Space 173 ments. First consider Eq. (125). Increasing A^ reduces v of all members. By the time N is only a few times Nb, velocity of all members will be so reduced as to bias the probability of the social system surviving. Minimal velocity implies withdrawal from social interaction and restriction of activities to independent acciuisition of food and water. Now, assuming a vm, even though it might exceed 1.0, Fig. 39 suggests that increasing Z will eventually elevate Va to Vm, while v^ remains at Vm as shown in Fig. 38. Once Va reaches Vm, further increase of Z should reduce awareness of the ^^"^ of others to the point that vq departs from Vm and begins to approach vm- At Z = 'x , v^ = Vm. Far before Z = cc , the velocity of all members of N will be maximal for all practical purposes. A state of maximum conformity will then have been attained in which each individual views every other one as so like himself that no individual imposes re- straints on the actions of any associate. All social organization must col- lapse, leaving a state of maximally moving independent particles, the random contact between any two of which will be eciually satisfactory in consummating any interaction in which two individuals are necessary. This state demands equipotency of capacities. Complexity of behaviors will be limited to that degree possible by every individual having identical learning experience. Maximizing Z becomes incompatible with a high state of learning and culture. The human species appears to be embarked upon a journey of both maximizing A^ and maximizing Z. If we are to avoid one of the other of the nirvana-like states of uniform v^ or Vm, it behooves us to seek further insight from experimentation with animal groups. Returning from theory to reality, we may consider some correlates of velocity. Alost of the lA and 2A rats discussed above survived to autopsy during the 17th month of the study. Each set of males was divided into five velocity class intervals, with as nearly as possible the same number of rats in each velocity range. Associated conditions are graphed in Fig. 40. As velocity increases, the amount of scar tissue derived from fighting increases. The somewhat S-shaped character of this curve conforms with historical events. In general, the more rats withdrew from social interaction by reducing their velocity, the fewer wounds they received. However, a few individuals, though having a very low velocity in late adulthood, were characterized by extensive scar tissue because they failed to withdraw as early in life as had their low velocity comrades. At the other extreme of velocity, territorial males or highly dominant individuals, who were territorial in the time dimension but not in space (i.e., the "changing-of- the-guard" phenomenon through which several males share the dominant role in a particular area) , by their status avoided attack and thus avoided being wounded even though they were extremely active and inflicted 174 John B. Calhoun wounds on associates. Their lesser degree of scar tissue contributed to a reduction in the mean scar tissue index for high-velocity males. Weights of adrenals, kidneys, and heart all tend to increase as velocity increases. Despite lack of histological studies, what I suspect has happened is that as velocity drops as animals withdraw from social interaction, organ size decreases in accordance with decreased demands made upon them. 20 30 40 VELOCITY Fig. 40. Some major characteristics of rats affected In-^ conditions that determine velocity. Fig. 40(B) simply shows the product of the weight of these three differ- ent organs. Most sensitive to velocity and easy to measure is fat. Fig. 40(C). Fat here represents those abdominal deposits most easily removed: the dorsal lumbar-sacral deposit, that in the genital mesentery, and those in the mesenteries of the gut. Though these deposits are rarely as large among males as for females, it is nevertheless quite clear that as rats slow down by social withdrawal they exhibit greater propensities for converting food- stuffs into fat. 1. The Social Use of Space 175 G. Exploratory Behavior Ultimate exposure to some new configuration of stimuli represents the common factor in the three phenomena encompassed by the term, "ex- ploratory behavior." These three phenomena are: (a) the rise and decline of a hyperactive state following exposure to a new configuration of stimuli (see Section III, A, 4) ; (b) the rejection of new configurations (see Sec- tion III, A, 3) ; and (c) the seeking of new configurations. We shall now examine how the opportunity for expressing such behaviors alters an in- dividual's attitude toward its physical and social environment. 1. The Hyperactivity Phexomenon In an animal's normal habitat this phenomenon may be anticipated to follow an encounter with a new configuration of stimuli at places in the normal home range where it has not occurred during customary travels. Field studies directed toward the elucidation of the consequences of such encounters are essentially nonexistent. Pearson (1960), by photographing marked mice as they move along their trailway systems, has found that, following the experience of being trapped and handled, mice not only be- come more active but also visit places within or near their normal home range which are normally infrequently visited. My study of the reaction of domesticated Norway rats following exposure to an activity alley (Sec- tion III, A, 4) represent this same type of situation with the exception that the induced state of hyperactivity must take place in the presence of the new configuration of stimuli represented by the alley. Recall that the rat is placed in a compartment with an access door at one end of the alley. It does not have to enter, but many rats do so rather immediately. For example consider the 73 rats involved in the analysis of distance of termination of trips shown in Fig. 3. Analyses (Fig. 6) have been made of their hyperactivity during the initial 2.5 hours of their resi- dence in the activity alley. From an initial high level, activity declines exponentially over an approximate 3-4 hour period nearly to a base level maintained on the average through each of the 12 hours of normal height- ened activity during the next 3 days. This pattern is shown diagram- matrically in sketch (1) of Fig. 41. Such heightened diffuse motor activity lacks any aura of goal direction and will be designated by the symbol, DMA. Such a configuration of new stimuli as is represented by the alley will be designated as E. If a rat is placed again in the alley for 2 hours on each of several consecutive days, no appreciable amount or duration of DMA occurs on any day. This means that there has transpired an adjust- 176 John B. Calhoun ment, A, to E by the end of the initial 2 hours of exposure to E. After A, motor activity persists on the average at a base line intensity, b, unless some other new configuration E is encountered. Thus, DMA represents increments of activity above b. In the alley, E can only include nonsocial physical stimuli. And yet in a social milieu of others of an animal's own species, the responses of an as- sociate also represent an E. Provided such a social E has not previously (1) log GSS Th- log DMA b- "_v^ (2) log DMA ^ X Tob • -Th Drift fa- I— 7— "op 4— t (E,)2 t XE, Time log (3) t \ \ t No chonge in threshold GSS < \ t} aop ♦ ( log DMA ao"p"'| dMA 1 b- Jap \ aop * 1 i "■ t A, t E2 2 E 3 t 2E4 A4 (E \ t Eg EjRemoval to home cage DMA DECLINE ONLY IN HOME CAGE, THUS NO A ADJUSTMENT TO E3 Removal to home cage DMA DECLINE ONLY IN HOME CAGE, THUS NO A ADJUSTMENT TO E4 Fig. 41. Adjustment to configurations of stimuli. See text for comment. been encountered or if the associate is in the nonresponsive, [p], refractory state, then the latter's behavior, though perhaps experienced before, amounts to a previously unencountered E in the sense that it does not permit directed motor activity leading to a satisfactory refractory period by the other individual involved in the encounter. For this reason, it will here be presumed that the period of decline of hyperactivity is equivalent to the Gap frustrating type refractory period involved in normal social intercourse. 1. The Social Use of Space 177 If rats are maintained in isolation for several weeks or months and then placed in an emotional activity alley, a large proportion of them never go out into the alley from the "home" compartment. From this I infer that there is some upper threshold, Th, of DMA which "overloads" that neural circuit permitting its expression. The three dots in sketch (2) denote such overbadings. In any sample of subjects, most of whom avoid entering the alley, there are a few with various lengthened latencies, causing delays of up to nearly the end of the 2-hour test period before initiation of the initial phase of intense hyperactivity. From this fact it is apparent that the normal DMA becomes replaced by some generalized stress state, GSS, which follows a similar (but lower?) rate of decline than the DMA. GSS lacks a striated muscle component. Once it has dechned to Th, GSS becomes transformed to DMA. Such subjects, owing to their having been protected from impinging external stimuli for such a long time during their isolation, view the alley configuration as an increased intensity, E. An inference from this is that there is a slow drift downward of Th toward 6 during the weeks of isolation when opportunities for adjustments Ai • • • An in response to El • ' • to En are absent. Thus, depending upon how extensive this drift has been, any particular E, such as represented by the activity alley, raises the GSS different amounts above Th. I suspect, though my data are not conclusive, that the more elevated GSS is above Th the lower will be its rate of decline. These differences are diagrammatically shown in sketch (2) of Fig. 41. Given sufficient time with no interference by other E's, DMA will eventually reach h and an adjustment, A, transpires. Now we may consider the more normal coiu-se of maturation, experience with a sequence of ^i • • • En [sketch (3) in Fig. 41]. One general observa- tion first. The greater has been the experience of rats in the sense of a larger number of different E's to which adjustments, A, have been made, the lower will be the probability of withdrawal in the form of failing to enter the alley from the starting "home" compartment. An explicit experiment concerning this point has already been cited with reference to Table lb. Such results indicate an elevation of Th to Tha following each A, and this elevation will be proportional to the magnitude of E provided E does not elicit a DMA exceeding Th. Thus, at some later time an intense E, desig- nated as 2Ei in sketch (3), will result in adjustment Ai, although had a 2E configuration occurred earlier it would have resulted in the undesirable consequences accompanying elevation of DMA above Th. There is another conclusion, somewhat more tentative, though some of my results do sup- port it. This is that with each successive E, the rate of decline of DMA increases. In other words, the aap refractory period decreases. Thus, the more adjustments an individual makes, the better he will be al)le to curtail oif„p = df. I have already mentioned the failure of a second exposure to a 178 John B. Calhoun particular E to induce any material increase in DMA. This means that if E merely represents a configuration of strange stimuli with which the individual can interact in no meaningful way, the second exposure to E, that is (£'1)2, will evoke no response. (£"1)2 will merely be ignored. However, if some aspects of the Ei configuration permit meaningful interaction, then (£'1)2 will result in an interaction having an «„„ refractory period proportional to the evoked directed motor action, dAIA. This a„„ will normally be of shorter duration than a„p to (£"1)1 since some components of the configuration are likely to be irrelevant to dAIA. Furthermore, dMA may be expected to be maintained at near its initial intensity until the evoked behavior terminates. No further elevation of Th accompanies (£1)1 ••• {Ei)n. Persistent recurrence of any specific E merely serves to prevent the drifting downward of Th. Each adjustment to a new E configuration resulting in an elevation in Th represents a contribution to the individual's psychological area. A" . 2. The Seeking of New. Configurations Consider two groups of individuals, A and B, of which the members of each for a fairly long period merely reexperience particular sets of £"s. Members of group A differ from those of B in that they are exposed to a larger assembly of different £"s. Two such groups have been considered in Section III, A, 5 and Table I la. The fact that more of the A-type individuals entered the alley when exposed to this new E configuration of stimuli in- dicates that reexperience of a larger assembly of different £"s does maintain Th at higher levels despite some downward drift. The A-type individuals obviously have a larger psychological area. A", than the B-type ones. A" essentially connotes capacity to adjust. In any environment presenting frequent necessity for adjustment, a high A" will prove advantageous. So we need to consider the question of maximizing A" . Persistence in repeated interaction with certain £"s is necessary or de- sirable because of acquired reward value accompanying the directed motor activity, dMA, appropriate to these £"s. Such dMA can only preserve Th at a given level. Response to these £"s involved in this dMA consumes time. If all w^aking time becomes relegated to dMA-evoking £"s, the individual will develop a static A". Furthermore, the more waking time becomes filled with repetitions of response to any given E, the more restricted will be A" . It is thus obvious that the best strategy for maximizing A" will be to reserve a portion of one's waking hours simply for responding to new £"s. Some as yet unknown but probably fairly long time, certainly of the order of several days even for rats, must elapse between one exposure to such a new E and a reexposure, permitting sufficient extinction of the A 1. The Social Use of Space 179 adjustment so that at the re-exposure the E eUcits a DMA comparable to that of the initial exposure. Because of the limitations of time and space in which any individual's activities must transpire, maximizing A" demands an active seeking of new £"s. This seeking, I term v". It represents a kind of velocity difficult to distinguish from the normal velocity, v, unless one is aware of the history of an individual with reference to its pattern of repeating specific dMA. In empirical experimental situations the relative magnitude of v'/ may be determined by observing the probability of ap- proaching a new E introduced into an individual's home range so that nor- mal movements will produce exposure. Ecologists concerned with con- trolling the density of species which damage human property or serve as hosts for diseases transmittable to man have been aware of v" in a negative sense. They (e.g., Chitty and Southern, 1954) have noted the avoidance of new objects, such as poison baits or traps. This avoidance has been termed "the strange-object response." 3. Active Rejection of New Configurations Distinct from the relative attraction to or avoidance of a new configura- tion is the phenomenon of physically rejecting or psychologically blocking awareness of new £"s. Processes included under this phenomenon of rejec- tion may be designated as d". A grasp of the -types of phenomena subsumed under d" may be obtained through considering a case observed in my laboratory. Large "life-space" cages, LSC, were designed to provide an optimum situation for the breeding of the very sensitive wild Norway rats in the laboratory. A 16 X 25-inch floor provided access to an activity wheel on one side and a lever on the other, which when pressed, provided a drop of water. From this floor two ramps led to a partitioned second floor of eciual dimensions. From one side of the second floor rats had access to one 8 X 8 X 6-inch nest box, while two next boxes w^ere accessible from the other side of the second floor. One male and two female adult rats lived in each of six cages. At the time in question three of these cages each also contained a recently weaned litter. Up to this time the water-providing lever apparatus had not been delivered by the manufacturer. In its place the adults were provided water through a drinking tube from a bottle, as had been the practice since they were captured in the wild as juveniles. When the lever apparatuses became available, one was inserted into each cage and the water bottle was remo^xd. By the following morning when the cages were next examined, the situation in each cage was identical; all movable ob- jects available to the rats, paper used as nesting material and orange peels, had been piled over the lever, completely hiding it. 180 John B. Calhoun In those cages containing recently weaned young, the young soon scat- tered the pile of objects, exposing the lever, and in so doing accidentally pressed the lever and gradually learned its function. There then followed a repeated process of covering the lever by the adults and its removal by the young. Through this process the adults were forced to face E, represented by the lever and its attached water reservoir, sufficiently to permit an A adjustment to E thi-ough the DMA decline process. Several points may be deduced from these observations. Th for the adults had previously drifted downward toward b so that the E lever configuration caused DMA to exceed it. Furthermore, at weaning Th is sufficiently removed from b that many ^'s will fail to evoke DMA elevation above Th. Had evolution not resulted in such a balance between neurology and physiology, animals just emerging out into the many E's of their environment would immediately be forced into a withdrawal state. Although I shall not go into this problem here, it is obvious that retardation of "weaning" increases the probability of withdrawal . In the three cages lacking recently weaned young, the pile of material covering the levers remained undisturbed for several days until the rats were so weak from lack of water that it was apparent that their rejection of the lever was so complete that they would die before getting the op- portunity to learn its function through chance depression of it. Replacing the former water bottle merely satisfied their thirst but failed to alter their rejection of E. "Teaching" the rats the lever was finally accomplished by taking all movable objects from the cage and gradually increasing the interval during which the water bottle was removed. It took 3 weeks to reach the same level of lever pressing by these rats that was obtained within 3 days by adults when young not only made rejection impossible but also set an example of adjusted interaction with the E lever configuration. Other examples of such d" active rejection, but toward social E's, have already been given in Section XIII, B, 4 in connection with the three examples involving Barnett's Norway rats, the "Freedom Riders," and the formation of the Co7 Colony IB of house mice. Thus, in terms of active rejection, d" becomes essentially synonymous with intensity of action tow^ard another, i'-^f as given by Eq. (114). But d" must also encompass the more strictly psychological phenomena of psychological deafness or psychological blindness such as characterizes the "malingering type" of individual. Note that this consideration of exploratory behavior has lead to formu- lations of d", v", and A". As for prior comparable terms: /' = (d"v"/A") (127) Here /x" represents a third contact modifying function when relating to 1. The Social Use of Space 181 a social group. Just as with /x aud n', so it is apparent here that the magni- tude of v" and A" will normally change by comparable degrees in the same direction and that d" will approximately vary inversely with v". 4. The Effect of Interval between E's, on Velocity Further examination of the data in Table lib, in the light of the formu- lations relating to exploratory behavior and configurations of stimuli, pro- vides additional insight into the origin of reductions in velocity, both v and v". Refer to Section III, A, 3 for other comments. Presentation of the experiment in terms of the present formulations is as follows : The subjects consisted of male albino Osborne-Mendel strain rats iso- lated at weaning. At this time each rat was placed in a 6 X 6 X 8 inch cage from which it could not see out. Water and food were introduced through channels from the outside which prevented the rats from seeing the experimenters or being handled by them. AH rats remained in such isolation for approximately three months before further treatment. These isolation cages may be termed an Ei configuration of stimuh. Due to the long absence of opportunity for adjustment to new configurations of stimuli, the Th of all rats probably drifted toward b. At the end of the three months of isolation the subjects were divided into four groups: A (20 rats), B (24 rats), C (16 rats), and D (16 rats). On each of 10 days during the next two weeks each member of Group C was exposed for two hours to a new configuration of stimuli, E2, which was a Wahman activity wheel; all rats so exposed entered the wheel and ran during each of the 10 days. Similarly, members of Group C were exposed to an E3 configuration of stimuh. This exposure consisted of placing the rats in a 2 X o-foot pen where they had the opportunity to climb onto a central platform where a lever could be pressed to receive a drop of water. Each day of this 10-day training period half the members of Group D were exposed for two hours to E2 and then, immediately following, for two hours to Ez. The other half of Group D were similarly treated but were exposed to E3 just prior to E2. Group A remained in their isolation cages during these two weeks. During the third experimental week every rat in all four groups was given a two-hour exposure to the NIH Emotional Activity Alley on each of four successive days. This alley represented an E4 configuration of stimuli. For half the rats in each group Ei had a stationary floor, a condition we may designate as Ei^. For the remaining rats Ei had a tilting floor which clanged as the rats ran across it. This modification is designated as Eis, which represents a much more intense or strange configuration than EiA. Many rats avoided entering the alley. 182 John B. Calhoun Regardless of the amount of prior opportunity to adjust to novel con- figurations, the more intense £"48 elicited a more marked avoidance than did Ei\. (See Section III, A, 3.) However, our present concern is with a different aspect of the results in Table lib. I'pon exposure to EiA it appears that prior experiences with E^ was much more effecti\'e than with E-i in reducing avoidance of the EiA con- figuration. But members of both Groups B and C evinced much less avoidance of Ei than did members of Clroup A. This supports the formula- tion that prior opportunity to adjust to new configurations elevates Th so that at a following exposure to another new configuration of stimuli, DMA is less likely to exceed Th. Avoiding entering the alley is taken as evidence of DMA exceeding Th. These results confirmed prior hypotheses. However, it was further as- sumed that rats of Group D would exhibit the most marked accommoda- tion to Ei since they would ha^-e had twice the opportunity for making adjustments to new E's. And yet e\ei\ to E^a, the rats of Group D showed little better capacity for adjustment than did members of Group B, and much less than did rats of Group C. Upon elevation of the intensity of Ei to EiB, members of Group D exhibited an extremely more marked reduc- tion in capacity to adjust than did the rats of Groups B and C, that pre- sumably had less opportunity for "training" in making adjustments. These results apparently contradict the theory. But consider the follow- ing. For rats exposed to new configurations of stimuli, such as £"4, but permitted to remain for several rather than for 2 hours, it has been noted that many individuals reciuire up to 3 hours for DMA to decline to h. In the 2000-odd tests where rats have been exposed to the AVtype alley con- figuration to test for emotionality, the tacit assumption has been made that the remaining decline in DMA will take place after the return of the rats to their accustomed environment. However, this opportunity did not prevail when, after 2 hours in E2 or E^, rats were transferred to the opposite E. Events presumably transpiring are diagrammed in the left-hand side of sketch (4) in Fig. 41. Upon exposure to Es after only partial decline of DMA following exposure to E2, the same increment in DMA is elicited, but its rise starts at the point of a still fairly high level of DAIA. Thus, this second increment in DMA forces it above the threshold, Th, where DjVIA is transformed from difi'use motor activity into the generalized stress state, GSS. Although GSS and DMA were not measured during E3 (or during E2, if it came second for Group D) , both must have eventually com- pletely disappeared after the usual return to the home cage. And yet the very failure of many members of Group D to enter the Ei alley when given 1. The Social Use of Space 183 exposure to it suggests that for each degree of GSS induced by too close spacing of consecutive new E's, there had transpired a drop in Th and B such that Th drops relatively more than h. Each of the ten opportunities for consecutive exposure to E2 and Es must have narrowed the gap between h and Th. Thus the later exposure to Ei must have caused "overloading" for most Group D rats to the extent that GSS had not declined to Th by the end of the two hours in Ei. This meant that decline in DMA to base level took place in Ei. Return to Ei for 2 hours on each of the following 3 days was characterized by persistence in avoiding entry into the Ei alley configuration by most rats avoiding it on first exposure. Avoidance, v", of any new E will thus be proportional to the degree of GSS "overloading" elicited by the new E's. Although new E's have been considered above in the sense of physical nonsocial configurations, we may consider the consequences of too closely spaced new or undesirable £"s in the social sense of i^'^'s of associates. Re- call that such i^^^'s represent social restraints or sanctions imposed by associates. For such sanctions to become effective in reducing velocity, v, that is for causing a drop in baseline of activity, consecutive sanctions by the same or different associates must be sufficiently closely spaced to induce a GSS. No opportunity for v" avoidance is possible. In fact, with the drop in velocity v (synonymous with h), psychological area A" must be re- stricted through failure to make adjustments A to E while still in the presence of E. And as we have seen, as A" decHnes so will v". This means that as velocity, v, declines, the individuals have even less capacity to avoid strange stimuli. However, recall that as v" declines d" increases. I can cite no quantitative data to support this conclusion of d" increasing as y" decreases. However, the following observations support its reality. While making the observations on velocity of rats summarized in Fig. 38, I was consistently impressed by the manner in which most very low-velocity rats moved "through" their associates. During those rare times when active, they would pass by associates as if completely psychologically blind to their presence. Furthermore, their blase, unaffective mode of posture equally failed to elicit response from associates. The completeness of this psychological rejection of reality is reflected in their smaller organ weight and larger amount of fat (Fig. 40), corresponding to states char- acterizing rats maintained in approximate isolation by restrictions to groups of 1 male with 2 females in small cages or pens. A further corroborative observation comes from the study referred to in Section XH, A. Among the wild Norway rats in that study was a small group designated as possessing an array of aberrant symptoms and be- havior which I called the "syndrome of the social outcast." From compari- 184 John B. Calhoun son with rats described in Sections XII, C and XIV, F, I now know that these social outcasts must have been very low-velocity rats. Of all the rats involved in the study referred to in Section XII, A, they were the only ones ever caught in "Havahart" traps. These large, shiny wire-meshed traps with a door opened at either end and shiny metal treadles on the center floor were regularly placed on trials. All other rats invariably ran around these traps. Yet the social outcasts apparently ran into them with- out ever sensing their presence. This sensory unawareness is the low v" factor characterizing low-velocity rats. XV. Conclusion Man did emerge from the trials, successfully overcome, of a myriad of ever more simple forms. I have attempted to formulate some phenomena which have affected man's social evolution. Some of these phenomena appear no longer directly operati^'e on the human animal. They neverthe- less left their imprint on man's capacity to adjust physiologically and psychologically to the social system in which he lives. Foremost among these presumed legacies are the limitations imposed upon him from his origin out of an evolutionary line in which optimum adjustment demanded living in small groups, not exceeding twice twelve individuals. Only yesterday, as one may measure evolutionary time in units of ten thousand years, did man begin his attempt to escape this evolutionary bond. But cultural evolution has not produced escape from this bond, merely accommodation to it. Human society has developed the form of a many-layered chain link armor. Each link is composed of not much less than, nor many more than, twelve individuals. The links have a fluid character. Through time, any one individual shifts his membership back and forth among several joining links. This poetic view embodies the es- sence of reality. In contrast to such evolutionary legacies, there exist certain principles of social physics which must affect all social animals, man included. These principles derive from certain universals I have called velocity, target diameter, area, basic group size, the social refractory period, threshold for tolerance for change, and the like. I am fully cognizant that my formulations represent only crude approximations to reality, and may in fact contain several errors of logic. Yet we must develop adequate formulations along the lines I have attempted or all efforts to gain insight into the individual's involvement in social action will prove sterile. This sterility will crown the endeavors of both classical physiology and 7. The Social Use of Space 185 psychology. We can no longer afford to ignore the impact of the social setting on the individual's behavior and physiology. And without knowl- edge of evolutionary limitations and universal principles of social physics, consideration of the social setting will also prove of little avail. 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An evaluation of the removal method of estimating animal populations. Biometrics 12, 163-189. Endocrine Adaptive Mechanisms and the Physiologic Regulation of Population Growth* J. J. CHRISTIAN V^^ Division of Endocrinology and Reproduction, Research Laboratories, Albert Einstein Medical Center {North), Philadelphia, Pennsylvania General Introduction 189 Part 1. The Endocrine Adaptive Mechanisms 191 I. Introduction 191 II. The Endocrine Glands of Adaptation 192 A. The Adrenal Glands 192 B. The Thyroid Gland 228 C. Other Endocrine Adaptive Factors 240 D. General Measurements of the Endocrine Adaptive Responses 242 Part 2. Physiologic Adaptation and Mammalian Populations 261 I. Introduction 261 II. Endocrine Responses to Social Pressures and to Population Density- - 263 A. Experiments in the Laboratory with Populations of Fixed Sizfc_-_ 263 B. Freely Growing Populations 281 C. Natural Populations 300 III. Conclusion 325 References 328 General Introduction Endocrine adaptive responses have become of particular interest to the mammalogist in recent years because of the likelihood that they play an important role in the regulation of the growth of mammalian populations. Sufficient evidence has accumulated from the field and laboratory to war- rant stating with fair certainty that these adaptive mechanisms are opera- tive in and related to changes in the size of mammalian populations. However, there is still considerable uncertainty about their precise role and relative importance in the regulation of population growth, especially with regard to generalizing to a large number of species from the few species for which data are presently available. There also exists a great deal of un- * Note added in proof. For additional references pertaining to recent work on endocrines and population, the reader is referred to Christian (1961, 1963a & b). 189 190 /• /• Christian certainty about the relationships of various environmental factors to the adaptive mechanisms. Then, besides the interest in adapti\-e mechanisms in relation to population growth, there is the frequently overlooked fact that these same phj^siologic reactions may effect profound morphologic changes in the members of a population and therefore directly affect the taxonomist who must use morphologic criteria for distinguishing species and subspecies. It is entirely possible that many subspecific descriptions have been based on morphologic differences resultmg from differences in the densities of the populations on which the descriptions are based. The mammalogist inter- ested in reproduction in mammals must take adaptive mechanisms into consideration, as alterations in reproductive functions are an integral part of these same adaptive responses. Therefore there is adequate justification for this chapter on the endocrine adaptive responses, their effects, and their relationships to the densities of mammalian populations. No matter how well an animal may be genetically adapted to its general environment, it still must have sufficient adaptive flexibility to meet the daily and seasonal environmental changes, as well as emergency situations, to which it will normally be subjected, and still maintain a constant internal environment. Nothing in the daily life and external environment of an animal remains constant; on the contrary there frequently are very sudden, often extreme, shifts in the environment which are stimuli that, if unop- posed, would alter the internal environment of the animals. But the internal environment must remain constant if the animal is to survive. Therefore there must be a constantly active system of physiologic feedback mecha- nisms to compensate immediately for any tendencies to shift the internal environment. However, these adaptive responses do not take place without producing measurable effects in the organs and glands primarily responsible for meeting the altered demands. Compensation for a life-maintaining change frequently occurs at the expense of some function less immediately important for survival, for example, reproduction. Consequently reproduc- tive function declines measurably in the face of a need to maintain a con- stant internal physiologic state in the presence of adversity. The adaptive responses are changing constantly in degree to meet constantly changing daily circumslances, and it is generally thought that a certain amount of change is necessary to maintain the integrity of the system so that it will be capable of responding to more demanding circumstances. It is not sur- prising that at any given moment the physiologic status of a mammal reflects its total environment and that the whole system is in a constant stage of change, but for these same reasons it becomes difficult to study such a dynamic system in the complex environments of natural populations. Therefore a great deal of the existing evidence on the adaptive mechanisms of mammals, especially in relation to population density, has been gained by studies in the laboratory. 2. Endocrines and Populations 191 Past research on the adaptive mechanisms has emphasized the adrenal cortices and to a lesser extent the thyroid gland and their hormones. Un- questionably the adrenal cortex is essential to life and plays a basic role in the adaptive responses, nevertheless there is a real tendency to overlook the paramount importance of other systems and organs which also respond to adverse circumstances. In fact their actions are simultaneous with and inseparable from the actions of the adrenal cortex in many instances. A great many responses on the part of the organism act in concert to prevent any alteration in the basic physiology of the animal and to meet emergency needs. The central nervous system is a major and integral part of these adaptive mechanisms. Our understanding and interpretation of the physio- logic changes taking place under a given set of circumstances too frequently suffer from a tendency to think statically and in terms of isolated organs, systems, or hormones — a result of the kind of experimental approach necessary to understand the actions of various glands and their secretions. The isolated organ concept must give way to thinking in terms of dyna- mically interacting systems. However, to describe these mechanisms and their effects in dynamic inclusive terms is extremely difficult and has been made even more so by the recent elucidation of the key role played by the central nervous system in regulating the activities of the glands of internal secretion, as well as by the realization that we are dealing with an enor- mously complex interacting system further complicated by the complex temporal relationships of the responses of these systems to the applied stimulus and to each other. The balance of this chapter will be devoted to a more detailed discussion, first of the physiologic adaptive mechanisms themselves, and then with particular attention to the evidence implicating these responses in the regulation of the growth of mammalian populations. An attempt will be made to clarify some of these responses and to indicate areas where further research is needed, especially in relation to behavior and population density. Subjects which are adequately covered in the usual textbooks of physiology will be omitted or only briefly summarized. Part 1. The Endocrine Adaptive Mechanisms I. Introduction When a mammal is subjected to a stimulus which, if unopposed, would result at least in a change in its internal physiology, and more likely produce; a circulatory collapse, a series of neural, neuroendocrine, endocrme, and vascular responses follow which counteract the deleterious effects of the 192 J- J- Christian stimulus and also supply the increased needs of many tissues in order to meet the situation. Selye (1950) introduced the phrase "alarm stimulus" to describe such a stimulus which produces shock and evokes the usual physiologic responses to shock. In the present account an alarm stimulus is defined as any stimulus which, when applied to a mammal, tends to alter fluid and circulatory homeostasis, and therefore necessitates a physiologic adaptive response. This definition is somewhat circular insofar as it is in terms of a response, but it is not restrictive, and it does not imply that the adrenal cortex (at least that part responsible for the secretion of carbo- hydrate-active corticoids) is an essential participant, as is so often assumed. There may be qualitative similarities in the responses to different stimuli, but detailed studies suggest that there are all degrees of variation in the degree of participation of various systems and organs to a gi\'en stimulus. Probably the prime objection to the current concept of "nonspecific" response is the practical one that uncritical usage has tended to obscure important differences in the physiologic responses to different stimuli. It should be pointed out that the degree of these responses appears to be relative, as the same responses qualitatively are essential for daily life, but must increase quantitatively in the face of adverse circumstances. A pri- mary function of the endocrine adaptive responses is to insure an adequate circulation with an adequate supply of glucose and oxygen to tissues essen- tial for emergency situations. Part of this function is the maintenance of an adequate circulatory volume and proper electrolyte and fluid balances. These adaptive responses will be discussed in greater detail in the following account. II. The Endocrine Glands of Adaptation A. The Adrenal Glands 1. Introduction This discussion is primarily for the benefit of those who are interested in the physiological and comparative aspects of mammalogy. Therefore what is known of the endocrine adaptive mechanisms will be outlined without dwelling on details or becoming involved in the minor details or contro- versies of today's frontiers in endocrinology. Research on adaptive mechanisms to a large extent has centered around the adrenal glands, especially the cortex. One of the factors tending to synonomize "stress" with adrenocortical activity has been the measure- ment steroid secretion, weight, ascorbic acid depletion, and cholesterol 2. Endocrines and Populations 193 content of the adrenals to determine whether and to what degree a stunulus produces ''stress." Although the adrenals are of primary importance in physiologic adaptation to changing needs, it is important not to equate adaptation solely with adrenal function or to assume that the only function of the adrenals is to enable an organism to meet new and sudden demands. It is appropriate, especially for the mammalogist, to discuss adrenal glands in some detaU because of their importance and because of the convenience of using them as indices of the degree of adaptive response to particular situations or stimuli. However, judgment must be used in interpreting the results of measurements of adrenal function, and one must realize that there are many other responses which are measured with extreme difficulty, and yet others may be completely masked by extraneous factors. a. General morphology of the adrenal glands. The anatomy of the adrenal glands is discussed in detail in many texts and papers on histology, gross anatomy, and comparative anatomy. Attention is called to the books by Bourne (1949), Hartman and Brownell (1949), Bachman (1954), and Jones (1957) for general treatments, especially from the comparative point of view. The adrenal glands are yellowish paired organs lying at or near the anterior poles of the kidneys. Their position and form vary considerably from species to species. For example, in rabbits (Stjlvilagus, Oryctolagus) they are oval discoid organs closely applied to the vena cava; in wood- chucks (Marmota) they are sausage-shaped and lie between the kidneys and the midline, usually closer to the latter; in mice and voles of almost all species they are round, oval, or pyramidal and lie approximated to the poles of the kidneys; and in the bats Myotis and Pipistrellus they lie be- neath a layer of the renal capsule. These examples simply serve to illustrate the wide variations that occur in their gross shape and position. Two distinct portions of the adrenal are discernible when they are sec- tioned and examined grossly: a dark reddish brown or gray central core, the medulla ; and a wide outer portion, the cortex, which is usually yellowish but may be gray or even translucent reddish brown, dependmg on the activity of the gland. The yellow color is imparted by lipids contained in the cortical cells; thus color will vary with changes in the lipid content. Usually the cortex is quite wide, comprising from one-half to two-thirds of the radius of the gland. However, in some of the adult soricid shrews (Sorex jumeus, S. cinereus, S. palustris, S. dispar, and Microsorex hoyi) the gland consists almost entirely of medulla and has a very narrow cortex only a few cells wide. The extreme narrowness of the cortex is especially pronounced in mature male shrews. The adrenal gland is surrounded by a connective tissue capsule from which a stromal framework of connective tissue descends into the cortex. 194 /• /• Christian The amount of cortical stroma may vary considerably; it is inconspicuous in most rodents whereas it is marked in most carnivores. b. Zonation of the adrenal cortex. Three distinct major zones usually are identifiable histologically in the cortex, although the zonation is difficult to discern in a number of species (Bourne, 1949) . An outer thin zona glomeru- losa lies just beneath the capsule and consists of loops or balls of rather large cells with relatively clear cytoplasm. Central to the zona glomerulosa is a wide central zona fasciculata, which is composed of radially arranged straight cords of polyhedral cells that usually contain numerous cytoplasmic lipid vacuoles. Lipid vacuoles occur in the cortical cells of most species, but they may be absent in some, for example, the golden hamster (il/c.so- cricetus auratus) (Alpert, 1950; Knigge, 1954a; Schindler and Knigge, 1959a). Little or no lipid is present in the cortices of cattle, sheep, and pigs (Deane and Seligman, 1953). When present, the vacuoles may vary considerably in size and number, depending on variations in the activity of the cortex. The cells of the outer half of the zona fasciculata usually are larger and contain more lipid than those in the inner half of the zone. The fascicular cords are arranged as paired columns of cells lining vascular sinusoids in man and monkeys (Elias and Pauly, 1956), but is continuous in rats, the sinusoids penetrating the continuum (Pauly, 1957). The latter normally contain large amounts of blood circulating from the arteries in the capsule to the medullary venous sinusoids and adrenal vein. There are variations in the circulatory arrangement with species, and it is more com- plex in detail than has been described here, but these matters are thoroughly covered elsewhere (Gersh and Grollman, 1941; Hartman andBrownell, 1949; Harrison, 1951, 1957; Elias and Pauly, 1956; Pauly, 1957). The cells of the fasciculata, when stamed by routine procedures, bear a marked resemblance to the luteal cells of the ovary, interstitial cells of the testis, and, although less closely, the cells of the "brown fat" or "hibernating gland" in its usual functional state. The zona reticularis forms a fairly wide cortical band between the medulla and the zona fasciculata in most species, but it is not always present (Hartman and Brownell, 1949). Its cords (or cortical continuum) are more or less continuous peripherally with those of the zona fasciculata, but they rapidly break up into a reticular network as they proceed centrally toward the medulla. The cells are generally smaller than other cortical cells and usually contain no vacuoles. However, when vacuoles are present, they are usually very large. There is need for a detailed, well illustrated, and thorough discussion of the comparative morphology of the adrenal glands which would include a wide variety of species and a sufficient number of animals of each species to describe age and sex, as well as seasonal and environmental, relation- ships. It is not the purpose of the present discussion to dwell on the anatomy 2. Endocrines and Populations 195 of the adrenal glands, but a brief summary of the particularly useful and more recent publications on the subject will be given. The books which already have been listed discuss the adrenals of a large number of species, but the descriptions and illustrations are limited. However, the histology and histochemistry of the adrenals of a few species are discussed in con- siderable detail in a number of papers. The recent publications of Elias and Pauly (1956) and Pauly (1957) describe the microscopic anatomy of the adrenal glands of laboratory rats and humans. These papers are well illustrated, and the stereographic reconstructions of serial sections are helpful in understanding the adrenal morphology of these two species. One of the important facts brought out in these papers is that the adrenal cortex of the rat is not arranged in cords as it is in humans and monkeys. The parenchyma of the rat adrenal cortex is a continuum which is tunneled by vascular channels. A number of additional papers deal with the anatomy, circulation, or histochemistry of the adrenals of laboratory rats, especially with regard to function, zonation, and reactions to various stimuli (Howard, 1938; Flexner and Grollman, 1939; Greep and Doane, 1947, 1949a; Deane et al., 1948; Deane and Morse, 1948; Cain and Harrison, 1950; Feldman, 1950, 1951; Cater and Stack-Dvmne, 1953, 1955; Josimovich et al, 1954; Jones and Spalding, 1954; Jones and Wright, 1954a, b; Christianson and Jones, 1957), and other more general papers on the histochemistry and function of the adrenals are based largely on material from laboratory rats (Dempsey, 1948; Greep and Deane, 1949a, b; Sayers and Sayers, 1949). The differences in morphology between the adrenals of wild rats {Rattus norvegicus and Rattus alexandrinus) and those of Norway rats from the laboratory have been described by Rogers and Richter (1948), and the histology of wild and laboratory Norway rats has been described and com- pared by Mosier (1957). A comparative study of the vascularization of the adrenals of rabbits, rats, and cats has been made by Harrison (1951) and followed by a description of the adrenal circulation and its regulation in the laboratory rabbit (Onjctolagus) (Harrison, 1957). The histology of the adrenal glands of the prototherians Onuthorlnjnchus and Tachyglossus has been described in considerable detail by Wright et al. (1957). The bulk of the chromaffin tissue was found in the lower pole in these species rather than in the more usual central position. The cortices of these species also differ considerably in their histologic appearance from those of eutherians. We have mentioned above that the adrenals of North American soricids have strikingly little cortical tissue, although a critical study of this material has not been made (J. J. Christian, unpublished) . Lanman (1957) has described the fetal zones of the adrenals of the fol- lowing fetal or neonatal primates: macques (Macaca midatta) , potto {Perodicus putto) , chimpanzee (Pan sp.), hybrids of Cercopithecus {Cerco- 196 /• J- Christian pithecus sp.), marmoset {Callothrix argentata) , slow loris (Loris sp.), colo- bus monkey {Colohus polykomos), and humans. The anatomy of the adrenals of the macaque has been described by Harrison and Asling (1955) . Variations in the histochemistry of the adrenals of cows, rats, and monkeys followmg "stress" or treatment with adrenocorticotropin, cortisone, or deoxycorticosterone were the subject of a paper by Glick and Ochs (1955) . Additional descriptions of the adrenals of cows and other domesticated ungulates are subjects of papers by Elias (1948) and Weber et al., (1950). Finally, Zalesky (1934) described in considerable detail the seasonal histologic changes in the adrenals of thirteen-lined ground squirrels ( Citel- lus tridecemlineatus) . The morphology and histochemistry of the adrenals of laboratory and wild house mice have been thoroughly studied, largely because of the endocrine relationships of the transitorj^ X-zone which was first described by Howard (1927). Tamura (1926) wrote a detailed description of the changes during pregnancy in the adrenals of mice. This was followed by Howard's (1927) description of the X-zone and Waring's (1935) descrip- tion of the development of the adrenal glands of the mouse. Following these there was a spate of papers describing the X-zone and its reactions to various hormones and experimental treatments (Gersh andGrollman, 1939; Waring, 1942; McPhail and Read, 1942a, b; McPhail, 1944; Jones, 1948, 1949a, b, 1950, 1952; Miller, 1949; Benua and Howard, 1950; Howard and Benua, 1950; Jones and Roby, 1954; Allen, 1954; Allen, 1957). The histology and histophysiology of the adrenals of hamsters (Mesocricetus auratus) have been described by Alpert (1950) and Holmes (1955), and the effects of hypophysectomy and starvation on their adrenals by Knigge (1954a, b). The adrenals of a number of species of European small mammals have been studied and described by Delost, particular attention being paid to the presence or absence of an X-zone and its relationships to the sexual cycle and sex accessories. The mammals in these studies included Microtus arvalis (Delost 1951; 1952a, b; 1954; 1956a, b) Microtus agrestis (Delost and Delost, 1955), Clethrionomijs glareolus (Delost and Delost, 1954), Pitymys (Delost and Delost, 1955), Sorex araneus (Delost, 1957), and Crocidura (Delost, 1957). Immature male and young nuUiparous female house mice (Mus muscu- lus) have an adrenocortical juxtamedullary zone, the X-zone, which un- equivocally shows sex relationships (Howard, 1927; Deanesly, 1928; Jones, 1957) . This zone is absent from mature male and parous or old females. Cortical X-zones have been described for a number of other species of small mammals including meadow voles (Microtus agrestis and Microtus arvalis), red-backed voles (Clcthrionomys glareolus, pine voles (Pitymys 2. Endocrines and Populations 197 suhterraneiis) , and shrews (Sorex araneus and Crocidura russula) (Delost, 1951, 1952a, 1954, 1957; Delost and Delost, 1954, 1955), but there is some question whether the X-zones of these species are entirely analogous to the X-zones of the house mouse. Delost (1954, 1956b) reports that cortisone involutes the so-called X-zone of voles, which is a response not seen in house mice. The X-zone of the shrew behaves like that of the house mouse with respect to its involution, but apparently has not been subjected to critical experiments in the laboratory (Delost, 1957). The X-zone consists of cords of small, deeply acidophilic cells with intensely basophilic nuclei and which are about one-half the size of those of the zona fasciculata (Howard, 1927; Deanesly, 1928; Jones, 1949a, b, 1950, 1957; Benua and Howard, 1950) . The cytoplasm of these cells, besides being more acido- philic than those of the fascicular cells, is unvacuolated ordinarily and lacks the sudanophilia of the other zones of the adrenal cortex (Jones, 1957) . Criteria for critically distinguishing the X-zone have been reviewed by Benua and Howard (1950) and Holmes (1955). The uniqueness of this zone rests on the fact that it is involuted by androgens and appears to de- pend on pituitary luteinizing hormone for its maintenance (Howard, 1927, 1959; McPhail and Read, 1942a, b; McPhail, 1944; Waring, 1942; Jones, 1949a, b, 1950, 1952, 1957). The function of this zone, if there is a specific function, is unknown. The so-called X-zone of voles which has been de- scribed by Delost (1951, 1952a, 1954;) and Delost and Delost (1954, 1955) reappears after castration or after the hibernal periods of sexual inactivity in the males and persists through gestation and lactation in the females, and in these respects it differs markedly from the X-zone of house mice. This zone may confound the use of adrenal weight as an index of increased cortical activity in the house mouse (Christian, 1956) and other species which possess it, but it provides a useful measurement for determining histologically the onset of androgen production, therefore puberty, in male house mice (Christian, 1956). A poorly defined X-zone has been described in mature nulliparous female hamsters, but not in males (Holmes, 1955), differing from the X-zone of house mice in this respect. It is likely that an X-zone will be described for other species when enough material from all age groups of both sexes has been critically examined, and that a variety of manifestations of this zone will be found. The morphology and size of the adrenal cortex varies with its functional status (see also discussion under reticularis) . The cortex undergoes rapid hyperplasia and hypertrophy in response to stimulation by adrenocorti- cotropin (ACTH) from the anterior pituitary. At first there is a rapid diminution in the size and number of lipid vacuoles, ascorbic acid, and cholesterol of the cortical cells (Sayers and Sayers, 1949). The vacuoles soon increase in number and size, providng the stimulation is not too 198 ./. J. Christian severe (Dempsey, 1948; Sayers and Sayers, 1949; Greep and Deane, 1949b) . The lipid vacuoles disappear first from the fasciculata next to the reticularis, so that it becomes indistinguishable from the latter. As stimula- tion continues, the disappearance continues centrifugally, and at the same time enzymes normally absent from the fasciculata, but present in the reticularis, make their appearance in the cells of the fasciculata, the inner- most portion moving outward (Symington et at., 1958). Upon withdrawal of the stimulus of ACTH the lipid vacuoles increase considerably in size and may become very large. This stage presumably represents lipid storage. The cellular hyperplasia and hypertrophy mainly account for increases in the size and weight of the adrenal glands. Initially the cortex responds to stimulation with a marked decline in its cholesterol, neutral lipids, and ascorbic acid content (Greep and Deane, 1949b; Sayers and Sayers, 1949). These soon return at least partially to their original state, and in the inac- tive gland they may exceed their original levels. These matters are dis- cussed in detail in the cited references in addition to discussions therein of the relationships of the cortex and its activity to various stimuli for varying lengths of time and with varying intensity. c. The adrenal medulla. The adrenal medulla consists of rather irregular masses of polyhedral chromaffin cells derived, along with the ganglia of the sympathetic nervous system, from the primitive neuroectoderm. The medulla is homologous with the sympathetic ganglia and receives myeli- nated cholinergic preganglionic fibers from the greater splanchnic nerve. The medulla itself serves as the ganglion and the postganglionic tracts. There apparently are several types of cells in the medulla; these are dis- cussed in more detail elsewhere (Hartman and Brownell, 1949; Eranko and Raisanen, 1957) . The cytoplasm of the medullary cells contains numerous minute deeply basophilic granules which stain blue with ferric chloride and brown with chromic acid (chromaffin) and which appear in some way to be related to secretory function. The adrenal medulla generally is not thought to hypertrophy following stimulation in the same way that the adrenal cortex does. Rogers and Richter (1948) reported the absence of medullary hypertrophy with changes in adrenal size in rats. However, there is good evidence that the medulla does hypertrophy, at least in some species and under some circum- stances, even though it may not contribute significantly to an increase in the total weight of the gland, as a consideration of its geometry will show. House mice have been shown to exhibit a marked medullary hyperplasia and hypertrophy during pregnancy (Tamura, 1926) or chronic stimulation due to crowding (Bullough, 1952). Medullary hypertrophy also has been observed in a variety of species of captive wild ungulates subjected to conditions in a zoological garden similar to the crowding of mice reported 2. Endocrines and Populations 199 by Biillough ( 19o2) (Ratcliffe, unpublished; J. J. Christian, unpubUshed) . These conditions which resulted in which medullary hypertrophy all constituted prolonged, chronic stimuli. Medullary hypertrophy due to hyperplasia probably occurs simultaneously with cortical hypertrophy in many species but perhaps requires a more sustained stimulus and develops at a much slower rate. There also seems to be some suggestion that emo- tional stimuli may be important in this effect. Finally, it has been shown that treatment with pituitary growth hormone will produce a marked hypertrophy of the adrenal medulla (Moon et at., 1951; Lostroh and Li, 1958) , and may eventually result in medullary tumors (Moon et at., 1950) . The role of sympathicomedullary function in physiologic adaptation re- quires more investigation, especially in regard to chronic stimulation, such as is produced by sociopsychologic pressures, and for a variety of species. 2. Hormones Secreted by the Adrenal Cortex: Their Actions and THE Regulation of Their Secretion. a. The zona glomerulosa. (1) The hormones. The adrenal cortex secretes two steroid hormones, aldosterone (18-aldocorticosterone) and deoxycorti- costerone (11-deoxycorticosterone), which have their primary effects on salt-electrolyte and water metabolism. However, aldosterone is the only bio- logically important sodium-retaining corticoid secreted by the adrenal cor- tex and it is many times more powerful than deoxycorticosterone in its effects on electrolyte metabolism (Farrell et al., 1955; Gaunt et at., 1955; Gross and Lichtlen, 1958) . Also aldosterone is an important secretory pro- duct of the adrenal cortex, whereas deoxycorticosterone is secreted only in trace amounts (Farrell et at., 1955; Jones, 1957) and is probably a precursor in the formation of aldosterone (Giroud et al., 1958). The actions of these two hormones are very similar within the physiological range of dosages for each, but their actions with overdosage differ considerably: overdosage with aldosterone does not lead to the excessive sodium retention and the diabetes insipidus-like state which are seen after overdosage with deoxy- corticosterone (Gross and Lichtlen, 1958). It is appropriate at this point to comment on the general classification of the adrenal corticoids into the two broad categories which are used in the present account. The hormones of the adrenal cortex have been loosely grouped as "sodium-retaining" or ''carbohydrate-active" according to whether their prunary actions are on salt-electrolyte metabolism or if they are among those steroids having marked effects on carbohydrate meta- bolism. The sodium-retaining steroids include aldosterone, deoxycorti- costerone, and, to a much lesser extent, 17-hydroxy-ll-deoxycorticosterone (Reichstein's compound S) . The principal carbohydrate-active steroids are 200 J. J. Christian hydrocortisone and cortisone (ll-oxy-17-hydroxycorticoids). Corticoste- rone is included in this latter group, although it has moderate effects on both salt-electrolyte and carbohydrate metabolism. It is considerably weaker in all these actions than the principal corticoids in either of the categories (Jones, 1957). This classification into primarily carbohydrate- active and primarily sodium-retaining corticoids is useful, but by no means does it reflect the entire spectrum of activities of the hormones; in many instances there is a considerable overlap in these activities for a particular hormone, for example, corticosterone. Recent morphologic and direct evidence shows that the secretion of aldosterone is a function of the zona glomerulosa, whereas the carbohy- drate-active corticoids, except corticosterone, and probably the C19 steroids are secreted by the zona fasciculata and zona reticularis. Probably the most conclusive evidence for the relationship between specific secretory function and zonation of the adrenal cortex has been provided by the in vitro incubation and determination of the secretory products of selected segments of the adrenal cortex. Aldosterone was found to be secreted only by incubated portions of the zona glomerulosa of the adrenals of rats and beef cattle (Ayres et al., 1956; Giroud et al., 1956; Giroud et at., 1958); hydrocortisone was produced only by the zonae fasciculata-reticularis, and corticosterone was produced at approximately equal rates by all three zones of the adrenals of beef cattle (Ayres et al., 1956; Giroud ct al., 1958 Stachenko and Giroud, 1959a, b) . It was also shown in these experiments that ACTH or corticotropin peptides or other steroids were without effect on the production of aldosterone by the zona glomerulosa but that they markedly increased the production of total corticosteroids and of hydro- cortisone by the fasciculata-reticularis (Stachenko and Giroud, 1959b). Additional evidence of functional zonation, less direct, has been obtained by relating changes in the composition of the secretory product with mor- phologic changes in the various zones of the adrenal cortex. A sodimn- deficient diet produces extreme hypertrophy of the zona glomerulosa and atrophy of the zona fasciculata of the adrenal cortices of rats (Hartroft and Eisenstein, 1957), and these changes are associated with a marked increase in the secretion of aldosterone and decreases in the secretion of corticoste- rone (Eisenstein and Hartroft, 1957). In somewhat comparable experi- ments it was shown that (1) sodium deprivation markedly increased the aliesterase activity of the zona glomerulosa but had no effect on its activity in the fasciculata of the adrenals of mice; (2) deoxycorticosterone or sodium flooding depressed the aliesterase activity of the zona glomerulosa and increased it in the zona fasciculata; and (3) injected ACTH markedly increased the aliesterase activity of the zona fasciculata but did not affect it in the zona glomerulosa, whereas blocking ACTH secretion with cortisone 2. Endocrines and Populations 201 depressed the fascicular aliesterase activity (Allen, 1957). The results of the foregoing experiments provide convincing evidence in support of the hypothesis of Greep and his co-workers that the zona glomerulosa secretes the electrolyte-active, and the fasciculata the carbohydrate-active, corti- coids (Greep and Deane, 1947, 1949b; Deane et at., 1948). This hypothesis was based on observations that (1) increased sodium intake or injections of deoxycorticosterone produced histochemical changes indicative of de- creased activity in the zona glomerulosa of the adrenals of rats, and that (2) a reduction in sodium or increase in potassium produced cytological changes indicative of increased activity of the zona glomerulosa. There is little doubt that the glomerulosa is responsible primarily for the secretion of aldosterone and that the carbohydrate-active corticoids are secreted by the zona fasciculata and possibly by the zona reticularis. Convincing evi- dence of a functional separation between the zonae fasciculata and reticu- laris is not available, but the reticularis generally is not believed to be as active a secretory zone as the fasciculata. The chief action of aldosterone is on sodium-potassium transport in the tubular cells of the renal nephron, and it is relatively more effective in pro- moting sodium retention than in promoting potassium excretion or water retention (Gaunt et al, 1955; Bartter, 1956; Jones, 1957; Gross and Lichtlen, 1958; Stanbury et al., 1958). It apparently stimulates the ionic exchange between potassium and sodium ions in the renal tubular cells (Bartter, 1956; Stanbury et al., 1958), although an overdosage of aldoste- rone will not produce excessive sodium retention and the animal therefore stays in sodium balance (Bartter, 1956; Gross and Lichtlen, 1958). In general the sodium-retaining corticoids act on the nephric tubular cells to promote an ionic exchange between sodium and potassium; so that sodium is retained and potassium is excreted (Bartter, 1956, 1957). Water is re- absorbed with the sodium or independently under the action of neurohy- pophyseal antidiuretic hormone (ADH) (Bartter, 1957). Proper fluid and electrolyte balance is mamtauied by these homeostatic endocrine activities acting in concert with water and salt intake and with hemodynamic and neural factors which affect fluid volume, blood pressure, and renal glomeru- lar filtration. The apparent anomaly of overdosages of aldosterone failing to produce excessive sodium retention depends on the fact that the blood pressure is raised and therefore the glomerular filtration rate is increased and sodium is lost accordingly (Stanbury et al, 1958) . Proper fluid and electrolyte balance is vital to any animal, and adrenalectomized animals can be maintained with injected deoxycorticosterone or aldosterone, al- though they cannot adapt to added stress (Gaunt et al, 1955) . The adrenal- ectomized laboratory rat or mouse also can be maintained alive by sup- plying W( sodium chloride in its drinking water to replace the sodium loss 202 J. J. Christian accompanying adrenalectomy. However, adrenalectomized wild Norway rats (Rattus norvegicus) cannot be maintained in this fashion, even with the NaCl content of the drinking water as high as 4 %(Richter et al., 1950) . These facts emphasize the wide divergence between laboratory and wild strains of the same species. Evidently the requirements for adrenocortical hormones are much greater in mammals under feral conditions than for those raised or maintained in the laboratory or zoo. There is a marked disparity in the adrenal weights of mammals raised in the laboratory and in the same species under natural conditions, the differences due largely to differences in the amount of cortical tissue (Rogers and Richter, 1948; Nichols, 1950; Christian and Ratcliffe, 1952; Christian, 1955a) ; some of this difference, however, may be associated with the unconscious selection in breeding colonies for docility and good breeding performance. (2) Regulation of aldosterone secretion} Since aldosterone acts pri- marily to maintain fluid and electrolyte homeostasis, it is not surprising that the secretion of this hormone is regulated largely by these factors. Changes in the volume of extracellular fluid (probably mainly the intra- vascular volume) , and the level of body potassium affect the rate of aldo- sterone secretion (Liddle et al., 1956; Bartter, 1957; Bartter et at., 1959), but to some extent the secretion of aldosterone in vivo can be stimulated by adrenocorticotropin (Farrell et al., 1955; 1958; Liddle et al., 1956), but apparently not in vitro (Stachenko and Giroud, 19596). This discrepancy may be explained by the increased production of the precursors of aldoste- rone by the f asciculata which then become accessible to the zona glomerulosa in the intact adrenal. Even though the secretion of aldosterone is mode- rately stimulated by ACTH, the stimulation is not maintained in spite of continued treatment with ACTH (Liddle et al., 1956), and the response is considerably less than that seen following changes in the volume of extra- cellular fluid or in body potassium (Bartter et al., 1959). The glomerulosa will respond to increased ACTH with increased secretion of aldosterone for only about 3 or 4 days, and then the rate of secretion declines in spite of continued ACTH and reaches base levels or even lower levels of secretion in about a week (Liddle et al., 1956). After this period, continued ACTH will not increase the secretion of aldosterone (Bartter et al., 1959). Finally, the secretion of aldosterone is only slightly depressed by suppressing ACTH secretion (Farrell et al., 1955; Liddle et al., 1956; Bartter, 1957) or by hy- ' Since completion of this chapter, there has been marked progresses in understanding the regulation of aldosterone secretion in response to hemodynamic changes. It is fairly certain that in response to decreased arterial pressure there is increased relea.se of renin from the kidney. The end product of this release is angiotensin II which, in the presence of basal levels of ACTH, stimulates aldosterone secretion. [For a review see J. (). Davis (1963).] 2. Endocrines and Populations 203 pophysectomy (Farrell ei al., 1955). These results, in addition to those discussed under the relationship between secretory function and zonation of the adrenal cortex, clearly indicate that the secretion of aldosterone is largely independent of adrenocorticotropin and the adenohypophysis and that its responses to ACTH may reflect the increased availability of aldoste- rone precursors from other parts of the cortex. Nevertheless, the secretion of aldosterone in dogs appears to be dependent on an intact pituitary gland (Davis, et al., 1959a). However, as one might expect, a variety of stimuli which produce an increase in the secretion of ACTH may also stimulate an increase in the secretion of aldosterone. Farrell (1958) lists position, surgery, emotional factors, hypertension, insulin shock, and other stimuli among those resulting in an increased secretion of aldosterone, but prob- ably none of these are without an effect on fluid and electrolyte balances which in turn would effect directly the mechanisms regulating the secretion of aldosterone. On the other hand, there is a marked increase in the secre- tion of aldosterone in those diseases which are characterized by striking disturbances in fluid and electrolyte metabolism, such as congestive heart failure, hepatic cirrhosis, and nephrosis (Liddle et al, 1956) . It seems likely that the increase in aldosterone secretion is slight in those circumstances which produce a marked increase in the secretion of ACTH and of the carbohydrate-active corticoids unless there is also involvement of fluid and electrolyte balances. It has been found that only one, the A-1 fraction, of the several distinct fractions of ACTH has an appreciable effect on the secretion of aldosterone, and this fraction is a relatively small proportion of the total amount of ACTH which may be secreted (Farrell et al, 1958; Farrell, 1959a) . The principal regulation of aldosterone secretion seems to be by a com- bination of neural and neurohumoral factors in response to changes in the volume of extracellular fluid or body potassium. However, there can be little doubt that a hormonal factor is involved in aldosterone secretion, as recently demonstrated with cross-circulation experiments by Yankopoulos et al (1959) . Recent experiments have indicated that the brain may secrete a hormone, glomerulotropin, not as yet isolated and characterized, from the region of the pineal body which stimulates the secretion of aldosterone from the adrenal zona glomerulosa (Farrell, 1959a) . Small changes in blood volume can effect striking changes in the rate of secretion of aldosterone (Bartter, 1957) possibly by affecting changes in pulse pressure (Bartter and Gann, 1960). Changes in blood volume elicit maximal reciprocal responses in the secretion of aldosterone and it appears that this system is the most sensitive, as well as the most important, of those involved in the regulation of the secretion of aldosterone (Bartter, 1957; Bartter et al, 1959). A rise in blood volume reflexly depresses the 204 /. /. Christian secretion of aldosterone via stretch receptors in the region of the right striiim or adjacent vena cava (Davis ct al., 1956, 1957, 1958; Liddle ct al., 1956; Bartter et al, 1958, 1959; Farrell, 1959a; Anderson et al, 1959), the vagus nerve (Mills et al, 1958), and central pathways possibly to depress the secretion of glomerulotropin from the pineal region of the brain al- through Davis et al (1959b) indicated that the vagus is not involved in the afferent pathways of this control. Conversely, a decrease in blood volume stimulates the secretion of aldosterone (Bartter et al, 1959), although the exact pathways and mechanism by which this is achieved is unknown. Bartter and Gann (1960) have suggested that pulse pressure is a factor in changes in blood volume which affects aldosterone secretion. A drop in pulse pressure stimulates the release of aldosterone and a rise inhibits its release. These changes apparently come about through changes in the rate of tonic impulses over receptor nerves in the region of the thyrocarotid artery. Another system that regulates the secretion of aldosterone involves the levels of potassium in the body. A deficiency of potassium, therefore a lowered concentration of body potassium, results in a lower rate of secretion of aldosterone if it was originally elevated, whereas an increase in body potassium results in an increase in the secretion of aldosterone (Bartter, 1956; Bartter et al, 1959). A rise in serum potassium, either absolute or relative to the concentration of sodium, is associated with an increase in the secretion of aldosterone, but it is not known whether a fall m potassium actively inhibits its secretion or permits it to return to base levels passively (Farrell, 1958) . It has been shown that these changes in the rate of secre- tion of aldosterone in response to changes in body potassium are inde- pendent of sodium concentration in the serum or the total amount of so- dium in the body and are also independent of the sodium: potassium ratio in the serum (Bartter, 1956; 1957; Bartter et al, 1959). Similarly, there is no evidence to suggest that altered renal hemodynamics are responsible for the altered secretory rates of aldosterone (Bartter et al, 1956; Cole, 1957). It is not known yet whether the regulation of the secretion of aldosterone by the body potassium is directly on the cells of the adrenal zona glomerulosa or is mediated through central channels (Bartter, 1956; Bartter ct al, 1959) . It cannot be said whether serum potassium, intracellular potassium, or a combination of both effects the control of the secretion of aldosterone, but there is evidence that the adrenal cortical cells themselves may respond directly to this type of stimulus (Bartter, 1956) . On the other hand, Farrell (1958) suggests that the effect is through central channels. However, changes in potassium are not as important in the regulation of the secretion of aldosterone as changes in the volume of the extracellular fluid (Bartter, 1957; Bartter efaL, 1959). 2. Endocrines and Populations 205 In summary, three mechanisms are involved in regulating the secretion of aldosterone. The first and most important regulating factor is the volume of the extracellular, probably intravascular, fluid, changes in which act through atrial stretch receptors and other as yet unknown pathways to effect reciprocal changes in the rate of secretion of aldosterone. Decreased pulse pressure also stimulates increased aldosterone secretion and may be one way in which changes in blood volume act. Depression of the secretion of aldosterone by increases in blood volume requires an intact vagus nerve. The second mechanism responds to changes in body potassium; a rise in potassium resulting in elevation of the rate of secretion of aldosterone and a fall in potassium permit the secretion of aldosterone to fall back to normal. Finally, adrenocorticotropin, or at least a fraction thereof, is capable of stimulating the secretion of aldosterone in the intact animal, but only to a moderate degree and for a relatively short period of time, although the secretion of aldosterone or its regulation and the functional integrity of the adrenal zona glomerulosa apparently do not depend upon adrenocorti- cotropin. Glomerulotropin, a recently described hormone from the pineal complex region of the brain which stimulates the secretion of aldosterone, may be an important link in the regulating system depending on the volume of the extracellular fluid or body potassium or both, but this work requires confirmation. The actions of aldosterone are essential in combatting incipient shock mammals, and this hormone apparently plays a vital role in the daily maintenance of fluid and electrolyte homeostasis. Aldosterone also may be more directly responsible for maintaining blood pressure and counteracting hemoconcentration through its activity in correcting alterations in blood volume. h. The zona fasciculata. (1) The hormones. This zone of the adrenal cortex normally secretes hydrocortisone (Kendall's compound F), corti- costerone (Kendall's compound B), small amounts of cortisone (Kendall's compound E), 11-deoxycorticosterone (Kendall's compound A), 11-de- oxycorticosterone (DOC, DCA, or DOCA), ll-deoxy-17-hydrocorti- costerone (Reichstein's compound S), and C19 ketosteroids, usually andro- genic, the amounts and proportions depending on the species and the circum- stances. Although modification of this concept is required in the light of the work of Symington and his co-Avorkers (1958) (c/. above). Their experi- ments indicate that the reticularis is the part of the cortex that normally produces corticoids and 17-ketosteroids at rest, and that the fasciculata be- comes functional with increased stimulation. In other words, the reticularis is the active part of the cortex and the fasciculata is a resting portion. Actually this work indicates that the morphologic separation of the cortex into fasciculata and reticularis is unjustified. In addition to aldosterone, the 206 /• /• Christian normally important adrenocortical hormones are corticosterone and hydro- cortisone, and their respective ratios vary from species to species (Bush, 1953; Nelson, 1955) and possibly with the degree of cortical stimulation (Bradlow and Gallagher, 1957). The ratio of hydrocortisone to corticoste- rone (F:B ratio) may vary from less than 0.05 in rats and rabbits to greater than 20 in monkeys (Bush, 1953; Reif and Longwell, 1958; Dorfman, 1959) . Most species lie between these two extremes (Bush, 1953) . However, there is little doubt that in most species studied, exclusive of rats and mice, these two steroids form from 80% to 95% of the total adrenal secretion of corticoids (Jones, 1957). Corticosterone is the principal carbohydrate - active corticoid secreted by mice, rats and, rabbits (Bush, 1953; Hofmann, 1956; 1957; Reif and Longwell, 1958; Wilson et al, Bloch and Cohen, 1960) . whereas hydrocortisone is the principal corticoid in other species, including guinea pigs, hamsters, ferrets, cats, monkeys, sheep, and humans (Bush, 1953; Nelson, 1955; Jones, 1957; Peron and Dorfman, 1958, Schindler and Knigge, 1959a, b). The adrenals of house mice and rats apparently secrete large amounts of 1 l-hydroxy-**-androstene-3 , 17-dione ( 1 1-0H4AD) 1 1-hy- droxyandrostene-3,17-dione, and other closely related steroids as major components of their natural adrenal secretory product in addition to corticosterone and very small amounts of hydrocortisone and other corti- coids (Sweat and Farrell, 1952; Bush, 1953; Hofmann, 1956; Bahn et al., 1957; Poore and Hollander 1957; Wilson et al., 1958 Bloch and Cohen 1960). Probably all species secrete 11-0H4AD and closely related Cig steroids, but usually in proportionately small amounts (Bradlow and Gal- lagher, 1957; Gallagher, 1958). However, it has been shown recently that the adrenal androgen, dehydroepiandrosterone, comprises about 50% of the total secretion of steroids by the human adrenal cortex (Vande Wiele and Lieberman, 1960) . The general problem of the secretion of sex steroids by the adrenal cortex has not been studied until recently in the same detail as the carbohydrate-active corticoids, especially with regard to differences among species, but there is no doubt that they are secreted b}^ the cortex (Gallagher, 1958) . These Cig steroids may be normal products, metabolites, or intermediate metabolites in the synthesis of other steroids (Dorfman and Shipley, 1956; Gallagher, 1958). Apparently there is con- siderable variation with species with respect to the secretion of androgens and androgen precursors (Bush, 1953; Jones, 1957; Gallagher, 1958; Wilson et al., 1958) . In any event, the adrenal cortex is the starting point of C19 steroids which may act as weak androgens (Dorfman and Shipley, 1956; Gallagher, 1958) . Normally cortisone, hydrocortisone, and corticosterone appear in the urine as metabolites which can be identified and related to the parent corti- coid by the appropriate procedures (Gallagher, 1958; Dorfman, 1960). 2. Endocrines and Populations 207 However, there are other metaboHtes in the urine in smaller (juantities which cannot be related specifically to particular adrenocorticoids without radioactive labeling, but these ordinarily are not produced in appreciable ciuantities (Gallagher, 1958). The types and quantities of the metabolites of a particular hormone which appear in the urine usually provide a good index of adrenocortical activity for relatively longer periods of time than can be obtained by the measurement of the corticoids in the plasma, which only reflect the immediate situation (Nelson, 1955). However, the urinary metabolites do not always reflect the actual adrenal secretory pattern, as has been shown for mice (Bradlow et at. 1954; Wilson ct al., 1958) although in many instances this may be surmised with confidence (Dorfman, 1960). In summary it may be said that hydrocortisone or corticosterone and C19 weak androgens are the major secretory components of the adrenal fascicu- lata, but that other carbohydrate-active corticoids, sodium-retaining corti- coids, and adrenal androgens are also secreted, although usually not in appreciable quantities. It is impossible to make hard and fast statements about the quantitative relationships of the adrenocortical hormones to one another because of a certain degree of inherent variability and because the techniciues for their measurement are not sufficiently refined and certain for such detailed comparisons. A large number of steroids have been isolated from the adre- nals of various species, frequently from perfused glands. Some of these may be biochemical artifacts, but many are probably intermediate products in the biosynthesis of the normal secretory products, or possibly steroids which are secreted only under unusual conditions (Jones, 1957; Bradlow and Gal- lagher, 1957; Gallagher, 1958) . It is not known whether or to what extent, some of these steroids are secreted naturally. The picture is complicated further by the fact that the liver and other tissues metabolize the steroid hormones to new steroids which appear in the circulation and urine and which may have biological activity to varying degree (Gallagher, 1958). Therefore, the specific roles of the various adrenocortical steroids and their metabolites, especially those that appear in very low concentrations, in the economy of the w^hole mammal, and the variations in their secretory pat- terns from species to species and under normal and abnormal circumstances, needs clarification. Some of the discrepancies that appear in the literature regarding the relative amounts of various steroids secreted by the adrenals of a particular species seem to depend on whether the measurements were made in vivo or on perfusates of isolated glands (Bush, 1953; Jones, 1957). It seems evident that appreciably higher proportions of steroids which normally are secreted in low concentrations are found in perfusates than in vivo. However, it suffices for the present to know that the carbohydrate- active corticoids, hydrocortisone and corticosterone, are the major na- 208 /. /. Christian turally secreted corticoids of the zona fasciculata and to discuss the actions of these hormones as a class. (2) Adiojis of the fascicular hormones. Hydrocortisone, cortisone, and corticosterone have important effects on carbohydrate metaboHsm and therefore are classed loosely as carbohydrate-active corticoids. They have in common either a hydroxyl group or ketonic oxygen at the carbon-11 position, and those with the most pronounced effects on carbohydrate metabolism, hydrocortisone and cortisone, have a hydroxyl group on the C-17 of the steroid nucleus. Corticosterone has a weaker action on carbohy- drate metabolism than hydrocortisone or cortisone (Dorfman, 1949; Ingle, 1950; Parmer et al., 1951; Santisteban and Dougherty, 1954; Dougherty and Schneebeli, 1955; Kass et al., 1955; Noble, 1955) , but it has appreciably more effect on salt-electrolyte metabolism than either of the others (Noble, 1955; Farrell et al., 1955; Jones, 1957) . Because of these facts, the relatively small amounts of hydrocortisone which are normally secreted by the adre- nals of mice and rats, along with corticosterone, have been held responsible for most of the carbohydrate-active corticoid activity, such as involution of the thymus, which has been observed in these animals (Wilson etal., 1958). The designation "carbolwdrate-active corticoids" for this group of steroids by no means reflects all their activities. These corticoids have sup- pressive effects to varying degrees on inflammation and therefore are classified also as anti-inflammatory (antiphlogistic) hormones (Selye, 1950; Dougherty 1953) . As a class they have profound effects on protein metabo- lism, fat metabolism, growth, oxygen consumption, and a number of other physiological functions (Noble, 1955; Jones, 1957). Hydrocortisone and cortisone are the most powerful of the fascicular carbohydrate-active corticoids and corticosterone the least powerful with respect to the enume- rated activities (cf. above), although cortisone is not produced in bio- logically important quantities in any of the species so far investigated (Bush, 1953; Nelson, 1955). As a general rule, the degree of activity of a corticoid on carbohydrate metabolism is related inversely to its sodium-re- taining ability. Finally, it should be noted that other steroids may affect the actions of the corticoids; for example, testosterone and estradiol potentiate the anti-inflammatory action of the carbohydrate-active corticoids (Tauben- haus, 1953), and testosterone enhances the thymolytic activity of cortisone (Selye, 1955; Dorfman and Shipley, 1956) . The carbohydrate-active corticoids, secreted by the zona fasciculata, will maintain life in adrenalectomized mammals (Ingle, 1950) ; nevertheless the exact functions of the adrenocortical hormones in the intact normal animal are difficult to delineate precisely, as these hormones are integral elements in a complex system of endocrine and neural responses which form a feed- 2. Endocrines and Populations 209 back system to maintain homeostasis or to meet emergencies. Nevertheless, much has been learned about the specific activities of these hormones by the classic experimental approaches to such a problem : the substitution of pure hormones or extracts into intact and adrenalectomized animals and refinements of these procedures. The effects of injected carbohydrate-active corticoids are closely paralleled by those produced by injecting adreno- corticotropin (ACTH), the hormonal protein of the anterior pituitary responsible for stimulating the secretion of the carbohydrate-active and Ci9 steroids from the adrenal cortex (Poore and Hollander, 1957; Li et al., 1957; Lostroh and Li, 1957; Wilson, et al., 1958; Farrell et al., 1958). The carbohydrate-active corticoids stimulate gluconeogenesis from pro- teins, and this activity is reflected by hyperglycemia and glycosuria (Ingle, 1949; 1950; Jones, 1957). The increased levels of glucose in the blood and urine are also partly due to the inhibition of glucose utilization (Jones, 1957) . These hormones also increase glycogen deposition in the liver by accelerating its formation and depressing its release (Ligle, 1950; Jones, 1957) . Glycogen deposition commonly is used to bioassay steroids for their gluconeogenic activity and other effects of carbohydrate metabolism (Dorf- man, 1949). The carbohydrate-active steroids not only increase protein catabolism, but they also depress protein anabolism (Engel, 1952). These two actions on protein metabolism are reflected by an increase in the non- protein nitrogen of the blood as well as an increase in the excretion of uri- nary nitrogen (Selye, 1950) . Lipogenesis is inhibited by the carbohydrate- active corticoids, but their effects on lipid metabolism are poorly understood (Jones, 1957) . There is considerable evidence to indicate that hydrocorti- sone and cortisone increase the sensitivity of blood vessels to the actions of epinephrine and norepinephrine, and that these steroids perform an essen- tial function in maintaining normal tonus of the vasculature (Zweifach et al., 1953; Ramey and Goldstein, 1957). The carbohydrate-active hor- mones also decrease capillary permeability and fragility and antagonize the spreading action of hyaluronidase, presumably by their effects on the ground substance; these corticoids appear to decrease permeability of the ground substance, and their ability to decrease capillary permeability may be dependent on this effect (Seifter et al., 1953; Zweifach et al., 1953). In these effects the carbohydrate-active corticoids are opposed by the actions of the sodium-retaining corticoids and growth hormone (Seifter et al., 1953; Kass et al. 1953b; Dougherty and Schneebeli, 1955; Kramer et al., 1957) . In addition to their catabolic effect on protein, the carbohydrate-active corti- coids have specific suppressive effects on osteogenesis, chondrogenesis, mitosis, growth in general, connective tissue growth, inflammation, phago- cytosis, granulation, and antibody formation (Taubenhaus and Amromin, 1950; Baker, 1950, Selye, 1951; Dorfman, 1953; Dougherty, 1953; Tauben- 210 /. /. Christian haus, 1953; Bullough, 1955; Dougherty and Schneebeli, 1955; Kass et al., 1955; Irving, 1957) . The effects on inflammation result from a failure of the usual inflammatory cells, lymphocytes and fibroblasts, to appear at the site of injury (Dougherty, 1953; Dougherty and Schneebeli, 1955). The lack of an adecjuate inflammatory response together with the failure of adetiuate granulation to take place markedly delays wound healing (Dougherty, 1953; Dougherty and Schneebeli, 1955) . These effects, coupled with inhibi- tion of phagocytosis and antibod}^ formation, result in a marked decrease in resistance to infections, so that an animal may be rapidly overwhelmed by an infection (Thomas, 1953). There is ample experimental evidence to show that cortisone and hydrocortisone decrease host resistance to infection by a wide variety of pathogenic viruses, bacteria, protozoan and metazoan parasites (Thomas, 1953; Shwartzman and Aronson, 1953; LeMaistre^ia/., 1953; Kass et al. 1953b; Robinson and Smith, 1953; Whitney and Anigstein, 1953; Pollard and Wilson, 1955) . Animals resistant to particular organisms may be made nonresistant by these steroids, and usually mild infections may become highly virulent. High physiological doses of cortisone or hydrocortisone in the pregnant mammal may result in the development of malformations, especially cleft palate, in the fetus, the particular anomaly apparently depending on the stage of development of the fetus when it is subjected to the actions of the hormone (Glaubach, 1952; Fraser et al, 1953; Davis and Plotz, 1954; Kal- ter, 1954; Moss, 1955). Cortisone and hydrocortisone both produce cleft palates and other congenital defects in the fetus when injected into pregnant mice, the incidence of these anomalies being greater when the injections were made on the tenth day than when later ( Fraser et al., 1953) . The tera- togenic effects of cortisone in mice have been shown to be decreased with increased maternal body weight and to be affected by maternal genotype (Kalter, 1954; 1956). Treatment of pregnant rats with high physiologic doses of cortisone results in a significant increase in intra-uterine mortalit3\ occurring minly at mid-term, and later (Seifter et al., 1951 ; Davis and Plotz, 1954) . High doses of cortisone administered to nursing mice 9-12 days after parturition depress the growth of progeny, whereas ACTH and low doses of cortisone were without effect on the offspring, except to abolish the difference in growth rate normally seen between male and female mice (Glaubach, 1952). Cortisone, and to a lesser degree ACTH, depresses the growth of infant rats, stimulates the eruption of teeth, opening of the eyes, and development of the gingivae (Parmer et al, 1951) . Cortisone in a total dose of 0.5 mg. given to newborn rats during the first week produced long- term damage, as indicated by the failure of the animals to attain normal body weight after three months (Parmer et al., 1951). Corticosterone and pregneninolone were without effect in these experiments. Cortisone treat- 2. Endocrines and Populations 211 mciit of neonatal rats can also result in marked morphologic changes in the brain and skull (INIoss, 1955). Cortisone or hydrocortisone may stimu- late lactation (Selye, 1954), but the mechanism by which this is accom- plished is unknown. These effects cannot be attributed to an inhibition of the secretion of gonadotropin by cortisone, as it has been shown that even relatively large doses of cortisone are without effect on the production of gonadotropins (Byrnes and Shipley, 1950), although it is well known that enormous doses of corticoids do exert some antigonadotrophic activity. The carbohydrate-active corticoids also involute lymphoid tissues by producing degeneration and actual fragmentation of the lymphoid cells, inhibition of differentiation, and depression of lymphocytopoiesis (Selye, 1950; Dougherty, 1953; Santisteban and Dougherty, 1954; Gordon, 1955; Weaver, 1955). These effects are also seen following injection of ACTH, with an increase in endogenous corticosteroid secretion (Baker ei al., 1951). Lj^mphocytolysis evidently serves to release a readily available store of amino acids and may serve to provide a sudden flood of stored antibodies, which are normally produced m the lymphoid tissues (Keuning et al., 1950; Dougherty, 1953; Kass et al., 1953a; Sundberg, 1955). These actions result in involution of the thymus, lymph nodes, and malpighian corpuscles of the spleen. Therefore weights of those organs may provide useful indices of adrenocortical activity when they are used along with other indices of adrenal activity, such as adrenal weight, and appropriate controls. It should be remembered, however, that androgens, and to a somewhat lesser extent estrogens, are capable of involuting the thymus (Burrows, 1949; Weaver, 1955) ; therefore cognizance must be taken of this fact when using thymic involution as a means of appraising adrenocortical activity. How- ever, the lymph nodes lose weight only after treatment of the animal with ACTH or carbohydrate-active corticoids (Weaver, 1955). Estrogen, tes- tosterone, thyroid extract, adrenalectomy, thyroidectomy, and gonadec- tomy were without effect on the lymph nodes in these experiments (Weaver, 1955) . The adrenal carbohydrate-active corticoids also depress the numbers of circulating eosinophils and lymphocytes, so that counts of these cells are frequently used to assess the functional integrity of the pituitary-adreno- cortical system (Speirs and Meyer, 1949; 1951; Gordon, 1955; Speirs, 1955). In using counts of eosinophils or lymphocytes as indices of adreno- cortical activity in wild mammals care must be taken (1) to standardize the procedures so that the results are completely comparable from count to count, and (2) not to elicit an adrenocortical response during the process of handling the animal. The biological activity of ll^-hydroxyA^-androstene-3,17-dione (llOH- 4AD) and the closely related steroid 11/3-hydroxytestosterone, as well as other related C19 steroids, deserve further comment, as one or the other of 212 J. J. Christian thefirst two, probably the first, is a major secretory product of the cortex, presumably of the zona fasciculata-reticiilaris of house mice, rats, and very possibly other rodents (Bush, 1953; Wilson ei al., 1958), and to these must be added dehydroepiandrosterone, which is now known to account for half of the steroid product of the adrenal cortex of human beings (VandeWiele and Lieberman, 1960) . These steroids, as a group, are very weak androgens with insufficient activity to maintain the seminal vesicles and ventral prostate in hypophysectomized mice (Bahn et al., 1957), although they evidently are sufficiently androgenic to produce histologically detectable changes in the epithelium of these organs, if not in changes in gross weight (Davidson and Moon, 1936; Lostroh and Li, 1957), and evidently, if they are secreted in large enough ciuantities, they can produce masculinization in humans (Dorfman and Shipley, 1956). In addition, Howard (1959) has shown that these weak androgens are more strongly androgenic if their activity is measured in terms of other assays, such as stimulation of the preputials and os penis. However, the C19 steroids with weakly androgenic activity, as measured by their ability to stimulate growth of the prostate or capon comb, can inhibit the secretion of gonadotropins in rats, especially in immature animals (author's italics) , although it has been shown that the carbohydrate-active corticoids are incapable of producing this effect (Byrnes and Shipley, 1950; Byrnes and Meyer, 1951; Wilson et al., 1958). Therefore, it is possible that an increased secretion of these androgens steroids by the adrenal cortex in mice and rats can account, at least in part, for the suppression of reproduction commonly associated with circum- stances which increase the secretion of ACTH and carbohydrate-active corticoids, as described by Selye (1939). These, in brief, are the actions of the important adrenal cortical hor- mones. Many questions remain unanswered regarding the functions of the cortical hormones, especially wath respect to their relationships to each other and to other endocrines, such as the thyroid and pancreatic islets. The carbohydrate-active corticoids in many respects are antagonistic to insulin and probably suppress thyroid activity, but these topics will not be dealt with here. The actions already listed are the major activities of the cortex which will enable an interpretation to be made of, as well as to anticipate, the results in other species. All the above effects have been duplicated by injecting adrenocorticotropin into intact mammals and thereby stimulating an increased secretion of endogenous adrenocortical steroids. They also have been produced by alarming stimuli, which increase the secretion of endogenous ACTH and in turn endogenous corticoids. Among these stimuli are cold, emotional trauma, physical trauma, toxic agents, and many others, although the general response to these stimuli is not necessarily quantitatively, or even quantitatively, similar in every case. 2. Endocrines and Populations 213 There is much to learn about the differences in hormonal response to different stimuli. There are excellent reasons to believe that the various adrenocortical hormones are not always secreted in any fixed proportion to each other independently of the nature of the stimulus or its degree of severity (cf. above). Therefore it seems advantageous to speak of the responses evoked by the specific stimulus in each case rather than of a generalized nonspecific response to "stress." (3) Regulation of secretion of the fascicular hormones. The regulation of the secretion of the hormones of the cortical zona fasciculata has been investigated intensively, and a great deal is known about the mechanisms involved, although many questions still remain unanswered. It is well established that adrenocorticotropin (ACTH), a protein hormone secreted by the anterior pituitary, stimulates corticoid production and release from the adrenal fasciculata and to a lesser extent stimulates the secretion of aldosterone from the zona glomerulosa (Wexler et al., 1955; Allen, 1957; Farrell ct al, 1955; Jones, 1957; Li et al, 1957; Farrell et al, 1958, and other references cited earlier) . ACTH also stimulates cellular hyperplasia and hypertrophy of the cortex, although pituitary growth hormone may play an important role in stunulating cortical hypertrophy (Cater and Stack-Dunne, 1953, 1955; Jones, 1957; Lostroh and Li, 1958), possibly acting synergistically with ACTH (Lostroh and Woodward, 1958). How- ever, growth hormone has no effect on the release of corticosteroids (Rosen- feld and Bascom, 1956; Guillemin et al, 1958) . ACTH also has a number of extra-adrenal actions; for example, it stimulates the preputial glands and other sex accessories, but not to the same extent as does testosterone (Davidson and Moon, 1936; Davidson, 1937; Jacot and Selye, 1951; Lostroh and Li, 1957) . The regulation of the release of ACTH from the pituitary is not clearly understood, although there no longer can be any doubt that for the most part a neurohumor from the hypothalamus has a major role in regulating the production and release of ACTH (IMcCann, 1953; McCann and Brobeck, 1954; Harris, 1955a, b; Fortier, 1957; Wood- bury, 1958). The regulation of the release of ACTH has been reviewed by Harris and Fortier (1954), Harris (1955b), and Fortier (1956), but advances in this field are rapid, and much additional information is available which is not included in these reviews. Some doubt has been cast on the role of the hypothalamus in regulatmg ACTH secretion in response to surgical trauma (Story efai., 1959). The adenohypophysis has a double arterial supply: a portal system draming from the hypothalamus and a direct systemic arterial supply (Green, 1951). Branches from the superior hypophyseal arteries form a tufted plexus of capillaries in the median eminence of the hypothalamus in 214 /. /. Christian intimate association with nerve fibers of the supraopticohypophyseal tract. These vessels drain into the adenohypophysis, where they break up to form a series of sinusoids. Here they are joined by capillaries from the systemic arterial supply. The direction of the flow is from the median eminence to the adenohypophysis. Neural fiber tracts from hypothalamic nuclei descend through the median eminence and give off branches which terminate in intimate association with the arterial portal plexus in the median eminence (Scharrer and Scharrer, 1954). The remaining fibers continue on their way, to terminate in close approximation to capillaries in the neurohypophysis. Neurosecretory material is believed to traverse the sheaths of these nerves from hypothalamic secretory nuclei (Scharrer and Scharrer, 1954; Rennels and Drager, 1955). There is evidence that a fraction of this neurosecretory material is responsible for stimulating the release of ACTH from the anterior pituitary (Drager, 1955; Rothballer, 1953; Saffran et al., 1955). Evidently the material is released by the appro- priate stimulus from the terminations of the neurosecretory fibers into the pituitary portal vessels and is then borne, via the portal system, to the cells of the adenohypophysis proper (Scharrer and Scharrer, 1954; Rennels and Drager, 1955). It is generally accepted that no nerve fibers terminate in the adenohypophysis and that there are no direct neural, only vascular, connections between the adenohypophysis and neurohypophysis (Green, 1951). The identity of the hypothalamic corticotropin-releasing factor (CRF) has not been determined, although it appears to be a small protein often associated with Pitressin (Saffran et al., 1955; Porter and Rumsfeld. 1956). One group of investigators believes that the ACTH-releasing ac- tivity is associated with Pitressin, in particular with its pressor activity (ADH, vasopressin) (McCann, 1957; jMcCann and Fruit, 1957). ADH exerts a powerful antidiuretic action on the kidney at many times the dilution that is necessary for it to exert a pressor effect or to stimulate the release of the ACTH (McCann and Fruit, 1957) . It has been suggested for this reason that the concentration of ADH, when it is released from the posterior pituitary into the systemic circulation, is sufficient to effect anti- diuresis, but insufficient to stimulate the release of ACTH, but that when it is released directly into the pituitary portal circulation, it reaches the adenohypophysis in a sufficient concentration to effect the release of ACTH (McCann and Fruit, 1957). It should be noted that ADH evidently is released simultaneously into the pituitary portal system from the hypothal- amus and from the neurohypophysis into the systemic circulation in re- sponse to stimulation. Nevertheless, as attractive as this theory may seem, good evidence is accumulating from a number of sources which indicate's that the corti- cothopin-releasing factor is an entity separate from vasopressin, although 2. Endocrines and Populations 215 the site of its origin in the hypothalamus and its exact identity remain mi- known (Saffran et al., 1955; Porter and Jones, 1956; Porter and Rumsfeld, 1956; Clayton et al., 1957; Schally and Guillemin, 1959), and that the release of ADH may be completely unrelated to the release of ACTH (Mc- Donald et al, 1957; Schapiro et al, 1958) . It appears that this substance is a small protein which is recoverable from hypophyseal portal blood, from the neurohypophysis, or from extracts of appropriately selected portions of the hypothalamus, and that it is probably loosely bound to and travels with a much larger protein which is inactive with regard to the release of ACTH (Porter and Rumsfeld, 1956; Guillemin et al, 1957; Schally and Guillemin, 1959). The activity of the corticothopin-releasing factor may be augented by the simultaneous action of epinephrine (Saffran et al, 1955) . As is so often the case, the solution to this problem may prove to be midway be- tween, or to be a combination of, the two opposing views. It is possible that there are hypothalamic substances, such as vasopressin, other than a specific corticotropin-releasing factor which are capable of effecting the release of specific ACTH fractions from the adenohypophysis. Recent- evidence indicates that different stimulating factors are involved in ac- tivating different adrenocortical functions (Fortier, 1956; Guillemin et al, 1958 ; Slusher, 1958 ; Nowell, 1959) . In spite of the existing uncertainty with regard to the nature of the speci- fic factor or factors from the hypothalamus which stimulate the release of ACTH, there is little doubt that hypothalamic substances carried to the adenohypophysis by the portal system can stimulate the release of ACTH in response to alarming stimuli, although Nowell (1959) has suggested that emotional and systemic stress involve different pathways for the release of ACTH. However, there are many other aspects of the overall regulation of the secretion of adrenocorticotropin which are not clear at the present time. One of these aspects is the control of the normal daily low- level secretion of ACTH. There probably is a basal release rate of ACTH which is independent of the hypothalamic-hypophyseal portal system and which is sufficient for normal maintenance of adrenocortical function (Fortier, 1957) . A number of workers maintain that the release of ACTH is subject to hypothalamic control only in response to acute stressful stimuli (Woodbury, 1958) . The level of circulating corticoids undoubtedly exerts a control over the rate of secretion of ACTH, as circulating adrenocorticoids are capable of inhibiting the release of ACTH under most circumstances, although the more severe the stimulus, the greater the level of circulating corticoids must be in order to block ACTH secretion (Sydnor and Sayers, 1954; Farrell and Laqueur, 1955; Sydnor et al, 1955; Richards and Pruitt, 1957). Fvu'thermore, Fortier (1959a, b) has shown that the corticotropin- releasing effect of stress is influenced markedly by the level of circulating 216 /• /• Christian corticoids. Withdrawal of the corticoids enhances both the release and synthesis of ACTH, its predominant effect being on the synthesis (Fortier, 1959a, b) . The steroids appear to act on the pituitary itself, but they may act also on the hypothalamic centers, or on the releasing mechanism or mechanisms themselves, or even may act to some extent on the adrenal gland directly (Birmingham and Kurlents, 1958). However, the corticoids evidently are not capable of blocking the release of ACTH in response to all types of tissue damage, unless the steroids are present in very large quan- tities. It has been suggested in the case of tissue damage, such as burns, that substances are released from the site of the injury (Hume, 1953; Woodbury, 1958; Share and Stadler, 1958), which are able to stimulate directly the release of ACTH by direct action on the pituitary, although final proof of such a suggestion is lacking. It is unlikely that histamine, epinephrine, serotonin or a variety of other compounds which are released during tissue-breakdown are responsible for directly stimulating the release of ACTH (Sandberg et al, 1953; Guillemin, 1955; Guillemin et al, 1957; Woodbury, 1958) as has been suggested. Nervous impulses from the site of injury cannot be responsible for initiating the release of ACTH following injury, as complete denervation of the part or transection of the cord fails to block the release of ACTH (Hume, 1953). The mechanism by which adrenocorticotropin is released following tissue damage needs to be deter- mined. Finally, there is evidence that two or more substances from the hypo- thalamus may regulate different activities of the adrenal cortex. Slusher (1958) has shown that lesions in one region of the hypothalamus will block the usual fall in adrenal ascorbic acid which follows cortical stimulation without preventing the release of cortical steroids. On the other hand, lesions in a nearby region can prevent the release of corticoids without pre- venting the fall in ascorbic acid. Guillemin ct al, (1958) have shown that there may be a functional separation of corticoid secretion from ascorbic acid depletion. These investigators found that a marked secretion of corti- coids could occur in the absence of detectable changes in adrenal ascorbic acid concentration when both variables were measured simultaneously fol- lowing stimulation by ACTH in hypophysectomized rats. Finally, there is other evidence which suggests that the factors controlling cortical hyper- trophy (adrenal weight factor: AWF) and ascorbic acid (ascorbic acid factor: AAF) reduction are separate entities and may respond differentially to different stimuli (Nowell, 1959) . Nowell (1959) has suggested that stim- ulation of the release of various ACTH factors from the pituitary may in- volve different mechanisms for different stimuli; for example, emotional stimuli may require activation of the hypothalamic centers, whereas adre- nal regeneration may not require hypothalamic activity. 2. Endocrines and Populations 217 Plainly there are many problems still to be solved before a complete and detailed explanation of the regulation of the release of ACTH and the fascicular corticoids will be possible, but the evidence for the mechanisms which have been described is strong. There is no doubt that the hypothala- mus has a major role in the regulation of ACTH release and of adenohy- pophyseal function in general, and there is no reason to question the existence of such a neurohumoral mechanism. The evidence for some of the details, however, is less conclusive. The cortical glomerulosa and the re- lease of aldosterone are largely independent of this system of regulation, as indicated earlier, except for a very moderate response to ACTH for a limited time. c. The junction of the zona reticularis. The zona reticularis has been thought to secrete sex steroids (Selye, 1947), especially androgens, but the evidence for such a function is poor and largely inferential (Dempsey, 1948; Creep and Deane, 1949b; Jones, 1957). This zone is made up of a continuation of the cords or continuum, as the case may be, of the zona fasciculata, the cells of which are in varying degrees of activity and respond accordingly to stimulation by ACTH (Jones, 1957). By and large they have the appearance of cells of the fasciculata which are declinmg in ac- tivity and becoming obsolete, but there is certainly some functional capa- city in the reticular cells, as indicated by various histochemical procedures and the presence of mitosis, although it is apparently much less than that of the zona fasciculata (Dempsey, 1948; Creep and Deane, 1949b) . Syming- ton et al. (1958) have presented convincing morphologic and histochemical evidence, coupled with secretory studies, that the reticularis normally secretes the hormones usually attributed to the zona fasciculata and that the latter is in a resting state until fvnther stimulated by ACTH. This sug- gestion is well worth considering especially as morphologic changes are related to steroid production by direct measurement. These studies necessi- tate a revision of the classic concepts of the functional roles of the reticularis and fasciculata which have been based only on morphologic evidence. d. The problem of the function of X-zone. The X-zone of the adrenal cortex of the immature house mouse (Mus musculus) is maintained by gonado- tropin rather than by ACTH or growth hormone (Jones, 1949b, 1950, 1952, 1957) . Its function is unknown, and histochemically it does not present the appearance of being a secretory zone (McPhail, 1944; Howard, 1939; 1946; McPhail and Read, 1942a, b) . The cells do not give the usual histochemical reactions for steroids or other lipids, although they do contain ascorbic acid (Jones, 1949a, 1950) . There is no evidence that the X-zone of the house mouse secretes sex steroids (McPhail, 1944; Jones, 1957), although such a function has been postulated by several investigators (Jones, 1957) . In fact the large amounts of Cig steroids secreted by the adrenals of mice in 218 ./• ./• Christian response to ACTH-secrcting pituitary tumors were from the cortictes of adrenals without X-zones (Bahn et al., 1957). On the other hand, Delost (1951) suggests that the X-zone may be that part of the cortex responsible for secreting the adrenal androgens which maintain the activity of the vas deferens and ventral prostate of meadow voles (Microtus arvalis) in winter and in adrenalectomized voles (Delost, 1954). The evidence for this sug- gestion is tenuous and requires further investigation and confirmation. The function of the X-zone, if there is one, remains undiscovered at the present time. 3. Adrenocortical-Gonadal Interrelationships This problem has been discussed by Jones (1957), and the reader is re- ferred to this work for a more detailed discussion of this intriguing problem. There is a very close relationship between the cells of the adrenal cortex and those of the gonadal cells with respect to their origin and function. Both groups of cells arise from the embryonic genital ridge of the coelomic mesothelium, both secrete steroid hormones in response to stimulation by pituitary hormones; and there is a definite overlap in their functional capacities. Even though the adrenal cortex is believed to be a source of sex steroids, gonadectomy in normal animals is followed by complete involution of the sex accessories to the immature condition (Jones, 1957) . The involu- tion occurs even in mammals such as mice and rats in which weakly andro- genic Ci9 steroids normally are an appreciable portion of the cortical secre- tory product (Dorfman and Shipley, 1956; Wilson et al, 1958). Similarly, the sex accessories and secondary sex characteristics which are under hor- monal control fail to develop in the prepubertal castrate mammals (Bur- rows, 1949; Jones, 1957) . Finally, the transplantation of the adrenal to the uterus does not alter the morphology of that part of the uterus or of the vagina which is in direct contact with the graft (Sakiz, 1956) . These facts cast considerable doubt on their ability of the normal adrenal cortex of any species to secrete steroids with strongly androgenic or estrogenic actions. There is much evidence, however, that under certain circumstances the adrenal cortex is capable of assuming sex steroidal activity, for example, in the androgenital syndrome and similar virilizing conditions in man (Dorf- man and Shipley, 1956; Gallagher et al, 1958). A striking increase in the secretion of weakly androgenic adrenal steroids may account for these effects (Jones, 1957) , but they may also result from the conversion of adre- nal androgens into testosterone in these circumstances (Dorfman, 1960). These conditions are usually associated with functional tumors of the cortex or with a marked increase in the secretion of ACTH with an accompanying cortical hyperplasia, but without an appreciable increase in the secretion of 2. Endocrines and Populations 219 the cortieoids, although with a marked increase in the secretion of C19 steroids (Dorfman and Shipley, 1956; Bradlow and Gallagher, 1957, Dorf- man, 19G0) . It is also possible that these effects arc a result of aberrant bio- chemical pathways in the synthesis of adrenal steroids which produce greatly increased amounts of weakly androgenic steroids or possibly some compounds with more strongly androgenic activity (Dorfman and Shipley, 1956; Bradlow and Gallagher, 1957; Gallagher, 1958, Dorfman, 1960). Finally there may be abnormal or greatly increased androgenic metabolites of adrenal steroids (Gallagher et at., 1958). It is well known that gonadec- tomy is followed by a marked increase in the production of gonadotropins ; therefore if the production of sex steroids by the adrenal cortex normally was controlled by gonadotropins, one would expect an increased secretion of these sex steroids to follow gonadectomy and to be reflected by con- tinued maintenance of the sex accessories. This is not the case, as the sex accessories involute nearly completely following gonadectomy (Burrows, 1949; Jones, 1957). However, it has been shown that increased secretion of ACTH is followed after a time by a marked increase in the secretion of Ci9 steroids (Bush, 1953; Dorfman and Shipley, 1956; Bradlow and Gal- lagher, 1957; Jones, 1957; Wilson et al, 1958, Vande Wiele and Lieberman, 1960). Apparently slight stimulation of the sex accessories by adrenocorti- cal androgens occurs following ACTH treatment of gonadectomized rats, but these effects can be detected only histologically (Davidson and Moon, 1936; Davidson, 1937; Lostroh and Li, 1957, Desclin, 1959) . In marked con- trast to the general tenor of these results, Delost (1951) reports that the adrenal cortex secretes hormones with androgenic actions on the sex acces- sories of male Microtus arvalis, as determined by morphologic criteria, but this work has not been confirmed. Delost (1956a) maintains that cortisone will stimulate some of the secondary sex organs in these mammals, but confirmation of these res ilts also is needed before acceptance of his conclu- sions is warranted. It is best for the present to assume that the adrenal cortex of most species normally does not secrete appreciable amounts of steroids with pronounced androgenic or estrogenic activity and that, it usually represents abnormal function when appreciable quantities of hor- mones with these activities are secreted by the cortex, (Bradlow and Gal- lagher, 1957). The ability of the adrenal cortical and gonadal endocrine cells to secrete steroids with overlapping activity is an intriguing problem, and the reader is referred to Dorfman (1960) for a more detailed discussion of the steroidal biosynthetic pathways involved and the elucidation of some of these paradoxes. There is certainly variation between species in the types of adrenal steroids normally secreted. Under abnormal conditions there is no doubt that the adrenals produce increased amounts of steroids which may have sex steroidal activity and that the ovaries, for example, can be induced 220 /. J. Christian to secrete steroids with cortical or androgenic activity. Hill (1948) has shown that under the proper conditions, the ovaries of mice can assume adrenocortical function when transplanted to the ears. Under other circum- stances the ovaries can be made to secrete androgens (Hill, 1937; Delost, 1955) . It must be apparent that the whole field of adrenal-gonadal relation- ships is poorly understood, especially with regard to species differences. There is one area of adrenal-gonadal relationships, however, which seems to be on relatively solid ground. Selye (1939) called attention to the fact that a variety of stimuli which elicited increased adrenocortical activity also inhibited reproductive activity. Female rats subjected to a variety of alarming stimuli exhibited ovarian atrophy and more or less permanent anestrus. These observations have been confirmed and extended for a variety of species, including mice, voles, man, and others, and for a wide variety of stimuli (Christian, 1959b). The entire and exact mechanisms by which inhibition of reproductive function is brought about are not known with certainty. It may be due in part to a direct suppressive action of the carbohydrate-active corticoids on the reproductive organs; for example, it has been shown that cortisone and hydrocortisone depress the ovarian re- sponse to chorionic gonadotropins in intact rats (Smith, 1955), possibly by direct action on the vasculature. However, it is more likely that the suppression results primarily from an inhibition of the secretion of gonado- tropins from the anterior pituitary when there is an increased production of adrenocorticotropin. Selye (1939) suggested that there is a "shift" in pituitary function; the production of gonadotropins is sacrificed in order to increase the production of "life-maintaining" ACTH. But it is equally, if not more, likely that the secretion of gonadotropin is inhibited by in- creased amounts of cortical androgens following stimulation by ACTH. The ability of androstenedione and other related weakly androgenic steroids to suppress pituitary gonadotropic activity has already been discussed and it has also been stated that these steroids appear to be major natural secretory products of house mice, rats, man and probably other species. It is particularly interesting, especially to those studying popula- tion phenomena, that immature mice are significantly more susceptible than mature mice to the suppressive effects of steroids on the secretion of gonadotropins (Byrnes and Shipley, 1950; Byrnes and Meyer, 1951) . There is also the possibility that nervous stimuli, acting directly through the hypothalamus, can depress gonadotropin secretion. Whether one or all of these mechanisms is involved, there is a decrease in the secretion of gonadotropin with the result that the secretion of sex steroids by the gonads is inhibited and the secondary sex organs may ap- proach the appearance seen following gonadectomy or hypophysectomy (Selye, 1939; Christian, 1959b). The germinal cells of the gonads also 2. Endocrines and Populations 221 reflect the withdrawal of stimuhition by the gonadotropins and sex steroids. Inhibition of these endocrine functions can result in a depression of all reproductive activities, including the onset of puberty, lactation, fertility, normal mamtenance of the embryos in utero, size of the secondary sex organs, and other functions associated with full functional competence of the pituitary-gonadal system (Christian, 1956, 1959a, b). It is pertinent here to note that androgen injected into female mice or rats under 10 days of age will produce permanent sterility ; this finding suggests a method for the production of sterility or markedly delayed maturation in natural popula- tions (Barraclough, 1961; Barraclough and Gorski, 1961). Most of these effects presumably are brought about by a decreased secretion of gonado- tropins, but some of the failures in reproductive function in these situations undoubtedly result from the direct effects of increased levels of corticoids follow^ing increased secretion of ACTH. Certainly the ability of the carbo- hydrate-active corticoids to increase protein catabolism and suppress growth, especially of the connective tissue and its products, and to suppress mitoses, must have appreciable effects on the reproductive process, espe- cially on the developing fetus, as we have indicated earlier. There is con- siderable evidence to indicate that alarming stimuli during pregnancy, pre- sumably with a marked increase in the secretion of adrenocortical steroids, can result in congenital anomalies dependent on the stage of fetal develop- ment (Fraser et al., 1953; Aycock and Ingalis, 1946; Ingalls, 1956; Curley and Ingalls, 1957; Ingalls and Philbrook, 1958). Finally it should be borne in mind that the degree of reproductive sup- pression will vary in some proportion to the severity of the inducing stimu- lus and that there w411 be some variation with species with respect to the particular part of the reproductive cycle which will be most severely cur- tailed. For example, intra-uterine mortality and resorption of the embryos is marked in house mice, but apparently is inconsequential in Norway rats, whereas the postparturitional loss of young is as great or greater in rats than it is in mice (Christian, 1959b). Voles evidently are quite susceptible to depression of fertility and development of maturity (Kalela, 1957) , but house mice are affected similarly (Crowcroft and Rowe, 1957). These variations are of particular importance to the investigator involved in comparative studies, especially in studies of phenomena relating to popula- tion density. It should be kept in mind that the severity and duration of the stimulus and the age of the affected mammal also will have an important bearing on the particular stage of the reproductive cycle affected as well as the degree of its inhibition. There are numerous examples of modification of reproductive function in response to various environmental stimuli, probably representative of activity of physiologic adaptive mechanisms. Baker and Ransom (1932) found that winter temperatures (5°C.) signifi- 222 /. /. Christian cantly reduced the number of births on Microtus agrestis even though they were maintained on summer food. Chitty and Austin (1957) have called attention to the effects of environmental factors, especially social "stress," on changes is estrous pattern and behavior exhibited by Microtus agrestis. Additional examples of the effects of deleterious environmental factors on reproduction will be given later. There is another aspect of the suppression of reproduction which should be mentioned at the present time, although it is not directly pertinent to adrenocortical-gonadal relationships. Inanition, starvation, protein defi- ciency, and probably other dietary inadequacies are capable of depressing or totally inhibiting reproduction, the degree depending on the severity of the inadequacy (Lutwak-]\Iann, 1958), without stimulating increased secretion of ACTH and therefore increased adrenocortical activity (Baker, 1952; Christian, 1959b, c; Eisenstein, 1959), and adrenocortical secretion is actuallj^ depressed in rats deficient in pantothenic acid (Eisenstein, 1957). The experimental evidence on which this statement is based has been derived from laboratory mammals and therefore does not necessarily apply to other species or to natural populations, but the burden of proof lies with those who claim otherwise. Recent experiments with house mice have demonstrated rather conclusively that inanition does not stimulate the pituitary-adrenocortical system, although its effect on the reproductive system is striking ( Lutwak-Mann, 1958; Christian, 1959b, c). Further- more, a deficiency of vitamin Be or partial starvation does not increase the secretion of corticoids nor impau- the ability of the adrenal cortex to secrete them, even though they may be a marked cortical hypertrophy (Eisenstein, 1959). These results are in agreement with those from a large number of earlier experiments (cf. Baker, 1952; Christian, 1959c) . In addition Srebnik et al. (1958) have shown that a protein deficiency results in a failure in the secretion of gonadotropins, and jVIarrian and Parkes (1929) had shown earlier that anterior pituitary extracts could correct the anestrus produced by a dietary insufficiency of vitamin B with the return of normal estrus and normal changes in the accessory organs of reproduction with the estrous cycle. One might hypothesize that an inadequate diet would impair the ability of the anterior pituitary to synthesize its protein hormones. How- ever, the ability of the pituitary-adrenocortical system of mice to exhibit the usual responses to alarming stimuli, and therefore the ability to elabo- rate adrenocorticotropin, in spite of inanition indicates that this is probably not the case (Christian, 1959c). Therefore, the decreased production of gonadotropins by animals subjected to inanition, starvation, or other dietary inadequacies probably operates through an unknown mechanism, probably at the hypothalamic level, which does not reflect an inability of the anterior pituitary to synthesize protein hormones. 2. Endocrines and Populations 223 4. Epinephrine and Norepinephrine ; the Hormones of the Aduexal Medulla and Sympathetic Nervous System The adrenal medulla and its hormones, epinephrine and norepinephrine, have been the subjects of numerous and ^"oluminous reviews and are also discussed in considerable detail in most good texts of physiology and phar- macology. Therefore, except for a few aspects, a detailed account of these hormones and their physiologic and pharmacologic actions will not be given here. The reviews of the following investigators may be referred to for a more detailed coverage of the subject: Hartman and Brownell, 1949; von Euler, 1951; Hagen and Welch, 1956; Gaddum and Holzbauer, 1957; Ramey and Goldstein, 1957; Elmadjian et al., 1958. The adrenal medulla is an integral part of the sympathetic nervous sys- tem. The medulla is homologous with the sympathetic ganglia and is in- nervated by cholinergic preganglionic fibers of the splanchnic sympathetic nerves. Upon stimulation of the sympathetic nervous system, the adrenal medulla discharges norepinephrine and epinephrine into the systemic circu- lation, the proportions of these two compounds varying with the species and with the nature of the stimulus (von Euler, 1951; Hagen and Welch, 1956; Gaddum and Holzbauer, 1957; Gray and Beetham, 1957; Elmadjian et al., 1958; Goldfien et al., 1958). Norepinephrine is also secreted by the postganglionic sympathetic nerves and by the extra-adrenal chromaffin tissue of the sympathetic nervous system (von Euler, 1951; Hagen and Welch, 1956). Norepinephrine probably is the neurohumoral transmitter substance of the postganglionic sympathetic nervous system, and appar- ently is released on nervous stimulation at the sympathetic nerve endings (von Euler, 1951 ; Hagen and Welch, 1956; Richardson and Woods, 1959). These two hormones have profound effects on the circulatory system and glucose and fat metabolism, but by and large their effects are short lived, owing to their rapid destruction in the body by the cytochrome oxidase system or by amine oxidases (Bell et al., 1950; Gaddum and Holzbauer, 1957). Norepineplirine and epinephrine have a variety of effects over the entire body which are brought about largely by their actions on smooth muscle and which in general parallel the effects of stimulating the sympathe- tic nervous system (Hartman and Brownell, 1949). Epinephrine and norepinephrine both have profound pressor effects on the cardiovascular system and on the levels of blood sugar; but epinephrine in general has a greater effect on carbohydrate metabolism and produces a greater hyperglycemic response than norepinephrine, whereas norepineph- rine has a greater pressor effect than epinephrine (Gaddum and Holzbauer, 1957). In many ways the actions of these two hormones are similar, but in others they have opposing actions. Norepinephrine in general produces a 224 /• /. Christian greater rise in blood pressure than epinephrine because it increases overall peripheral resistance, largely by constricting the vasculature of the muscles as well as of the skin (Bell et al., 1950) . Epinephrine produces a greater constriction of the vasculature of the skin, but dilates the vessels of the skeletal muscles and increases the cardiac output by increasing the rate and strength of the heart beat. The effects of norepinephrine on cardiac output are variable. Both of these amines decrease the formation of urine, produce relaxation of the gut by inhibition of its smooth muscle, produce splenic contraction, dilate the bronchi, inhibit the bladder, and produce pupillary dilatation (Bell et al., 19501 . Both produce a rise in blood sugar but, as we have mentioned, epinephrine produces a greater rise than norepinephrine. The rise in blood sugar and subsequent glucosuria result from the mobiliza- tion of glucose from the readily available stores in the liver, and secondarily from the muscles. The immediate effect of epinephrine is to release glucose from the available stores of liver glycogen ; therefore the magnitude of the resulting hyperglycemia depends on the amount of glycogen in the liver (Hartman and Brownell, (1949). The eventual effect of epinephrine, after an initial depletion of liver and muscle glycogen, is to shift carbohydrate from the muscles to the liver, as the uptake of glucose by muscle is de- pressed and it is well known that lactic acid derived from muscle glycogen is used by the liver to synthesize glycogen. The actions of these hormones are the classic preparations for "fight or flight" in response to emergency situations (Cannon, 1915, 1932) . The com- bined activity of epinephrine and norepinephrine ensure adequate blood and glucose to the muscles, increased oxygenation, and adequate blood flow. An increased supply of oxygen to the tissues is ensured by an increase in respiratory rate, bronchial dilatation, and contraction of the splenic capsule with release of stored red blood cells into the circulation. Other activities, unneeded in an emergency, are suppressed. The adrenal medulla and sympathetic nervous system respond to cold, fear, rage, trauma, pain, blood loss, anoxia, emotional tension, and a variety of additional alarming stimuli. A variety of chemical agents, such as potassium and serotonin, will release the catechol amines from the medulla (Gaddum and Holzbauer, 1957). The sympathico-adrenal system represents a major and immediate reaction system of the body to prepare for, or to counteract the effects of, an emergency situation. The acute response is relatively short lived and serves to maintain life and counteract shock until the emergency passes or until longer-acting adaptive systems, such as the pituitary-adrenocortical system, take over and aid in physiologic adaptation to the situation. Recent evidence has shown that norepinephrme is normally found in the walls of the arteries (Schmiterlow, 1948), and that it plays a major, per- haps decisive role in the maintenance of normal vascular tonus and reac- 2. Endocrines and Populations 225 tivity, achieving the latter by diminishing the sensitivity of the arterial musculature to epinephrine and norepinephrine by maintaining a constant low level of pressor amines in the arterial wall (Burn and Rand, 1958a, b). The source of the norepinephrine in the arterial walls is apparently the chromaffin tissue including the adrenal medulla, or sympathetic neural terminations which appear to release a low level of these cathechols amines constantly into the circulation (Bell et al., 1950; Gaddum and Holzbauer, 1957). Experiments with reserpine (Burn and Rand, 1958a, b; Eranko and Hopsu, 1958) , which depletes the epinephrine and norepinephrine from the adrenal medulla and sympathetic chromaffin tissue, depletes the con- tent of catechol pressor amines from the arterial walls and thereby makes them excessively sensitive to circulating epinephrine and norepinephrine. However, the arteries are unresponsive to other noncatechol pressor amines which apparently exert their usual effects by releasing the norepinephrine in the arterial walls (Burn and Rand, 1958a, b). There is also evidence that the adrenal carbohydrate-active corticoids have a part m the maintenance of arterial tonus and reactivity by increasing the sensitivity of the vascula- ture to the action of epinephruie and norepinephrine (Ramey and Gold- stein, 1957) . Reserpine is a pharmacologic agent which causes the disappearance of the catechol pressor amines from the chromaffin tissue and subsequently from the arteries (Burn and Rand, 1957, 1958b), but stimulation of the sympathetic nervous system also can exhaust the pressor amines from the sympathetic ganglia and adrenal medulla, although the stimulus must persist for 30 minutes or longer to achieve exhaustion of the adrenal medul- las of dogs (Gaddum and Holzbauer, 1957). Therefore, it is conceivable that prolonged and intense emotional stimuli, such as one might expect as a result of social interactions between animals in populations of excessive density, might exhaust the stores of pressor amines, especially in the sub- ordinate animals. If such an event occurs, one might anticipate that there would be a subsequent depletion of the arterial norepinephrine and loss of arterial tonus which might account for the occasional deaths due to the shock seen in mice shortly after they are first placed together (Christian, 1955b) or following more protracted periods of social strife (Frank, 1953). A loss of vascular tonus with a subsequent hypotension, and eventually shock with circulatory collapse, could explain the symptoms observed by Frank (1953) in dense populations of Microtus in the wild or in captivity or might be a part of the picture of "shock disease" (Green and Larson, 1938; Green et al, 1939; Christian and Ratcliffe, 1952). There is also the possibility of a simultaneous exhaustion of readily available glucose re- serves by the action of epinephrine, especially in animals with a high metabolic rate, or, perhaps more likely, a loss of the ability to mobilize 226 /. /. Christian reserves due to exhaustion of the supplies of epinephrine. Such a mecha- nism, albeit conjectural, may provide a better explanation for the immedi- ate and precipitate cause, the proximate cause, of "shock disease" than the previously postulated pituitary- adrenocortical exhaustion (Christian, 1950b) , although adrenocortical hyperactivity probably plays an additive or even synergistic role in the cause of the immediate mortality in "shock disease." These conjectures are not meant to relegate the pituitary-adreno- cortical-gonadal system to a secondary role in the more prolonged and chronic effects of increased population density or in the control of popula- tion growth, as we shall see later. However, the available experimental evidence places the sympathico-adrenal medullary system in the forefront of the mechanisms w^hich respond acutely and which need investigation in relation to "shock disease" and the sudden and mass mortality associated therewith, as well as in relation to those sudden deaths, resembling hypo- glycemic shock, which occur on first placing strange mammals together. The development of techniques to measure the secretion of the catechol amines has led to a number of investigations on the secretion of epinephrine and norepinephrine in response to a variety of stimuli. One can almost pre- dict which of these two amines will be secreted in response to a particular stimulus by knowing which has the greater effect on blood sugar or on blood pressure. Norepinephrine appears to be released preferentially by the adre- nal medulla during rest (Gaddum and Holzbauer, 1957). The plasma concentration of norepinephrine rises sharply with acute muscular work, but the response of epinephrine varies from no change to a marked rise, depending on the individual (Gray and Beetham, 1957). Both return to normal levels within 15 to 30 minutes after cessation of work. Hypoglyce- mia is followed by a marked and sharp rise in the medullary secretion of epinephrine with a much less marked rise in norepinephrine (Gaddum and Holzbauer, 1957; Goldfien ct al., 1958). Infusion of glucose promptly re- turns their secretion to normal levels. Repeated production of hypoglyce- mia with insulin eventually leads to a decline in the secretion of epinephrine, evidently due to medullary exhaustion (Elmadjian ct al., 1958). Hypoten- sion produces a marked rise in the secretion of norepinephrine, but little or no rise in epinephrine (Elmadjian et al., 1958). Surgical shock or a change in position from recumbent to standing leads to a sharp rise in the secretion of norepinephrine with or without a rise in epinephrine. (Elmadjian et al., 1958). Tense, anticipatory but passive emotional situations produce a marked rise in the secretion of epinephrine, norepinephrine being secreted in normal amounts, but active, aggressive emotional situations are related to a rise in norepinephrine (Elmadjian et al., 1958) . If the emotional display is intense enough, both epinephrine and norepinephrine are elevated. It is of particular interest that in adrenalectomized patients the secretion levels of norepinephrine and their diurnal variations are completely normal. 2. Endocrines and Populations 227 indicating that the normal daily secretion of norepinephrine is largely from extra-adrenal chromaffin tissues, whereas the secretion of epinephrine is largely from the adrenal medulla. These facts are particularly pertinent to investigations of the physiologic responses of mammals to sociopsychologic factors. The secretion of epinephrine and norepinephrine evidently is controlled by separate hypothalamic centers (Elmadjian et al., 1958). The secretion of norepinephrine apparently is related to an area in the posterior hypothal- amus and that of epinephrine to a lateral area. However, the vasomotor center is in the region of the floor of the fourth ventricle in the medulla oblongata, and it is the most sensitive area relating to the secretion of epinephrine (Elmadjian d o/., 1958). In addition to the actions of epinephrine and norepinephrine listed above, these compounds of the sympathico-adrenal system have important activity relationships with other endocrine organs and their hormones. The medullary hormones, thyroid, and pituitary growth and thyrotropic hor- mones have a number of interrelated and interdependent actions. We have already mentioned that growth hormone stimulates adrenal medullary hypertrophy (Moon ct al., 1950, 1951) . Hypertrophy of the medulla with a pronounced increase in its epinephrine content also follows chronic poi- soning of the thyroids of male and female rats with thiouracil (Marine and Bauman, 1945), whereas chronic nicotine poisoning causes a marked medullary hypertrophy mainly owing to an increase in the norepinephrine- containing cells (Eranko et al., 1959). The latter response cannot be elicited in mice or guinea pigs, although the adrenal medulla of the mouse has both epinephrine and norepinephrine-containing cells (Eranko et al., 1959). This difference clearly demonstrates the kind of difference one may anticipate between species, even as closely related as arc the rat and mouse (Rattus norvegicus and Mus musculus). The ability of epi- nephrine to mobilize depot fat and produce a rise in unesterified fatty acids in intact animals is thoroughly established (Hartman andBrownell, 1949), but its ability to mobilize depot fat, as well as its hyperglycemic action, seems to depend on the integrity of the adrenal cortex and the carbo- hydrate-active corticoids (Levy and Ramey, 1958; DeBodo and Altzuler, 1958). These results have led Levy and Ramey (1958) to suggest that the adrenal steroids and epinephrine may act in concert to regulate metabo- lism of fat cells. On the other hand, the ability of epinephrine to mobilize unesterified fatty acids depends on optimal thyroid function, but appar- ently is unrelated to adrenocortical function (Goodman and Knobil, 1959) . The mobilization of fatty acids evidently provides a readily available source of metabolites for the formation of glycogen (Hartman and Brownell, 1949) or for direct utilization by the muscles (Fredrickson and Gordon, 1958). 228 /• /• Christian It is well known that epinephrine produces a marked rise in calorigenesis and oxygen consumption in intact animals (Hartman and Brownell, 1949; Gaddum and Holzbauer, 1957). This calorigenic activity of epinephrine and norepinephrine is important in adaptation to cold (Hsieh ct al., 1957a, b) and is potentiated strikingly by thyroxine (Swanson, 1956, 1957) and further intensified by the action of growth hormone, apparently by the effect of the latter in increasing thyroid function (Evans ct al., 1958). Evidently both epinephrine and thyroxine (and an intact pituitary-thyroid system) are essential for survival in cold exposure and for adaptation to cold, as, in the absence of thyroxine, epinephrine does not exert its calori- genic action in rats (Swanson, 1956). It was found that oxygen consump- tion in thyroidectomized rats increased in proportion to the dose of epi- nephrine when thyroxine was supplied at a fixed standard dose (Swanson, 1957). On the other hand, oxygen consumption varied linearly with the log-dose of thyroxine when the animals were kept on a standard dose of epinephrine (Swanson, 1956). Epinephrine apparently is essential for in- creased calorigenesis, but requires thyroxine for its activity. Swanson (1957) has expressed the opinion that since reactivity to epinephrine is di- rectly and intimately dependent on the level of thyroxine, the main role of the increased secretion of thyroxine in acclimitization to cold may be to potentiate the calorigenic activity of epinephrine. In any event, both epinephrine from the adrenal medulla and an intact properly functioning pituitary-thyroid system are essential for increased calorigenesis and adap- tation to cold. The necessity of the adrenal medulla and an intact thyroid is shown by the fact that the calorigenic response to cold is abolished either by adrenal demedullation (Morin, 1946a, b) or by thyroidectomy (Swan- son, 1957) . It should be obvious from the foregoing discussion that the adrenal medulla and sympathetic nervous system and their hormones, epinephrine and norepinephrine, are vital components of a variety of adaptive mecha- nisms and, if anything, their importance has tended to be underestimated. It appears from the available evidence that the sympathico-adrenal hor- mones may play a key role in the physiologic responses to sociopsychologic factors associated with changes in population density, and therefore deserve more investigation. B. The Thyroid Gland 1. Introduction The thyroid gland and its hormones, primarily thyroxine and to a lesser extent triiodothyronine, are important components of the internal mecha- nisms which provide the organism with sufficient physiologic flexibility to 2. Endocrines and Populations 229 be able to maintain a constant internal environment in the face of stimuli from and changes in the external environment. The thyroid is intimately- associated with a number of adaptive mechanisms and has important interractions with the adrenal cortex, as well as with the adrenal medulla and its hormones. This is not the place for a detailed account of thyroid physiology, but a brief review of the functions and actions of the thyroid and its hormones will be given, largely derived from standard accounts and reviews. Emphasis will be placed on the role played in physiologic adaptation to environmental changes, especially in response to adverse stimuli. It has long been known that thyroid hormone is essential for normal growth and development, as well as for the normal metabolism of most tissues. Furthermore it has a vital role in permitting a mammal to adapt to changes in the temperature of the external envirormient, especially in adaptation to cold, by acting synergistically with the calorigenic action of epinephrine, as we have seen in the preceding section, as well as by playing an important physiological role of its own (Swanson, 1957) . The evidence that will be discussed subsequently shows that the thyroid also is involved intimately in the physiological responses to alarming stimuli. Therefore the thyroid, like the adrenal gland, assumes particular importance in a discussion of adaptive mechanisms. 2. The Thyroid Hormones and Their Actions The thyroid hormones, tetraiodothyronine (thyroxine) and Z-3,5,3'- triiodothyronine, have an overall action of increasing heat production by increasing the oxidative processes of many tissues and therefore their oxygen consumption (SoUman, 1957). This metabolic effect is in part brought about by the augmentation or facilitation of the calorigenic action of epinephrine, and it has been suggested that thyroxine and epinephrine influence consecutive rate-limiting reactions in the metabolic cycle, thyrox- ine acting at a later stage than epinephrine (Swanson, 1956) . The meta- bolic effect of thyroxine, however, is not exerted equally on all tissues. The rate of oxidation by brain tissue, for example, is not influenced at all (Tata et al., 1957), whereas the metabolism of the liver is increased more than of the body as a whole (Barker and Schwartz, 1953). However, the electro- encephalogram excitability of the brain, electrolyte distribution, and circu- lation of the brain are profoundly affected by thyroid hormones (Tata et al., 1957). Increased thyroid hormone first affects carbohydrate, then fat, and finally protein metabolism (Sollman, 1957) . Conversely, a defi- ciency in thyroid hormone reduces the oxidative activity of tissues in general. It has been suggested that all the actions of the thyroid hormones 230 /. /. Christian on metabolic processes may reflect a primary action at one biochemical site, possibly on cytochrome c (Rawson et al., 1955). Sollman (1957) has listed the following additional effects of thyroxine. Increased levels of thyroid hormones usually are accompanied by an increased pulse rate, increased nervous excitability, weight loss, and decreased liver glycogen. Thyroxine also sensitizes the tissues, especially the blood vessels, the actions of sympathomimetic compounds such as epinephrine (see above) as well as to the toxic effects of poisons. The increased sensitization apparently occurs at the receptor mechanisms. Thyroxine also effects the circulation, but mainly as a result of increased heat production. Thyroxine has a direct effect on the heart in increasing its oxygen consumption, but it also has an indirect effect on the heart and the rest of the circulatory system in the following way. The delayed, indirect, effect is due to an increased metabolic demand of the tissues which results in an increase in carbon dioxide and decreases in oxygen at the arteriolar level. These effects result in a subse- quent decrease in peripheral resistance, increased venous return, and, via cardiac reflexes such as the Bainbridge, an increased cardiac output and increased pulse pressure. The increased heat resulting from increased oxida- tion must be dissipated, and this is accomplished by dilatation of the vessels and opening of the arteriovenous anastomoses in the skin and other tissues with an accompanying increase in the amount of heat loss due to radiation. The normal calorigenic action of the thyroid hormones is essential for normal growth, maturation, and tissue differentiation. Proper functioning of the thyroid and the production of thyroid hormones is completely dependent on an adequate dietary intake of iodine. Inorganic iodine is essential for the formation of the thyroid hormone by the thyroid gland, as the thyroid is incapable of trapping organic iodine (Salter, 1949; Halmi et al., 1953; Rawson et al., 1955) . The way in which trapped inorganic iodide and tyrosine are converted into the thyroid hormone (s) has been critically reviewed by Rawson et al., (1955). Inorganic iodide is trapped and presumably momentarily oxidized to active iodine in the thyroid epi- thelium. Pituitary thyrotropic hormone promotes the trapping of iodide by the thyroid gland, although the gland has some autonomy in this ac- tivity (Vander Laan and Greer, 1950; Halmi et al., 1953; Vander Laan and Caplan, 1954; Vander Laan, 1955). The trapped and activated iodine is then used in converting tyrosine to diiodotyrosine, probably in the presence of peroxidases and cytochrome oxidases. Two molecules of diiodotyrosine are condensed to form a single molecule of thyroxine (tetraiodothyronine), which combines with thyroid globulin (thyroglobulin) and is stored as such in the colloid of the thyroid follicles. Other iodinated thyronines are found in the thyroid, but in much smaller amounts than thyroxine. These probably result from partial iodination and may represent other pathways 2. Endocrines and Populations 231 in the formation of thyroxine than the one given above (Rawson et al., 1955). However, the metabohc pathway given is the usually accepted scheme for the synthesis of thyroxine. Thyroxine presumably is released from thyroglobulin by the action of proteolytic enzymes (SoUman, 1957). Thyrotropin promotes the iodination of tyrosine and the release of thyrox- ine from thyroglobulin. A small amount of thyroxine loses one of its iodine atoms to become /-.3,5,o'-triiodothyronine in the thyroid, probably more in the peripheral tissues, and small amounts of this compound are found in the thyroid gland and in circulation (Gross, 1955). /-3,5,3'- Triiodothyronine has a more pronounced action on oxidative processes than thyroxine, and its action is much more rapid, but less prolonged (Sollman, 1957). It has been postulated that the triiodothyronine provides the immediate thyroid response and is the substance which enters the cells and exerts the ultimate thyroid action, whereas thyroxine is the circulating form of the thyroid hormone (Gross, 1955). The differential distribution of these two hormones in the circulation and in the cells of various tissues supports this hypothesis (Gross, 1955). Since inorganic iodide is essential for the normal functioning of the thyroid gland, the rate at which radio- active iodine is trapped and accumulated by the gland is a good index of thyroidal activity provided there is not an increased renal excretion of iodine. The rate of release of radioactive iodine from the thyroid is con- sidered a more reliable and reproducible index of thyroid activity, as each animal can serve as its own control in experimental procedures (Brown- Grant et al., 1954a). 3. Factors That Regulate the Activity of the Thyroid The secretory activity and hormone synthesis by the thyroid is largely under the control of the protein hormone thyrotropin (TSH) secreted by the basophils of the anterior pituitary (D'Angelo, 1955). However, the thyroid is capable of a low level of autonomous function without stimulation by the pituitary (Brown-Grant et al., 1954a). The rate of release of TSH from the anterior pituitary is apparently related to the level of circulating thyroid hormone (D'Angelo, 1955), although the mediation of the hypo- thalamus appears to be required (Harris and Woods, 1958; D'Angelo and Traum, 1958) ; therefore a low level of circulating thyroid hormone stimu- lates an increased secretion of TSH and a high level inhibits its secretion. This is the classic concept of an endocrine feedback mechanism which operates to regulate the release of hormone from the target gland and to maintain a more or less constant level of circulating hormone under normal circumstances. However, there is recent evidence to suggest that the secre- tion of TSH may not be a direct response to the level of circulating thyrox- 232 /. /. Christian ine, but rather to one or more of its peripheral metabohc actions (Goldberg et al., 1957) . The secretion of thyrotropin from the pituitary is undoubtedly under the control of the hypothalamus (D'Angelo and Traum, 1958; Harris and Woods, 1958, Harris, 1959). Like the secretion of adrenocorti- cotropin, the secretion of thyrotropin appears to be controlled by a humoral factor from the hypothalamus (Brown-Grant et al., 1957). Section of the pituitary stalk leads to a loss of the inhibitory response of the thyroid to restraint or pain, and regeneration of the pituitary portal vessels is accom- panied by a return of this response (Harris, 1955a, b; Reiclilin, 1957a, b). The thyroid remains at least partially responsive to exogenous TSH when the pituitary stalk is sectioned (Reichlin, 1957a, b; Harris and Woods, 1958). There is also evidence that the hypothalamus is necessary for a decreased blood concentration of thyroid hormone to effect an increased secretion of TSH (Greer, 1951; 1952; Bogdanove and Halmi, 1953; Harris and Woods, 1958; D'Angelo and Traum, 1958). Increased activity of the thyroid accompanies electrical stimulation of the anterior portion of the median eminence, but not other parts of the hypothalamus (Harris and Woods, 1958). The hypothalamic factor responsible for stimulating the release of TSH does not appear to be contained in or associated with Pitressin (Reichlin, 1957a; D'Angelo and Traum, 1958), but little else is known of the nature of this factor. In addition to these regulating factors, the release of TSH is also affected by cortisone and ACTH (Brown-Grant et al., 1954c) . Cortisone and ACTH inhibit the release of radioiodine from the thyroid of rabbits and rats, probably by inhibiting the release of TSH, although the mechanism by which this is accomplished is unknown (Brown- Grant et al., 1954b, c; Brown-Grant, 1955). Cortisone and ACTH have also been reported to inhibit the uptake of radioiodine by the thyroid of rats (Money et al., 1950; Albert et al., 1952; Perry, 1951; Verzar and Vido- vic, 1952) and of humans (Perry, 1951; Kuhl and Ziff, 1952; Albert et al., 1952; Berson and Yalow, 1952). However, reports of decreased uptake of radioiodine must be interpreted with caution, as it may reflect a lowered concentration of circulating iodide as a result of increased renal clearance of iodide following treatment with cortisone or ACTH (Brown-Grant et al., 1954c) . Adrenalectomy inhibits the release of iodine and therefore of thyroid hormone from the thyroid glands of rats (Fllickiger and Verzar, 1955). Bastenie and Ermans (1958) have shown that cortisone, in addition to its effect on the secretion of TSH, inhibits the stimulating effect of thyroxine on oxygen consumption and phosphorus turnover but fails to inhibit these actions of triiodothyronine. These authors concluded that cortisone inhibits the peripheral degradation of thyroxine to triiodothyro- nine. Nevertheless, there is little doubt that cortisone and ACTH do inhibit 2. Endocrines and Populations 233 thyroid activity, probably by inhibiting the release of TSH from the pitui- tary. Epinephrine, in addition to its synergism with thyroxine with respect to calorigenesis, appears to have more direct effects on thyroid activity, al- though the reports are conflicting. Badrick and his co-workers (1954, 1955) reported that epinephrine inhibited the uptake of radioiodine by the thy- roids of intact and hypophysectomized rats, and similar results were re- ported for intact rats by Money et al. (1950). Brown-Grant et al. (1954b) found that epinephrine decreased the release of radioiodine by the thyroids of intact rabbits. On the other hand, epinephrine has been reported to in- crease the release of radioiodine by the thyroid (Williams et al., 1949) and to increase the content of radioiodine in the thyroid (Botkin and Tew, 1952), although the latter could result from an inhibition of its release. More recently Ackerman and Arons (1958) have reported that epinephrine increases the release of radioiodine from the thyroids of intact and hypo- physectomized dogs. These divergent results are difficult to reconcile, al- though the fact that epinephrine acted in hypophysectomized as well as in intact rats and dogs (Badrick et al, 1955; Ackerman and Arons, 1958) suggests that the effects were directly on the thyroid gland. It is possible that these varying results may reflect the effects of epinephrine on the thyroidal vasculature in different animals and different circumstances, as was suggested by Badrick et al. (1955) . From the foregoing account it should be clear that the regulation of thyroid function is complex and involves a number of factors. However, there seems to be little doubt that the hypothalamus has a relatively basic role in regulating the secretion of thyrotropin from the pituitary, and evi- dently is capable of inhibiting its release (Brown-Grant et al., 1954b; Reich- lin, 1957a; Harris and Woods, 1958; D'Angelo and Traum, 1958) . D'Angelo and Traum (1958), in an extensive series of experiments on hypothalamic- hypophyseal-thyroidal relationships in rats, concluded that the hypothala- mus functions as a modulator, modifying the production and release of thyrotropin from the adenohypophysis not only under conditions of in- creased demand, but also in meeting day-to-day needs. Normal blood levels of TSH cannot be maintained in the absence of stimulation by the hypo- thalamus even with decreased levels of thyroid hormone. However, the adenohypophysis keeps its capacity to produce and release TSH, but regu- lated by the level of circulating thyroid hormone or by peripheral meta- bolic actions thereof (cf. above). The action of thyroid hormone may be directly on the pituitary (D'Angelo and Traum, (1958). The injection of minute amounts of thyroxine into the hypothalamus is followed by a rela- tively long latent period before the release of TSH is inhibited, whereas 234 /. J. Christian injection into the anterior pituitary is followed by a more immediate re- sponse (Yamada and Greer, 1959; Yamada, 1959). The thyroid was blocked in these studies (D'Angelo and Traum, 1958) by hypothalamic lesions or by treatment with propylthiouracil. Thyroid func- tion was evaluated by the rate of turnover of radioiodine, bioassay of the pituitaries and plasma for their content of TSH and thyroid hormone, and was finally correlated with the results of detailed histologic studies of the glands of experimental and bioassay animals. The results appear to be definitive. These workers were further able to demonstrate the independ- ence of ovarian, adrenocortical, and thyroid-regulating parts of the hypo- thalamus. How the adrenal corticoids and adrenocorticotropin fit into the regulation of thyroid function is unknown at present. 4. Thyroid Responses to External Stimuli Probably the best-known action of the tl\yroid is its ability to increase the secretion of thyroid hormone in response to cold and to decrease its re- lease in response to heat (Ring, 1942; Brown-Grant et at., 1954a; Stevens et al., 1955; Hellman and Collins, 1957). The gland also becomes hyper- plastic with prolonged exposure to cold (Money, 1955). Upon exposure to low temperatures, there is an increased release of thyroid hormone from the thyroid gland (Brown-Grant et al., 1954a; Woods and Carlson, 1956), apparently in response to increased secretion of TSH by the pituitary (Stevens et al., 1955) . However, Ring (1942) found that the thyroid per se can account for only a small part of the increase in heat production required to meet the demands of mice exposed to 2-4° C, and that epinephrine and thyroid hormone are required for a maximum continued metabolic response to cold. He therefore concluded that the principle action of thyroid in re- sponse to cold exposure was to sensitize the animal to the calorigenic action of epinephrine. Swanson (1956, 1957) essentially confirmed and extended Ring's findings and conclusions, as we have seen above. Thyroidectomy abolishes the response to cold and deprives the animal of the ability to survive exposure to cold (Swanson, 1957). Exposure to cold increases pituitary-adrenocortical as well as thyroidal activity, contrary to the more usual reciprocal relationship between ACTH and TSH secretion by the pituitary described below. Increased thyroidal activity apparently is the more vital of these two adaptive responses to cold. Thyroxine permits survival of hypothyroid rats subjected to cold, whereas adrenocorticotropin and adrenocortical extract do not (Freedman and Gordon, 1955). Similarly, minute amounts of thyroxine permitted 100% survival of rats treated with thiouracil upon exposure to cold, whereas adrenocortical extracts failed to increase survival (Ershoff, 1948). 2. Endocrines and Populations 235 Heat, on the other hand, diminishes thyroid activity (Hellman and Collins, 1957) . Rats and mice have been shown to have reduced thyroid activity in the warm summer months (Hurst and Turner, 1947) . Puntriano and Meites (1951) suggested that the seasonal changes in thyroid activity might be due to changes in day length rather than to seasonal changes in tempera- ture, on the basis of their findings that prolonged exposure to light inhibits thyroid activity in mice and exposure to darkness increases thyroid activity. However, these results could not be confirmed in rabbits (Brown-Grant et al., 1954b) . The rate of release of radio iodine by the thyroids of rabbits was unaffected by prolonged exposure either to darkness or to light. There- fore the validity of the hypothesis that day length affects thyroid activity is dubious. In contrast to the thyroidal-adrenocortical relationship in response to exposure to cold, there is abundant evidence indicating that the activity of the thyroids is inhibited in response to alarming stimuli which evoke an increased pituitary-adrenocortical activity. In fact it has come to be generally accepted that there is a reciprocal relationship between ACTH and TSH secretion in response to "stress" (Harris, 1955a). Anoxia, neph- rectomy, vitamin deficiencies, tourniquet shock, fasting, injected typhoid vaccine, swimming in cold water (15° C), injections of formalin, spinal cordotomy, electroshock, and gastrointestinal and peripheral trauma all inhibit the activity of the thyroid glands of rats (Williams et al, 1949; Paschkis et al, 1950; Bogoroch and Timiras, 1951; Hamolsky et al, 1951; Van Middlesworth and Berry, 1951; Badrick et al, 1954, 1955). Similar results were obtained with rabbits, using the release of radioiodine as the basis of measurement (Brown-Grant et al, 1954b) . Hemorrhage, anesthesia, laparotomy, intraperitoneal injections of turpentine, draining subcutaneous abscesses, or emotional stress in the form of restraint, subcutaneous faradic stimulation, or sudden changes from light to dark or vice versa were all found to inhibit thyroid activity in rabbits for 1-2 days. After this time the rabbits evidently became used to the procedures and were no longer alarmed by them, as thyroid function gradually returned to normal with continued exposure to these emotional stimuli. In some instances of these experiments the release of radioiodine from the thyroid was totally inhi- bited (Brown-Grant et al, 1954b). Emotional stimuli also were followed by a time lag of somewhat less than 3 hours between their first application and the first thyroid response. These experiments demonstrate that emo- tional factors, visual stimuli, and the central nervous system can affect thyroid function, presumably via the hypothalamus, just as they can in- crease the secretion of ACTH or adrenal medullary hormones (Brown- Grant et al, 1954b). Kracht (1954) described a "true thyrotoxicosis" in wild rabbits stimulated by fear in response to being chased by ferrets and 236 /• /• Christian stated that this reaction was a "model of a thyrotrophic alarm reaction." His evidence was, for the most part, indirect and his conclusions that there was increased thyroid activity on the basis of increased renal excretion of injected radioiodine is untenable, especially for animals with a marked increase in adrenocortical activity. Finally, Brown-Grant et al. (1954b) found that the release of radioiodine by the thyroids of wild rabbits was inliibited by emotional stress, just as it was in the usual domestic rabbit. In view of these facts, the concept of a "fright thyrotoxicosis" is inaccepta- ble. The inhibition of thyroid activity by emotional stress was not as consistent in adrenalectomized as it was in intact rabbits, otherwise their responses were similar. There is little doubt that the inhibition of thyroid activity in these experiments was due to a decrease in the secretion of thyrotropin (Brown-Grant et al., 1954a, b). It is true that cortisone and ACTH inhibit the release of TSH from the pituitarics of rats (Brown- Grant, 1955) and rabbits (Brown-Grant ct al., 1954a, b; Harris and Woods, 1958), but the adrenal corticoids cannot be responsible for the major part, if any, of the inhibition of the release of thyrotropin in the above experi- ments, as adrenalectomy did not affect the inhibition of the thyroid, and cortisone was without effect on the release of radioiodine by the thyroids of rabbits injected with TSH. Finally, injected TSH abolishes the inhibition of the thyroid produced by ACTH and cortisone (Harris and Woods, 1958) . There has been some confusion in the literature about the effect of alarming stimuli on the thyroid. The experiments which have been dis- cussed so far indicate that the thyroid is depressed under these circum- stances, but it is also well known that emotional factors can precipitate thyroid crises in humans (Selye, 1950). These apparently contradictory experiences may depend on species differences, dose-time relationships, or both, as the recent work of Gerwing et al. (1958) has indicated. These investigators have shown that thyroid activity in mice, rats, and rabbits subjected to chronic toxic "stress" (injection of small doses of bacterial endotoxins repeatedly for 24 days) is inhibited at first, but returns to normal and eventually exceeds the original normal level as the stimulation continues (Gerwing, 1958; Gerwing et al, 1958) . On the other hand, guinea pigs and rhesus monkeys exhibit increased thyroid activity from the be- ginning. Injected thyrotropin stimulates the thyroids of mice, rats, and rabbits with inhibited thyroids following injection of the toxin, indicating that the depressed thyroid function was due to a diminished secretion of TSH. It may be coincidental, but it is nevertheless interesting that these differences in thyroid function between species in response to bacterial toxin coincide with the differences in the secretory patterns of the major corti- coids in these same species (cf. above) : rats, mice, and rabbits secrete pri- marily corticosterone, and the other two species, hydrocortisone. These 2. Endocrines and Populations 237 investigators (Gerwing, 1958; Gerwing et al., 1958) conclude that the hypothesis of a reciprocal relationship between the secretion of TSH and ACTH by the anterior pituitary is compatible with the evidence for rats, mice, and rabbits, but not for guinea pigs and monkeys. They suggest that in the latter two the inhibitory effect of increased corticosteroids does not occur. However, we have seen that the corticosteroids probably have no effect in the inhibition of TSH release and thyroid function in rats and rabbits in response to alarming stimuli; so that some other explanation must be sought. Man is probably similar to guinea pigs and rhesus monkeys in the above responses of the thyroid (Gerwing et al., 1958) . These studies emphasize the importance of careful comparative work as well as the im- portance of dose-time relationships in physiologic functions in different species of mammal. Starvation causes a profound depression of thyroid activity, probably by suppressing the secretion of TSH, as it has been shown that acute starva- tion markedly depresses the blood level of TSH in mice and rats (Monej'-, 1955). However, if starved animals are subjected to cold, the degree of thyroid depression is inversely related to the degree of the reduction in environmental temperature (Reichlin, 1957a). The thyroidal iodine release rates at the lower temperatures, even though reduced, are appreciably higher than they are in starved animals at higher temperatures. The mainte- nance of body temperature appears to take precedence over the conserva- tion of nutritive reserves and tissues in the regulation of thyroid activity activity (Reichlin, 1957a). In contrast to some of the above relationships, increased thyroidal ac- tivity increases adrenocortical activity in white rats (Wallach and Reineke, 1949). Administration of thyroxine decreases adrenal ascorbic acid to minimal levels after 2-4 days and is followed, upon continued treatment with adequate doses of thyroxine, by a progressive increase in adrenal size and ascorbic acid content which reaches maximum in 4 weeks. The in- crease in adrenal weight in these circumstances is roughly proportional to the dose of administered thyroxine. There is a narrow dose range of thyrox- ine in which there is no effect on the adrenals. Perhaps this dose range repre- sents the normal physiologic daily secretion rate. It may be that 'the adrenal hypertrophy observed in rats exposed to cold is in part a result of the increased thyroid activity. On the other hand, adrenocortical function does not seem to depend on the presence of a normally functional thyroid, as thyroidectomy does not cause adrenal atrophy in rats although the zona fasciculata is reduced in width (Hess, 1953), nor does thyroidectomy de- crease the ability of the adrenals to respond to stress (Hess and Finerty, 1952) . The adrenals of rats treated with antithyroidal compounds (thioura- cil) also (were) responsive to injected adrenocorticotropin (Freedman and 238 /. J. Christian Gordon, 1955), although others report adrenal atrophy following blockade of the thyroid with antithyroid compounds (Seifter et al., 1949). Finally, thyroxine augments the adrenal hypertrophy produced by growth hor- mone, although it does not augment the adrenal hypertrophy produced by ACTH (Bois and Selye, 1957). There are many other factors which affect thyroid function. A high dietary salt intake can increase thyroid activity, even with a reduced iodine intake, in a rather circuitous way (Isler et al., 1958). The mechanism ap- pears to be that with increased NaCl intake, and consequently an increase in the excretion of NaCl, there is apparently an increase in the excretion of iodine with the sodium chloride. The loss of iodine produces a low serum concentration of iodine and secondarily a low output of thyroxine. The low thyroxine in turn stimulates increased secretion of TSH from the pituitary and a resulting stimulation of the thyroid gland. 5. Thyroidal-Gonadal Ixterrelatioxships In addition to its more or less reciprocal relationship with the adrenal cortex, the thyroid, and therefore thyroidal adaptive responses, has im- portant effects on reproduction and the reproductive organs. These effects are of particular interest here, because they may occur in response to alarming stimuli and must be evaluated as possible factors producing the changes in reproductive function seen in mammals, especially in relation to the density of the population. A thyroidal-gonadal relationship is indi- cated by the tendency for goiters to occur at puberty, during pregnane}^, or during estrus; also the serum protein-bound iodine is elevated during pregnancy, and stilbesterol increases the release of iodine by the thyroids of rats and mice (Sollman, 1957) . There is considerable evidence indicating that hypothyroidism is associated with abnormal ovarian function in humans (Rawson et al., 1955). Cold exposure causes a marked increase in the length of the estrous cycle in rats which is prevented by administering thyroxine (Dempsey and Uotila, 1940; Denison and Zarrow, 1955) . Thyrox- ine also augments the recover}^ of function of the testes of immature rats from the atrophic effects of starvation (Horn, 1955) . The recovery of the testes in this case is not related to the recovery in body weight, and the recovery of the sex accessories following treatment with thyroxine was only partial and required a greater period of time. jMaqsood and Reineke (1950) found that high temperatures (30° C.) decreased the weights of the testes and seminal vesicles of mice, but the administration of thyroprotein in- creased the weights of these organs at that temperature. Alild hj^perthy- roidism stimulated, and hypothyroidism inhibited, sexual development in growing male mice (Maqsood and Reineke, 1950). Higher doses of thyroid 2. Endocrines and Populations 239 hormone decreased the weights of the reproductive organs. However, thy- roidectomy was followed by an increase in the relative weights of the testes and seminal vesicles of rats (Hess, 1953). Hess (1953) concluded that thyroidectomy appears to sensitize the gonads and secondary sex organs to the actions of gonadtropins. Hyperthyroidism is associated with ab- normal reproductive function in female rats (Denison and Zarrow, 1955). Prolonged exposure to 2° C. resulted in a marked increase in the length of the estrous cycle: proestrus and estrus were markedly prolonged, while metestrus and diestrus were shortened. Treatment with 50 fxg. of thyroxine corrected these changes. On the other hand, brief (3 days) treatment of female rats with thyroid hormone just prior to mating apparently resulted in an increase in subsecjuent litter size, but the same amount of thyroid hormone given during hot weather or an increased amount of thyroid hormone adversely affected reproduction (Kraatz, 1939) . These results seem to indicate that there is an optimal level of thyroid function for proper functioning of the reproductive system, and that any appreciable deviation from this level in either direction leads to diminished reproductive function. The role of the thyroid in reproduction has been investigated by using radiothyroidectomized mice (Bruce and Sloviter, 1957). Radiothyroidec- tomy apparently had no effect on male fertility, female fertility, or litter frequency, but estrus and gestation were prolonged. Litter size possibly was reduced owing to increased resorption of embryos, but the matter requires further investigation. In contrast to these results, Chu (1944) found that surgical thyroidectomy in rabbits during early pregnancy re- sulted in total loss of fetuses due to resorption or abortion. The same opera- tion in later pregnancy resulted in the young being stillborn. Induction of pregnancy in thyroidectomized rabbits was followed by resorption or abortion of the embryos or a prolongation of gestation, the young subse- quently being born dead. Feeding desiccated thyroid tended to prevent the adverse effects of thyroidectomy (Chu, 1944) . Hypothyroidism induced by thiouracil in rats apparently was without effect on fertility in males and females but interferred with gestation in pregnant females, causing resorp- tion in 100% of the animals (Jones et al., 1946). Thiouracil treatment of rats for shorter periods of time, less than 100 days, did not prevent some of the rats from delivering litters, but the young exhibited abnormal growth and development. It is quite evident that pregnancy is adversely affected by severe hypothyroidism with a marked increase in intrauterine mortality. In general reproductix'e function is altered by marked increases or de- creases in thyroid activity, and it seems that the depression in thyroid activity in response to alarming stimuli must play a role, along with in- creased adrenocortical activity, in the commonly observed suppression of 240 /. /. Christian reproductive function. However, a great deal more investigation is neces- sary to clarify thyroidal-adrenal-gonadal relationships. 6. Other Thyroid Relationships In addition to its relationship to the adrenals and gonads and to its general metabolic effects, the thyroid hormones play specific roles in the maintenance of other organs, and these may offer means of evaluating thyroid function in intact mammals in the field, providing they are used in conjunction with other information. For example, the harderian glands of rats and mice are maintained by thyroid hormones and as yet unknown pituitary factors (Boas and Bates, 1954; Hellman and Collins, 1957), al- though the thyroid may not be essential for the maintenance of these glands in guinea pigs (Smelser, 1943). Thyroid hormone, in conjunction with androgens, is required for the maintenance of the size and granulation of the cells of the serous tubules of the submaxillary glands of male rats (Grad and Leblond, 1949) . The thyroid alone restores the number of these cells to normal, but does not affect the size or granulation. Thyroid function in general declines moderately with age and increased size (Hurst and Turner, 1947), but there are no marked effects of this decline on growth or other functions. It should be clear from the above account that the thyroid and its hormones participate actively in the adaptive responses and probably play a significant role in many aspects of these responses. Investigations on the reactions of the thyroid with changes in the size of mammalian populations and its relationship to adrenal and reproductive functions are needed. C. Other Endocrine Adaptive Factors 1. Pancreatic Islets A discussion of the physiology of the pancreas with respect to glucose metabolism is not properly the function of this chapter, but it should be mentioned as one of the important endocrine organs regulating glucose utilization. The hormone best known of the islets of Langerhans is insulin, which is derived from the beta cells. More recently glucagon, presumably from the alpha cells, has been described. Insulin, in brief, increases the utilization of glucose and in many of its actions is antagonized by cortisone. Glucagon, on the other hand, is a hyperglycemic factor. The function of these hormones wdth respect to the generalized adaptive responses has been little studied, but they certainly must play an important part in the general economy of the mammal under adverse circumstances. Anything affecting 2. Endocrines and Populations 241 the mobilization and utilization of glucose is inevitably going to have an important bearing on the adaptive responses when a more or less final picture is available of the entire scheme of responses. The frequency of diabetes in, and its effect on, natural populations is unknown, although recent work indicates that under certain circumstances it is far from being a rare disease. 2. Posterior Pituitary The posterior pituitary, or neurohypophysis, has been mentioned re- peatedly in the discussions on the regulation of the secretion of the hor- mones of the anterior pituitary, but in addition the posterior pituitary has important functions of its own in physiologic adaptation. A lengthy discus- sion will not be indulged here, as these functions more properly come under the purview of discussions elsewhere or are insufficiently well known to warrant elaboration in detail. a. Antidiuretic hormone. The posterior pituitary secretes an antidiuretic factor (ADH) which is important in regulating the reabsorption of water from the renal tubules. Section of the pituitary stalk with a resultant denervation of the posterior pituitary is followed by diabetes insipidus as a result of the lack of antidiuretic hormone. ADH is apparently manufac- tured in the hypothalamus and traverses the fibers of the supraopticohy- pophyseal tract and is released into the systemic circulation in the posterior pituitary. A vasopressor activity is associated with the antidiuretic factor of the pituitary, but the neurohypophyseal hormone is much less effective in this activity than in its antidiuretic action. There is evidence that the secretion of ADH is increased in response to alarming stimuli as well as to dehydration, but there is also evidence that its secretion is independent of the release of ACTH from the anterior pituitary (cf . above) . For a more detailed account of the pituitary antidiuretic hormone, the reader is re- ferred to the recent review by Thorn ( 1958) . h. Lipid mobilizing factor. The recent work of Seifter and his colleagues ( 1959) has indicated the existence of a posterior pituitary lipid-mobilizing factor (LMF) which is released in response to adrenal corticoids. The hormone appears to be a peptide capable of mobilizing triglycerides from the mesenteric fat depots following injections of cortisone, exposure to cold, or subjection to other stimuli which induce an increased adrenocortical secretion. The lipid mobilization is blocked by adrenalectomy or hy- pophysectomy. The pathway for lipid mobilization by LMF in response to alarming stimuli appears to be anterior pituitary, adrenal cortex, and posterior pituitary (Seifter et al., 1959). 242 /• J- Christian 3. Other Gland Systems Many other glands, organs, and organ systems participate in physio- logic adaptation, either directly or in response to increased adrenal or other hormones or diminution thereof. The essential integrative role of the central nervous system has been implicit throughout the foregoing discussion. The gastrointestinal tract and its appendant organs such as the pancreas, liver, and salivary glands also actively participate in adaptation (Ehrich and Seifter, 1948; Selye, 1950; Baker and Bridgman, 1954; Baker and Abrams, 1954). The responses of the stomach to the adrenocortical hormones and to "stress" have been reviewed recently by Gray and Ramey ( 1957) and will not be discussed further here. One example of the participa- tion of the digestive organs in the adaptive responses is the response of the serous glands to increased adrenocortical secretion, first, with a loss of zymogen granules followed by a depletion of cytoplasm nucleic acids (Ehrich and Seifter, 1948) . However, as most of these reactions are second- ary to the increased activity of the pituitary and adrenal cortex, it does not seem appropriate here to dwell on them in detail since the entire organ- ism responds to one degree or another to the physiologic alterations subse- quent to increased activity of the primary adaptive mechanisms. D. General Measurements of the Endocrine Adaptive Responses 1. General The actions of and responses to specific hormones and adaptive mecha- nisms have been discussed, but often there are responses in the intact ani- mal that cannot be attributed to a particular hormone or system. The splenic hypertrophy and enlargement of the nucleus pulposus which is seen in mice and voles are examples of such responses (Clarke, 1953 ; Chitty et al., 1956; Christian, 1959c). The lymphoid tissue of the spleen is involuted by the adrenal glucocorticoids, but the resultant atrophy is more than offset by increased hematopoiesis in the spleens of mice and voles subjected to social stress or other alarming stimuli (Dawson, 1956). However, it is not known at present what specifically is responsible for the increased hemato- poiesis. This seems to be the proper place to review the physiologic adaptive reactions and to do it in terms of these responses which are found in the intact animal in response to specific stimuli. Wherever possible, the re- sponses will be related to the specific mechanisms responsible for their occurrence. It is appropriate first to discuss the stimuli which are known to elicit endocrine adaptive responses. These stimuli have typical dose-time-re- sponse relationships: the severer or the longer the stimulation, the greater 2. Endocrines and Populations 243 the response (Sayers and Sayers, 1949). Nevertheless, it should not be assumed that all adaptive responses are qualitatively similar. Some stimuli may elicit quite similar responses in kind and degree, whereas others will be manifested in qualitatively and quantitatively different manners. This statement should be apparent from the preceding accounts of the mecha- nisms involved. All have in common that if uncompensated they will pro- duce widespread physiologic changes which come under the heading of shock (Selye, 1950). However, whether or not the symptoms commonly associated with shock are elicited depends on the severity of the stimulus (Selye, 1950). In short, almost any change in the external environment of the animal, physical damage to the animal, or emotional upset is po- tentially capable of producing profound deleterious effects on the animal, but within reasonable limits the adaptive mechanisms provide it with the flexibility to accommodate most changes or adverse stimuli. It is not until the latter reach rather serious proportions and evoke marked responses that we customarily consider the animal to be subject to "stress" or that the stimuli are labeled "alarming." These stimuli act through or are received through a number of receptor pathways in the host. For example, physical damage, including burns, surgery, acute physical trauma of all sorts, will evoke adaptive responses probably by direct neural pathways as well as via unknown chemical mediators, resulting from tissue damage which may stimulate the release of ACTH or other adaptive responses directly. Hemorrhage, by decreasing blood volimie, can effect the release of aldosterone directly. Many stimuli act directly through the central nervous system, such as light, noise, fear, and rage. Heat, cold, and similar environmental factors act through recep- tors in the individual and produce physiologic responses directly. Regardless of the receptor or pathway, all these primary environmental stimuli, if severe enough or chronic enough, have the ability to produce the symptoms of shock through several common pathways. In so doing they produce physiologic changes, either directly or through the central nervous system, which in turn activate a chain of responses leading to defensive reaction against any adverse physiologic shift which may have been produced bj^ the initial stimulus. The variety of stimuli which have been found to elicit adaptive reactions is legion (Selye, 1950). In fact, one could conclude that almost every experience encountered in daily life by any mammal, if severe enough, is capable of producing shock and evoking marked adaptive re- sponses, but for the purpose of the present discussion, the importance of emotional stimuli in evoking these reactions will be emphasized. These may be acute stimuli, and all of us are personally familiar with some of the reactions that they are capable of producing. However, it should be noted that emotional stimuli of a more chronic nature can produce profound 244 /. /. Christian long-term physiologic reactions which may have widespread effects on the host (Elmadjian ct at., 1958; Ratcliffe and Cronin, 1958; Christian, 1959b; Mason, 1959) . Close confinement, for example, can result in atrophy of the adaptive mechanisms with a resultant marked susceptibility to any subse- quent alarming stimulus (Christian and Ratcliffe, 1952). Social competi- tion, social pressure, or chronic anxiety have been shown to produce marked physiologic responses (Christian, 1959a; Mason, 1959) Emotional factors, of necessity, have their begmning in the central nervous system as a result of sensory stimuli received from the external environment via the visual, aural, and olfactory sensory receptors. Therefore they are part of the com- plex system responsible for integrating the mammal with its immediate environment. Whatever the particular adverse stimulus may be and regardless of the pathway of its reception by the animal, whether sensory, traumatic, or otherwise, all stimuli have the ability to produce shock and evoke physio- logic adaptive responses in the mammal. Shock is a vaguely defined entity, and there is no general agreement with regard to its exact nature or cause (see Selye, 1950; Scudder, 1952; Bing, 1952; Zweifach, 1952; Engel, 1952; Agate, 1952; Randall, 1952). Moreover, its primary effects and the re- sponses to it are often difficult to separate. Fundamentally the principal manifestations of shock involve changes in the circulatory system leading to inadequate circulatory function and eventually circulatory collapse. If one keeps in mind that the fundamental changes seem to be blood sludging (Knisely et at., 1947), changes in selective permeability of the peripheral vascular bed (Zweifach, 1952), capillary and arteriolar atony and hypo- reaction of the vascular musculature to epinephrine and even direct stimu- lation with a resultant visceral vasodilatation (Zweifach, 1952), then the secondary effects of hemoconcentration, hypotension, fall in blood volume, decreased cardiac output, and increased hematocrit are more easily under- stood. In general shock seems to involve a generalized failure of circulatory integrity. With a superimposed relative circulatory stasis and hypoxia, these alterations became more profound and the whole process becomes a vicious circle (Zweifach, 1952) . It is not known by what specific means these alterations in circulation are effected, but that they involve both neural and humoral components can hardly be questioned. We have re- peatedly emphasized that the basic role of the adaptive reactions is to maintain vascular integrity in opposition to forces tending to destroy it as well as to prepare the organism to meet emergency situations. Most alarming stimuli also produce an immediate discharge of the medullary hormones epinephrine and norepinephrine with mobilization of glucose reserves, increased heart rate and strength of beat increasing cardiac out- put, and constriction of visceral and cutaneous blood vessels with a re- 2. Endocrines and Populations 245 suiting shift of the blood to the musculature and central nervous system. If at the same time the output of ACTH is stimulated, adrenal glucocorticoids will also be increased, and among their effects is an increase in the reactivity of the blood vessels to the effects of epinephrine and norepinephrine. None of the reactions is completely isolated, but the balance between them may shift considerably depending on the nature of the stimulus. There are also temporal relationships. In many ways the immediate and short-lived ac- tivity of epinephrine is mimicked more chronically by the glucocorticoids. The response of the adrenal medulla is immediate, whereas the cortex re- sponds somewhat more slowly and can be sustained for a great deal of time. It is worth describing some of the measurable changes effected in a mammal by activation of the adaptive responses. Many of these have been described earlier under actions of the various hormones, but it is appropri- ate to discuss these as measurable changes in such a way that they might be useful in detecting and interpreting the effects of physiologic adaptation to potentially harmful stimuli. Many of the actions of the adrenocortical and other hormones serve specifically to restore the equilibrium of the internal environment after an alarming stimulus. These actions may be a decided disadvantage to the animal when they are prolonged. For example, in- creased secretion of the carbohydrate-active corticoids serves to maintain proper fluid and electrolyte balances and to provide readily available glucose reserves in an emergency, but they also suppress inflammation, granulation, and antibody formation and thereby reduce host resistance to infection. The following list of adaptive responses is by no means complete, those effects having been selected which might prove useful or of basic con- ceptual importance to the investigator wishing to study the effects of physiologic adaptation. 2. Measurements Indicating Increased Adrenocortical Function a. Adrenal weight. This is a presumptive measurement of ACTH activity and response to an acute or chronic distress. Weights are the best available index of adrenocortical activity for many studies. For many long-term changes, weights are much more useful and much less subject to pitfalls than techniques such as changes in adrenal ascorbic acid, lipids, cholesterol, the production of plasma corticosteroids, or circulating eosinophils or lymphocytes. All these measurements are labile and reflect rapid changes in adrenal function: they indicate the status of the animal at the moment of making the measurement, thus they often may reflect nothing more than the process of trapping or handling an animal and may completely obscure longer-term changes, especially with excitable, highl}^ reactive 246 J. J. Christian wild mammals. The problem of adrenal hypertrophy with weight changes and the relationship of these changes to the length and severity of the stimulus has been discussed at length by Sayers and Sayers (1949). Adrenal weight changes largely reflect changes in the zona fasciculata, which undergoes hyperplasia and hypertrophy following stimulation by ACTH and therefore is indicative of changes in the secretion of glucocorti- coids. Under different circumstances, already discussed, the zona glomeru- losa may hypertrophy, but changes in its size are relatively unimportant with respect to changes in the total weight of the gland because of its rela- tively minor contribution to the total mass of the adrenal. The same state- ment is generally true for the adrenal medulla. Fmally, changes in adrenal weight, when used as an index of cortical activity, should be evaluated in the light of histologic studies, as the amount of lipid in the cells of the fasciculata may vary sufficiently with various functional states to have a marked effect on adrenal weight. For example, stimulation of sufficient intensity to deplete the cortex of visible lipids may result in a decrease in weight whereas activity may actually be greater than in a heavier gland containing a large amount of stored lipid (Christian, 1959b). The adrenal medulla in some species may hypertrophy and contribute to changes in adrenal weight. Although the contribution of the medulla to adrenal weight changes is usually negligible, it would be appreciable for the Soricidae, in which the adrenal is composed largely of medulla. Changes in the medulla and cortex of the long-tailed shrews (soricids) have not been studied, although these medullary-cortical relationships have been ob- served in mature individuals of Sorex cinereus, S. dispar, S. fumeus, S. palustris, and Microsorex hoyi. There may be a relationship between body size, adrenocortical mass, and metabolic rate in these minute animals. Adrenal weights are useful for field studies, as they may be obtained on fresh or fixed material. From a practical standpoint it is almost essential to obtam adrenal weights from fixed material in mammals the size of mice or smaller, as it is very difficult to clean the glands properly and obtain reliable weights on the fresh glands. Rapid water loss from fresh glands of such small size further complicates the problem. In most circumstances increased adrenal weight is an acceptable indicator of increased adreno- cortical activity, but an effort should be made to obtain the adrenals from suddenly killed specimens, not from captive animals or from those held in a live trap for extended periods, if one wishes to assess adrenocortical func- tion in the animal in its natural state. Animals which have been killed sud- denly are not subject to changes in adrenal weight resulting from capture or handling A word of caution is appropriate here with regard to sample size and adrenal weight-body weight relationships. Adrenal weight varies consider- 2. Endocrines and Populations 247 ably from individual to individual in the same species, as well as with sex, size, and therefore presumably age, in most mammals. Consequently, it is necessary to obtain large enough samples of each sex in each age category (at least mature and immature) to have reliable criteria for evaluating adrenal changes in a population and with time. In most studies of natural populations the investigator does not have the privilege of selecting animals for size, weight, and sex each time a sample is collected, and it is therefore necessary to determine adrenal weight-body weight, adrenal weight-body length or some similar relation- ship for the species and population with which he is working in order to establish a common baseline for all samples. For example, it has been found that the logarithm of adrenal weight in milligrams on body length (exclu- sive of the tail) gives the best straight-line relationships for all sizes and for both sexes of Norway rats (Christian and Davis, 1955). In other species, for example Microtus pennsylvanicus, there are marked differences in body-adrenal relationships between the sexes. The oft-used relationhsip of milligrams of adrenal weight per 100 grams of body weight is quite arbitrary and usually overcorrects for lighter and undercorrects for heavier animals, therefore this relationship is useful for only a very narrow range of body weights. Too often adrenals are collected as an afterthought along with other data for which the investigation was originally designed. As a result the data on adrenal weights usually are inadequate. A study of changes in adrenal weight must be designed specifically to obtain this and the necessary related data. Samples should be consistent with respect to time, size, and sex and age composition. Many potentially useful field studies involving an immense amount of effort have been of little value because of poor sampling, usually a result of treating the collection of data on adrenal weights as a secondary consideration in the investigation. Sampling usually does not alter the populations, as the normal rate of re- cruitment more than offsets losses due to sampling, in addition to which compensatory changes in mortality rate will usually compensate for sam- pling losses, unless the sampling is very frequent and intense. b. Routine Idstologic measurements. It is very useful in evaluating adrenal activity to measure the widths of the various zones and to coimt the number of cells in cortical cords in an area where cords are in straight columns (Zwemer, 1936; Zwemer et al., 1938; Christian, 1956). A variation of this is the somewhat more precise technique of projecting a section through the center of the gland and outlining the various zones, cutting them out and weighing them or else measuring their areas with a planimeter. It is possible with serially sectioned glands to repeat such a procedure every so many sections and in this way obtain precise information on the contributions made by the individual zones to the total weight of the gland. These tech- 248 J- J' Christian iiiques necessitate selection of appropriate sections and therefore require serial sections, especially on animals with adrenals weighing less than 20 mg. For glands heavier than this it is possible to select a portion through the middle of the gland grossly. All these measurements can be made on sec- tions stained routinely with hematoxylin and eosin. c. Adrenocortical sudanophilia. Fat stains, such as Sudan IV, are useful in evaluating the secretory activity of the adrenal cortex. The normally active cortex ("resting cortex") usually exliibits marked sudanophilia of the fasciculata and glomerulosa with the fat in vacuoles of moderate size. The sudanophilia becomes markedly reduced in acutely stimulated glands, and upon continued stimulation the sudanophilia may return to some degree, but the size of the vacuoles is reduced. Upon cessation, sudanophilia becomes intense and the vacuoles large. Sudanophilia may be completely absent from some species, such as the hamster, under all conditions. These details are discussed in greater detail elsewhere (Dempsey, 1948; Sayers and Sayers, 1949; Greep and Deane, 1949a, b; Symington ct al., 1958). d. Adrenal ascorbic acid declines on stimulation with ACTH, and this has been used as a means of assaying ACTH in blood and other fluids (Sayers and Sayers, 1949; Greep and Deane, 1949b). In general adrenal ascorbic acid is a useful histochemical means of assaying adrenal stimulation, al- though it may not reflect cortical secretory activity in the intact animal (Slusher, 1958). e. Adrenal cholesterol also declines on stimulation and can be used to assess cortical activity (Dempsey, 1948; Sayers and Sayers, 1949; Greep and Deane, 1949b) . IVIeasurement of adrenal steroids in the adrenal venous affluent, plasma, or their urinary metabolites can be used to assess cortical activity directly. These are subject to daily variation and also respond rapidly to stimulation. In addition, they are involved techniques to carry out properly. There is also some question concerning the biologic signifi- cance of the particular steroids measured. These measurements are there- fore of limited use for investigations outside the laboratory and are subject to numerous pitfalls in dealing with species which cannot be handled in the laboratory without stimulating adrenal activity. Measurements of urinary corticosteroids when practical and appropriate would probably be more useful than blood levels for studies relating to mammalian populations. Measurement of the products of corticosteroid metabolism in the urme is somewhat intermediate between weight and direct functional measure- ments, such as plasma steroids as a measure of chronic cortical stimulation. Urinary steroids may be collected daily ad infinitum under laboratory conditions and are unquestionably ^'ery valuable. However, steroid deter- minations are complex and difhcult to interpret, and in the last analysis represent only those steroids which escape as such via the urine and consist 2. Endocrines and Populations 249 largely of metabolites of steroids. Furthermore, a large proportion of the steroids are excreted in the feces in some species (Barry et al., 1952; Brad- low et al., 1954) . Finally, techniques for the measurement of urinary steroids have not been developed for use in the field. It should be apparent from the foregoing discussion that assessing adrenocortical activity by physio- logic or biochemical means in living wild animals or animals which have been live-trapped is fraught with difficulty, and under most circumstances measurements as such of the blood steroids will probably reflect the im- mediate situation of the animal. In general, weight and histologic criteria from animals killed suddenly seem to offer the most dependable informa- tion at the present time for studying population phenomena, although the other procedure should be explored further. Even though there is always a question of the presumptive relationship between hypertrophy, morpho- logic change, and function, in most circumstances it is generally accepted that cortical hypertrophy reflects functional change. The probable depar- tures from this general statement have been discussed above. /. Thymicolymphatic system. In the foregoing account it has been stated that the carbohydrate-active corticoids produce involution of the thymico- lymphatic system, mainly by effecting involution of the lymphoid elements proper. Therefore the weights of the thymus, lymph nodes, and spleen provide useful indicators of increased adrenocortical activity, especially if appropriate histologic checks are used. g. Thymus weight. Cortisone, hydrocortisone, and endogenous adrenal corticoids cause thymic involution (Dougherty, 1952a, b; Weaver, 1955). Increased phagocytosis, edema of the connective tissue stroma, and hyper- plasia of the reticulum are associated with the destruction of the lymphoid tissue proper (Gordon, 1955). If the reaction is severe enough, only the stroma and a modified reticulum may remain, with no distinction between the cortex and medulla of thymus and lymph nodes in degree of involution (Weaver, 1955) . The weight of the thymus therefore will be greatly de- decreased. Within a few hours following stimulation there is a marked edema, and during this period of edema there is a marked reduction in the number of lymphocytes; those remaining exhibit degenerative changes (Dougherty, 1952b). The effect is greatest on the small and medium-sized lymphocytes and thymocytes. These exhibit pycnosis, karyolysis, frag- mentation, and other degenerative changes. The fragments arc phagocy- tized by macrophages in reaction centers of the lymph nodes and are carried off in the lymphatics. Mitosis ceases in the lymphoid organs with treatment with cortisone, hydrocortisone, or with chronic stimulation of the adrenal cortices by endogenous or exogenous ACTH (Weaver, 1955; Gordon, 1955) . These changes are common to the lymphoid follicles where- ever they occur — spleen, nodes, gastrointestinal tract — but are most 250 /. /. Christian marked in the thymus. The greater sensitivity of thymocytes over the l3'mphocytes of the lymph nodes and spleen may be due to their greater rate of proliferation. Hydrocortisone is more effective in involuting lymph- oid tissue than cortisone or corticosterone and tends to produce degenera- tive changes among immature lymphocytes of the lymph nodes to a much greater degree than cortisone (Dougherty, 1953; Santisteban and Dough- erty, 1954) . On the other hand, pituitary growth hormone and deoxycorti- costerone appear to promote the growth of lymphoid tissue. The apparent increase in lymphoid tissue in gonadectomized or adrcnalectomized animals (or in those animals with adrenocortical atrophy from inactivity or over- feeding) (Christian and Ratcliffe, 1952) apparently results from protection against involuting agents rather than a true hyperplasia (Dougherty, 1953; Santisteban and Dougherty, 1954) . The thymus is also involuted by androgens, estrogens, and to a variable degree by thyroidectomy (Weaver, 1955) ; androgens also potentiate the ability of the carbohydrate-active corticoids to effect thymic involution (Selye, 1955; Dorfman and Shipley, 1956) . The cortex and medulla remain as distinct zones after this type of in\'olution, although they are less clearly defined than in normal (Weaver, 1955). All elements of the thymus share equally in the involutional process. Thymocytes are reduced, but no acute destructive changes are noted. Therefore involution of the thymus by sex hormones is a nonspecific action (Weaver, 1955) . The so-called involution due to aging of the thymus is prevented by gonadectomy in either sex (Selye, 1947) ; it is therefore logical to assume that the normal involution of this gland, seen especially at puberty (Christian, 1956) , is due to the sex steroids. It should be clear that thymic mvolution, and therefore thymic weight, can be a useful index of adrenocortical activity providing adequate con- sideration is taken of the action of the sex steroids. h. Lymph node weight is a useful index of adrenocortical activity as their lymphoid tissue is involuted by adrenal corticoids as discussed above, but to a less marked degree than for the tlwmus (Weaver, 1955). The iliac lymph nodes are involuted by prolonged administration of ACTH, acute administration of cortisone (Weaver, 1955), or a variety of stimuli evoking increased adrenocortical activity, but the sex steroids or thyroidectomy are without effect on the lymph nodes (Weaver, 1955) or maj^ even cause a hypertrophy of the nodes (Money et al., 1950) . A weight loss of the lymph nodes should therefore more specifically reflect increased adrenocortical activity than the thymus. However, tlwmic weight, properly controlled, is more frequently used because of its much greater sensitivity to the carbo- hydrate-active corticoids. Selye (1950) has indicated that the lymph nodes 2. Endocrines and Populations 251 even may hypertrophy in infectious disease or other circumstances which demand increased phagocytosis of particulate matter. i. Splenic weight. The lymph follicles of the spleen also are involuted by corticoids. A decrease in splenic weight is sometimes used to indicate in- creased adrenocortical secretion. However, contraction of the splenic cap- sule further decreases splenic weight. This may be a valid procedure in the laboratory with injected hormones, particularly in hypophysectomized or adrenalectomized animals, but often may not be a valid indication of in- creased adrenocortical activity, especially in intact small mammals. Voles (Microtus agrestis) and house mice, and possibly other species, exhibit a marked splenic hypertrophy when exposed to stimuli which cause in- creased pituitary-adrcnocortical activity (Clarke, 1953; Chitty, 1957; Christian, 1959c). Ln-olution of the lymphoid follicles occurs in these circumstances as might be expected, but the decrease in weight from this cause is overridden by the hypertrophy resulting from congestion and markedly increased hematopoietic activity. The increased hematopoiesis in these animals is accompanied by a reticulocytosis of the circulating blood. The cause of increased hematopoiesis in these animals has not been demon- strated. j. Lymphocijte counts. After an alarming stimulus there is an immediate rise in the number of circulating lymphocytes, which is then followed by a characteristic lymphopenia and eventually a return to normal levels. The initial rise in circulating lymphocytes probably is at least in part due to release of lymphocj-tes from lymphoid tissues in response to an initial re- lease of epinephrine, but this release by no means accounts for the entire rise (Gordon, 1955). The prolonged phase of lymphopenia which begins in the early stages of the increased pituitary-adrenocortical activity probably results from the destruction of medium and small-sized lymphocytes within the lymphatic organs by the corticoids (Gordon, 1955) . However, there is also some reason to believe that lymphocytes may migrate to depot situa- tions. Over a prolonged period the main cause of the lymphopenia appears to be due to the reduced amount of lymphoid tissue and decreased lympho- cytopoiesis with a decreased delivery of lymphocytes into the circulation. However, with small amounts of adrenal factors there may be an acutal hyperplasia of lymphoid elements, so that interpretations must be made with caution. Lymphocyte counts as criteria of stress in wild mammals are subject to the same criticism as other measurements made on the living mammal : the response is rapid enough and the counts labile enough so that there is real danger that counts may reflect alarming stimuli induced by handling, thus masking any other effects which may be the main point of the study. 252 /. J. Christian k. Eosinophil counts. The numbers of circvilating eosinophils are beyond doubt diminished by adrenal factors and eosinophil counts are commonly used to assess the response of the adrenal cortex to ACTH or indicate in- creased pituitary-adrenocortical activity (Speirs and Meyer, 1949; Speirs, 1955). The reduction in eosinophils appears to result mainly from their increased destruction under the influence of cortical hormones. A reduction in eosinophils can be effected by epinephrine as well as by cortical hormones, and there is evidence that the presence of cortical hormone is required for epinephrine to produce an eosinopenia (Gordon, 1955). It is mainly with respect to whether or not cortical hormones are necessary for the eosino- penic action of epinephrine that the specificity of eosinopenia as an indica- tor of increased adrenocortical activity has been questioned. Nevertheless, if epinephrine produces a marked eosinopenia in the intact animal, eosino- phil counts in mammals, especially wild, appear to have limited value. Fear resulting from handling, trapping, etc., not only would produce eosinopenia, but could produce it without necessarily having an increase in adrenocortical activity. Nevertheless Louch (1958) used eosinophil counts to assess adrenocortical function in relation to changes in popula- tions of voles and with adequate precautions the use of eosinophil counts for assessing adrenocortical activity in natural populations seems to have considerable value in these experiments. However it is not possible to state definitely whether the declines in eosinophils were due to cortical or medullary hormones, although it seems logical that the former were respon- sible and there was cortical hypertrophy. Southwick (1959) has also related declines in eosinophil counts in mice to increased adrenocortical functions, but again the role of epinephrine has not been evaluated. Eosinophils de- cline about an hour after acute stimulation of the pituitary-adrenocortical systems (Louch, 1958) ; therefore using counts as criteria of cortical func- tion with respect to chronic stimuli has many inherent hazards. Acute re- sponses to handling, fear, or line trapping could easily mask any effects pro- duced by the chronic stimulus of changing population density. The relative roles of epinephrine and of the cortical hormones in producing the observed declines in eosinophils following emotional stimuli in mice must be assessed before one can state with finality that the cause was increased cortical activity. I. Neutrophil counts. A rise in circulating neutrophils accompanies in- creased pituitary-adrenocortical activity, but similar changes can be in- duced by so many factors that, even though they may involve increased adrenocortical secretion, neutrophil counts are not very useful indices with which to measure pituitary-adrenal activity. m. Liver glycogen. The accumulation of glycogen by the liver has been used as a means of assaying various steroids for their activity on carbohy- 2. Endocrines and Populations 253 drate metabolism in adrenalectomized rats (Dorfman, 1949; Ingle, 1950). This response is a reflection of the ability of adrenal corticoids to stimulate gluconeogenesis. Glycogen in the liver can be measured chemically (Marto- rano, 1957) or can be visualized histochemically by the appropriate proce- dures (Dempsey, 1948; Lillie, 1954). Liver glycogen presumably falls as a result of exhaustion of the animal's ability to adapt (Frank, 1953) . Exactly what becomes exhausted under these circumstances is problematical, but it apparently is not the ability of the adrenal cortex to secrete steroids (Rosen- feld, 1958) . Nevertheless, it is true that blood glucose and liver glycogen eventually fall to extremely low levels following intense and prolonged stimulation by alarming stimuli. This result may follow prolonged stimula- tion of the sympatho-adrenal system. Exhaustion of glycogen, consequently of glucose reserves, has been observed in natural populations of snowshoe hares (Green and Larson, 1938; Green et al, 1939) and voles (Frank, 1953) during episodes of mass mortality and may possibly be explained on the basis of exhaustion of the adaptive reserves. A word of caution should be inserted on the use of liver glycogen as an indicator or activity of the carbohydrate-active corticoids. Under carefully controlled conditions in the laboratory such measurements are very useful, but they do require rigid controls and precise, highly standardized proce- dures. Martorano (1957) has studied the variables having important effects on liver glycogen. The amount of time between killing and enzymatic immobilization, the manner of killing, and a variety of other factors can alter glycogen levels. Glycogen and glucose levels in the liver decline rapidly after death. There also is a daily cycle in the levels of liver glycogen which is associated with feeding and activity (Martorano, 1957). Therefore, re- ported liver glycogen levels must be critically examined in relation to the procedures used and their reliability. n. Changes in the digestive organs and gastrointestinal tract. Alarming stimuli, ACTH, or cortisone produce a marked loss of the acidophilic zymogen granules and basophilic cytoplasmic pentose nucleic acids from the acinar cells of the pancreas and serous salivary gland cells (Ehrich and Seifter, 1948; Selye, 1950). The pituitary adrenocortical system also pro- foundly affects the function of the mucosa of the stomach and intestinal tract (Baker and Abrams, 1954; Baker and Bridgman, 1954; Gray and Ramsey, 1957). The adrenocortical hormone apparently stimulates the secretion of pepsinogen by gastric zymogenic cells (Gray and Ramsey, 1957; Mason, 1959), which is reflected morphologically by a loss of the intracellular pepsinogen granules and increased cytoplasmic basophilia (Baker and Bridgman, 1954). Additional changes may not be noted histo- logically in the mucosal cells of the intestine (Baker and Bridgman, 1954). 254 /. /. Christian 3. Generalized Effects of Physiologic Adaptation a. Growth. Associated with acute adaptation there is usually a suppres- sion of growth (Selye, 1950) . Selye (1950) has suggested that during actua- tion of the pituitary-adrenocortical system there is a decreased production of the other hormones of the adenohypophysis, including growth hormone. However, injected corticoids or ACTH into intact animals also results in suppression of growth and ACTH will inhibit growth produced by growth hormone in h^Tpophysectomized rats (Jones, 1957). It was pointed out earlier in this chapter that the adrenal carbohydrate-active corticoids in- crease protein catabolism, prevent the gro^^iih of bone, lymphoid tissue, skin, connective tissue with the production of collagen, and block mitoses in general. Therefore the suppression of growth by alarming stimuli may reflect decreased secretion of growth hormone as well as the direct suppre- sive action of the carbohydrate-action corticoids on mitoses and therefore growth and development. Diminished thyroid activity during periods of actively increased adrenocortical activity may also play a role in this phe- nomenon. Selye (1950) has pointed out that most of the observed changes following an alarmmg stimulus serve to maintain life and that other, less immediately important, functions are suppressed. b. Inflammation and granulation. The adrenocorticoids, cortisone, hydro- cortisone, and to a lesser extent corticosterone, exert powerful anti- inflammatory effects which stem from the suppression of growth of connec- tive tissue, the depression of Ij'mphocyte activity, and interference with the phagocj^tic process (Dougherty, 1953; Robinson and Smith, 1953; Thomas, 1953), but in addition they prevent the mobilization of all of the usual elements of an inflammatory response around the site of injury (Taubenhaus and Amromin, 1950; Dougherty, 1953; Robinson and Smith, 1953; Gordon, 1955; Dougherty and Schneebeli, 1955). Androgens and estrogens potentiate these anti-inflammatory responses. They decrease the destruction of fibroblasts and the invasion of polymorphonuclear leuco- cytes and macrophages. The appearance of epithelioid macrophages, giant cells, and formation of new fibroblasts and macrophages are suppressed by cortisone, either injected or implanted as pellets (Baker, 1954) . Dougherty and Schneebeli (1955) explain the inhibition of the inflammatory response around the site of injury in the following way: When there is cellular injury, substances are released from the injured cells which trigger a series of re- sponses which comprise inflammation (Menkin, 1955; Dougherty and Schneebeli, 1955). Cortisone or hydrocortisone inhibit the inflammatory response by protecting the surviving cells from the actions of the released products of cellular injury. Growth hormone, deoxycorticosterone, and aldosterone appear to exert a stimulating effect on inflarmnation and the 2. Endocrines and Populations 255 development of granulation tissue (Selye, 1955; Dougherty and Schneebeli, 1955) . These hormones, however, also inhibit the anti-inflammatory action of cortisone, hydrocortisone, and corticosterone and may enhance the local inflammatory response by increasing the susceptibility of the cells to the inflaming stimulus (Dougherty and Schneebeli, 1955). Therefore, if there is a reduction in the secretion of growth hormone with a simultaneous in- crease in the production of ACTH and the adrenocortical steroids, there will not only be a direct suppression of the inflammatory responses to infec- tion or injury, but also a withdrawal of the factors which ordinarily would stimulate such activity. The effects of various alarming stimuli or hormones on inflammation and granulation in the intact animal have been studied and measured by using experimental granulomas (Meier et at, 1950; Selye and Bois, 1954; Robert and Nezamis, 1957; Christian and Williamson, 1958) or other means of inducing inflammation and granulation. It has been shown that in addition to suppressing inflammation the carbohydrate- active corticoids also suppress the formation of granulation tissue and healing, primarily by preventing connective tissue growth. There can be little doubt that the normal defenses against infection are severely depressed in stressed animals. c. Antibody formation. Antibodies are formed mainly in the lymphatic tissues (Kenning and Van der Slikke, 1950; Kass et al., 1953a; Kelsall and Crabb, 1958) . One school maintains that this function resides primarily in the plasma cells, w^hile another group holds that lymphatic cells in general are capable of manufacturing antibodies (Kenning and Van der Slikke, 1950; Dougherty, 1953; Kelsall and Crabb, 1958). We do not intend to enter into this controversy at the present time, but it seems relatively certain that the lymphoid tissues are primarily responsible for the produc- tion of antibodies. A variety of experiments have shown that injected corticoids or the increased secretion of endogenous corticoids, brought about either by injected ACTH or in response to alarming stimuli, markedly suppress the formation of antibodies (Kass et al., 1953a) . Protein manufac- ture, and therefore the formation of antibodies, requires the presence of nucleic acids in the cells, especially in the cytoplasm, and antibody forma- tion is normally associated with an increase in nucleic acid content of the lymphoid organs (Kass et al., 1953a; Kelsall and Crabb, 1958). Therefore, when there is interference with nucleic acid metabolism or its formation, there is an accompanying reduction in the rate of formation of antibodies (Kass et al., 1953a; Kelsall and Crabb, 1958). We have seen that in addi- tion to actually destroying lymphoid tissue, the glucocorticoids reduce the PNA content of the remaining lymphatic cells. The ability of the reticulo- endothelial system, and possibly other cells, to dispose of phagocytized particulate material is also impaired (Thomas, 1953) even though phago- 256 /. /. Christian cytosis may be stimulated (Gordon and Katsh, 1949; Thomas, 1953). By these several mechanisms the production of antibodies may be seriously impaired following activation of the adrenal cortex although there appears to be a dose-response relationship (Dougherty, 1953; Dougherty and Schneebeli, 1955). While most of these effects were demonstrated most clearly by injecting adrenocortical hormones, the same effects have been shown repeatedly following stimulation of adrenocortical secretion in the intact animal. d. Resistance to infection. The three immediately preceding topics all deal with factors involved in the resistance to infection. It stands to reason that reducing the inflammatory response to, and depressing the formation of antibodies against, infectious agents will inevitably impair the ability of an animal to resist infection. Cortisone, hydrocortisone, and ACTH have been shown to decrease resistance to a variety of experimental infections caused by a variety of infectious agents including streptococcal, pneumo- coccal, tuberculosis infections in mice, rats, and guinea pigs, brucellosis, malaria in monkeys, and others (Kligman etal., 1951 ; Schmidt and Squires, 1951 ; Selye, 1951 ; Kass et al., 1953b; Le Maistre et al., 1953; Robinson and Smith, 1953). The pathogenicity of various agents has been increased by cortisone injection. For example, the virulence of Coxsackie infections in mice was greatly enhanced by cortisone (Boring et al., 1955), and polio- myelitis can be made a paralytic disease in the normally resistant hamster by cortisone or hydrocortisone (Shwartzman and Aronson, 1953). Vire- mias may likewise be prolonged appreciably by the adrenal glucocorticoids (Whitney and Anigstein, 1953; Pollard and Wilson, 1955). The list of experimental infections which have been made more virulent, prolonged, or otherwise increased in their pathogenicity by treatment with carbohy- drate-active adrenocorticoids or ACTH (Selye, 1951) is long, and there is no point in listing them in detail here. Whenever experiments with injected hormones are considered the ques- tion arises whether or not the same events may occur as a result of in- creased endogenous secretion of the same or similar hormones. A criticism frequently made of experiments with exogenous hormones, especially with large doses, is that the results are pharmacologic rather than physiologic. However, it is by using isolated hormones in highly controlled situations that an understanding of the basic mechanisms is gained. Nevertheless, before one can extrapolate from these data to natural events, comparable changes must be shown to occur in natural or seminatural conditions. Changes in host resistance may result from adverse environmental stimuli, possibly as a result of adrenocortical activity. It has long been common knowledge that excess fatigue, chilling, and a variety of comparable stimuli increase the susceptibility of humans to colds and other infections. It should 2. Endocrines and Populations 257 be apparent now that most of these same stimuH also increase the secretion of adrenocortical steroids. However, commonly accepted truisms still do not constitute experimental evidence and proof of such conclusions, but several experiments have shown that host resistance is decreased by ex- posing the animals to stimuli which are known to increase adrenocortical activity. When mice are exposed to 4° C. for a period of time, Coxsackie infections become much more pathogenic, spreading especially to the heart and liver in adult mice (Boring et al., 1956) . Duninished resistance of mice to trichinosis and to tuberculosis has been demonstrated by procedures which also produce increased pituitary-adrenocortical activity and depress inflammation and granulation (Christian and Williamson, 1958; Tobach and Block, 1956; Davis and Read, 1958) . Some aspects of these studies will be considered in more detail later. e. Reproduction. Suppression of reproduction is a very important aspect of the endocrine adaptive responses (Selye, 1939, 1950). The decrease in reproductive function is in many ways a more sensitive measure of the existence of altered physiologic functions in response to adversity than the increase in adrenocortical activity and some of its sequelae (Christian, 1955a, b, 1956, 1959b, c) . The bulk of the experimental evidence indicates that, like growth hormone, the secretion of pituitary gonadotropins is sup- pressed in response to alarmmg stimuli which evoke an increased secretion of ACTH (Selye, 1939, 1950; Christian, 1956, 1959b, c). It is another indication that the immediate restoration of the normal internal environ- ment takes precedence over functions which are less important to the im- mediate siu-vival of the individual. Cold, heat, disease, trauma, severe emotional stress, and other stimuli will depress normal reproductive func- tions (Marrian and Parkes, 1929; Selye, 1939; Bohanan, 1939; Poindexter, 1949; Denison and Zarrow, 1955; Barnett and Manly, 1956; Christian and LeMunyan, 1958; Christian, 1959b). The suppression of gonadotropin secretion is evidently the primary cause of the inhibition of reproductive function (Mulinos et al, 1939, Selye, 1950; Srebnik et al, 1958), although there may be direct effects of increased adrenocortical activity and altered thyroid function, as mentioned earlier (Brynes and Shipley, 1950; Baker et al, 1950; Smith, 1951; Brimblecombe et al, 1954). The secretion of gonadotropins seems to be regulated principally by the hypothalamus (Anderson and Haymaker, 1948a, b; Markee et al, 1952; Everett and Sawyer, 1953; Hammond, 1954; Critchlow and Sawyer, 1955; Nalbandov et al, 1955; Laqueur et al, 1955; Fortier, 1957; Greer, 1957; D'Angelo and Traum, 1958 Everett, 1959) , although there is evidence that the secretion of luteotropin by the pituitary may be independent of the hypothalamus (Everett, 1956). The hypothalamic centers involved in the regulation of the secretion of the gonadotropins apparently are distinct from those 258 /. /. Christian responsible for the regulation of ACTH and TSH secretion (Laqueur et al., 1955; Greer, 1957; D'Angelo and Traum, 1958). In addition there are neurogenic factors involved in ovulation which consist of adrenergic and neurogenic components (Markee et al., 1952; Everett and Sawyer, 1953; Nalbandov et al, 1955) and probably also in the milk let-down reflex (Grosvenor and Turner, 1959a). Finally, as in other endocrine regulating mechanisms, the level of circulating sex steroids seems to exert a regulating effect on the release of the particular gonadotropin responsible for their release (Selye, 1947; Sturgis, 1950; Byrnes and Shipley, 1950; Byrnes and Meyer, 1951). Whether these steroids exert their effects on the hypothala- mus or on the anterior pituitary itself is not known. In any event, with- drawal of stimulation by the gonadotropins leads to atrophy of the gonads and decline in the production of their respective steroids (Burrows, 1949). The decline in the production of sex steroids is in turn followed by atrophy of those accessory organs and secondary sex characteristics which depend on the sex steroids for their activity and maintenance (Burrows, 1949). If a male animal is subjected to adverse circumstances for any length of time, there is a marked decrease in spermatogenesis and a reduction in the secretion of androgens as indicated by atrophy of the seminal vesicles, prostate, and preputial glands (Christian, 1956; 1959b; Christian and LeMunyan, 1958) . These changes may all be followed by the changes in their weights, but weight changes should be assessed by appropriately selected histologic examination of the organs. In young animals there may be either a delay in the onset of puberty or a total suppression of the de- velopment of puberty, as indicated by the development of spermatogenesis and the sex accessories or, in the mouse, by a failure of the X-zone to involute at the usual time (Christian, 1956, 1959a, b). If mature animals are subjected to severe stimuli, there may be easily discernible degenerative changes in the tubules of the testes and cells of the spermatogenic series. Changes in the female reproductive function are less easily seen than in the male, as organ weights do not provide as useful a criterion of changes. Nevertheless, changes in estrus are usually evident and can be detected by vaginal perforation or by vaginal smears. Depending on the severity of the inducing stimulus, estrus may be prolonged or totally suppressed. Uterine weight may reflect reproductive suppression, and would be especially valuable in demonstrating a delay in the onset of puberty in female animals. In some circumstances there may be a total suppression of reproductive activity. It is in actual reproductive performance that the effects of sup- pression of the reproductive endocrine system becomes most evident. De- pending on the severity of the stimulus and on the species involved, there may be a complete failure to become pregnant, which may be due to a failure of ovulation or a failure of the shed ova to implant in the uterus or, 2. Endocrines and Populations 259 if the females do become pregnant, there may be a marked increase in fetal mortality with increased resorption of the embryos (Christian, 1959a, b) . The causes of fetal mortality in these circumstances have not been explored in detail, but a number of factors may be involved. It is well known that cortisone and hydrocortisone have serious effects on the fetus, apparently by inhibiting growth and development (Glaubach, 1952; Fraser et al, 1953; Davis and Plotz, 1954; Kalter, 1954). The resultant defect probably depends to a large extent on the developmental stage of the fetus when these hormones are active, as is the case with nutritional deficiencies (Lutwak-Mann, 1958) . A variety of congenital defects have been produced experimentally by the injection of these hormones. However, high doses are required to produce these effects; furthermore, with chronic injection of cortisone some fetuses do not seem to be affected (Seifter et al, 1951). Hydrocortisone and cortisone increase the incidence of fetal mortality in rats during the second half of pregnancy. The mechanism is unknown, but it has been suggested that it may be due in part to premature ''aging" of the vasculature of the placenta (Seifter et al, 1951). Increased mortality may reflect fatal defects in the growth of the embryos due to the action of these hormones. In other words, there may be time-dosage relationships which determine whether the effects of these glucocorticoids will be fatal or will result in "congenital defects," such as cleft palate or cardiac anomalies. However, these explanations leave unanswered the question why many embryos subjected to the same influences are born viable and free of de- fects, even from the same pregnancies. However, there are many other factors to consider when discussing intrauterine mortality resulting from activation of physiological adaptive systems. One must consider the in- creased secretion of adrenal androgens by those species in which androgens or proandrogens constitute a major secretory product. These compounds possibly may directly inhibit the action of estrogens and progestins. For example, it has been shown that testosterone can completely inhibit the feminizing action of estrogens on developing rat embryos (Greene et al, 1941). More importantly, the adrenal androgens can inhibit the secretion of gonadotropins, especially of FSH (Byrnes and Shipley, 1950; Byrnes and Meyer, 1951 ; Dorfman and Shipley, 1956). Whether the decline in the secretion of gonadotropins with increased ACTH secretion is due to inhibi- tion by increased circulatory levels of adrenal androgens or whether it is independent of the androgens, cannot be said. However, it seems probable that the androgens are not important or, if so, only in a limited number of species. The adrenal secretion of androgens or their precursors in many species does not appear to be sufficient to account for the effects seen. For example, in humans pituitary blockage requires much higher doses of testosterone than is required to produce overt androgenic responses. Very 260 J' J' Christian likely the reciprocal relationship between ACTH and gonadotropin secre- tion is independent of the adrenal androgens in most species, although the latter possibly may enhance a pre-existing inhibition of the gonadotropins. However, they may be of considerable importance in house mice, rats, and other species which secrete appreciable amounts of adrenal androgens. There undoubtedly are many other factors contributing to intra-uterine mortality which have not been discussed here. In general, however, it is evident that factors increasing pituitary-adrenocortical activity are asso- ciated with increased intra-uterine mortality, although the details of the mechanisms are largely unknown. Finally, if the young are born, there may be a failure of lactation due to deficiency in the hormones normally required for the maintenance of adequate lactation (Christian and LeMunyan, 1958). The changes in re- productive function following inanition have been show^n to be due pri- marily to a decrease in the secretion of gonadotropins, as the gonads remain responsive to injected gonadotrophin (Srebnik et al., 1958). Most of these alterations in reproductive function will be discussed in more detail later. /. Acute visceral degenerative changes. Acute degenerative changes of the liver, pancreas, and parotid glands have been described as occurring during an alarm reaction to a variety of stimuli (Selye, 1950; Ehrich and Seifter, 1948). Selye (1950) states that similar changes also occur during the "exhaustion" phase of adaptation. The most constant hepatic changes are pycnosis, cloudy swelling, and stromal edema. Occasionally there is fatty infiltration, severe atrophy, focal necrosis, and leucocytic infiltration. However, many of these changes are duplicated by a variety of specific stimuli and cannot be considered as diagnostic in any sense unless all other possible factors, other than increased pituitary-adrenocortical activity, have been ruled out. The salivary glands, especially the parotid, also exhibit degeneration and necrosis of the parenchyma, often with suppurative inflammation, during an alarm reaction (Ehrich and Seifter, 1948). In addition to the zymogen discharge already alluded to, the pancreatic parenchyma may exhibit focal necrosis and inflammation comparable to that seen in the salivary glands (Selye, 1950). The cytoplasmic nucleic acids are markedly decreased during acute adrenocortical stimulation or in response to injected adreno- corticoids, and may precede the degenerative changes. Loss of cytoplasmic basophilia in hepatic cells under the same circumstances reflects the same kind of influence of adrenal steroids on cytoplasmic nucleic acids. g. Other effects. In addition to those effects of physiologic adaptation which have been discussed, there are others which stem from a general shift in physiologic functions or as yet have not been related to the activity of any specific hormone. Among these is enlargement of the intervertebral 2. Endocrines and Populations 261 discs (nucleus pulposus) which has been found in voles {Microtus orcaden- sis) subjected to emotional stress (Chitty et al, 1956) . The enlargement of the intervertebral discs could result from altered fluid and electrolyte balances brought about by increased activity of adrenal corticoids, or might follow alterations in the ground substance by cortical hormones; however, these explanations are conjectural as the mechanism is as yet unknown. Physiologic adaptation may be accompanied by a variety of shifts in the composition of the blood with changes in hematocrit, electrolyte concentra- tions, and various metabolites. Blood lipids and sugar may also shift mark- edly, as we have mentioned earlier. However, these factors are discussed in considerable detail elsewhere (e.g., Selye, 1950; Hartman and Brownell, 1949; Jones, 1957) and will not be considered further in this discussion. Part 2. Physiologic Adaptation and Mammalian Populations I. Introduction The foregoing account dealt largely with the basic endocrine and other physiologic adaptive mechanisms that serve to maintain physiologic homeo- stasis in the face of a variety of stimuli tending to alter the internal environ- ment and to equip the animal to meet the demands of emergency situations. In general, any stimulus which imposes physiological demands on an organ- ism beyond those ordinarily met in undisturbed idyllic daily life calls into play a series of feedback mechanisms that regulate the secretion of hor- mones responsible for the maintenance of a relatively constant internal environment. These mechanisms act upon the distribution of the internal environment via the circulatory channels, the composition of the internal environment with respect to fluids, electrolytes, glucose, fats, and a variety of other metabolites and metabolic products, and on the supply of readily available nutrients and oxygen, especially for the skeletal muscle and ner- vous system. We have seen that these effects are not achieved withovit sacrificing functions less immediately vital to the individual, such as re- production, growth, and resistance to infectious disease and parasitism. We also have pointed out the error in thinking that the responses to all adverse stimuli are the same and that all necessarily are associated with increased secretion of adrenal carbohydrate-active corticoids. 262 /. /. Christian The mechanisms, hormonal effects, and general responses so far described have been confined largely to the results of experiments in the laboratory with the usual laboratory species. Very little work has been done on native mammals in the laboratory, and comparative studies are certainly needed. In addition, the work has been to a great extent limited to studies of the effects of injected hormones or of subjecting laboratory animals to ex- tremely severe conditions. The role that physiological adaptive mechanisms play under natural conditions was not investigated in most of these studies. However, it was postulated in 1950 that these same responses could be evoked by increased population density and that these same physiological reactions could serve as a feedback to regulate the growth of mammalian populations, their declines, and the mass mortality which occasionally terminates the build-up of a natural population to extremely high densities (Christian, 1950b). It was first suggested that the intraspecific strife and social competition that force animals into adverse circumstances, together with all of the other adversities which become aggravated by high population densities, would elicit adaptive responses such as those which have been described. There- fore one would anticipate a direct relationship between adrenocortical activity and a more or less reciprocal relationship between reproductive function and population density. The hypothesis that physiological mecha- nisms were active in all populations in response to changes in density and that most environmental deficiencies acted through this mechanism was inherent in the original postulate. This hypothesis implied that social competition or pressure was the sole factor, always present in all popula- tions, which could logically be expected to elicit the gamut of adaptive responses in every population. However, these relationships had to be demonstrated, and it was necessary to show that changes in population alone could induce a proportional increase in pituitary- adrenocortical activity, decrease in reproductive activity, decrease in resistance to disease, or even death from shock, and all the other reactions and responses which have been described in the preceding section. Since that time considerable evidence has been accumulated from the laboratory and from natural populations which indicates that these re- sponses to population density do occur and that they can regulate popula- tion growth. The balance of this chapter will be devoted to a presentation of the experimental evidence for the response of physiological adaptive mechanisms to social competition and therefore population density, and the evidence implicating these mechanisms, acting as a feedback system, in the regulation of mammalian populations. Finally there will be a discussion of the pertinence of this evidence to the regulation and control of natural populations. 2. Endocrines and Populations 263 The general plan of the following discussion will be to explore first the ability of purely social factors to affect adrenocortical and reproductive function. Next the relation between population density and adrenocortical, reproductive, and other functions as well as alterations in resistance to disease, will be investigated. In general the plan will proceed from popula- tions of fixed size in the laboratory to freely growing populations in the laboratory, and finally to natural populations. Under each of these experi- mental categories adrenocortical function, reproductive function, disease resistance, and mortality will be discussed with all appropriate experiments and species. The effect of population density on growth will be discussed where appropriate, and the effects of food and other environmental factors on social interactions and endocrine function will be discussed. It is not possible to stay strictly within this framework, as it is somewhat artificial, but it does seem to offer the most logical means of presenting the available information as it progresses from the most artificial but most highly con- trolled experiments to natural populations which are controlled with great difficulty, if at all. II. Endocrine Responses to Social Pressures and to Population Density A. Experiments in the Laboratory with Populations of Fixed Size One of the basic tenets in the theory that physiological feedback mecha- nisms can regulate population growth is that a fundamental regulating factor must be present and active in all populations. Whether or not this particular factor is the proximate factor limiting population growth in a given instance is not important if it is universally present. The only known element common to all populations is social interaction, or intraspecific competition. Basically, competition depends on the behavioral characteris- tic of the species, but some sort of social organization or mutual intolerance is exhibited by all species of mammals. 1. Social Factors, Adrenocortical and Reproductive Functions Social interactions may arise from two kinds of situations: one in which there is invasion of the private territory of one animal by another; and another in which there is conflict involved in the establishment and mainte- nance of a hierarchical situation. The first requirement of the hypothesis that physiologic mechanisms can and do control population growth is to show that purely behavioral or social interactions, acting through the central nervous system, can induce endocrine responses, especially of the pituitary-adrenocortical and reproductive systems, and to be able to rule 264 /. J. Christian out other factors which are known to produce the observed changes. That pure sociopsychologic factors can produce these effects is clearly demon- strated by the following experiments. When a strange vole {Microtus agrestis) of either sex was placed daily for 27 days in a cage containing a resident pair of voles, and therefore in what was essentially their private territory, vicious fighting ensued (Clarke, 1953). The introduced voles lost weight and exhibited a significant hyper- trophy of the adrenals and spleens and atrophy of the thymus compared to the residents. In similar experiments with Microtus orcadensis there were significant increases in the size of the livers, adrenals, intervertebral discs, and spleens, and decrease in the thymus in the "stressed" animals, those introduced as strangers to resident pairs (Chitty et al., 1956). Clarke (1953) attributed the changes in organ weight to the actual fighting, stating that fighting is a very effective form of stress since it involves vigorous muscular exercise in addition to the trauma of wounds (Selye, 1950) . However, the fact that the resident voles had to fight as much as those which were introduced, and yet did not reflect this with increased adrenocortical activity, apparentlj^ was overlooked. This problem may be explored by data on albino mice (Christian, 1959d). An analysis of the relationship between scars from fighting and adrenal weight from 280 male albuio house mice from 55 populations of 4, 5, or 6 each showed that, al- though the mean adrenal weight of every population increased appreciably with respect to isolated controls, there was no relationship between the amount of scarring, as an indication of the severity of fighting, and adrenal weight. Fm'thermore, the presence or absence of scarring in a population made no difference in adrenal weight. The results were similar irrespective of whether the analysis involved only the differences between populations or the difference between individuals. Adrenal weight increased the same amount in populations in which there was no fighting, or so little that none of the mice had injuries from biting, as it did in populations in which fighting was severe enough that most of the animals were badly scarred. It should be pointed out that these injiu'ies were superficial and for the most part represented bites through the skin only. These results indicate quite clearly that fighting or injury per se are not the stimuli responsible for stimulating increased adrenocortical activity with thymic involution when animals are placed together. Conclusive evidence that sociopsychologic pressures alone are mainly responsible for evoking these physiologic adap- tive responses lies in the following experimental results (Davis and Chris- tian, 1957) . When house mice are placed together in groups of six, there is immediate fighting which soon ceases with the establishment of a social hierarchy with one mouse dominant over the others and another subordinate to all the 2. Endocrines and Populations 265 others. The remaining mice arrange themselves in some sort of hierarchy in between. It was found that adrenocortical hypertrophy was greatest in the most subordinate animals and was slight or absent in the dominant mice. The adrenals of those in between tended to fall in line in between in a reciprocal relationship to their dominance rank. Fighting cannot have been an important stimulus to mcreased pituitary-adrenocortical activity in these experiments, as the dominant animals fought as much as, or more than, any of the subordinate animals. The mice in these experiments also exhibited changes in the weights of their reproductive organs consistent with suppressed secretion of gonadotropms coincident with increased pituitary-adrenocortical activity. There was no clear-cut decline in the weights of the reproductive organs with decreasing social rank, but the dominant mice had much heavier reproductive organs, especially the pre- putial glands, then the subordinate animals (Davis and Christian, 1957). These results were confirmed and intended in dogs by Eik-nes (1959), who found that the dominant dogs in groups secreted about half the amount of corticoids that the subordinate dogs secreted. Therefore there can be little question that there are significant differences in adrenocortical func- tion associated with differences in social rank. In another series of experiments Southwick ( 1959) demonstrated that moving mice into a new environment daily could induce a marked increase in adrenocortical activity as determined by eosinophil counts. That the eosinopenia was not a result of handling was shown by the fact that mice handled in the same way but not placed in a strange situation responded with only a slight fall in circulating eosinophils. The mice transferred to new cages for a period of time every day adapted to the situation, as the eosino- phil count returned to normal levels by the end of the 8-day experimental period. A third series of anunals were placed in groups of four each day and these animals exhibited an 80% mean decline in their eosinophil counts and these counts remained low as long as the animals were placed in groups. Presumably the mice responded to grouping with a marked increase in adrenocortical activity and did not adapt to the situation. It is clear from these results that merely placing mice in a strange situation is an emotional stimulus sufficient to result in a decline in circulating eosinophils and pre- sumably in adrenocortical activity and that grouping constitutes a more profound stimulus to which animals fail to adapt. As we have pointed out previously, it cannot be concluded finally that the eosinopenia was due to increased adrenocortical activity, although it seems likely, imtil increased secretion of epinephrine is ruled out as a causative factor. Similar results were obtained when male Norway rats were placed in groups (Barnett, 1955) . The subordinate males, subjected to severe fighting for short periods, at first showed marked decreases in adrenocortical sud- 266 /. J- Christian anophilia, whereas prolonged exposure to less severe fighting resulted in normal sudanophilia with adrenal hypertrophy in the subordinate animals. None of the dominant rats showed adrenocortical hypertrophy or changes in sudanophilia in spite of the fact that they fought as much or more than the subordinate animals. Barnett (1958) has recently published additional evidence on a smaller number of rats from which he concluded that the adrenal cortices of both subordinate and dominant animals hypertrophy. Nevertheless his data show that the mean adrenal weight, relative or abso- lute, of subordinate animals in a group of rats introduced into a colony was appreciably greater than that of dominant animals. Barnett used very small numbers of rats and based his conclusions on absolute rather than on rela- tive adrenal weight, in spite of the fact that his animals varied from 250 to 400 gm. at the start and 170 to 420 gm. at the end of the experiment. He concluded, on the basis of thirty rats, that there was no relationship between adrenal weight and body weight for rats weighing more than 150 gm. This conclusion may be ciuestioned for several reasons. In the first place the mean adrenal weight of his animals increased with increasing body weight, athough the differences were not significant. However, had larger numbers of animals been used it is more than likely that a significant increase in adrenal weight with increased body weight could have been shown. Other data on over 1200 wild Norway rats shown conclusively that there is a definite increase in adrenal weight with increasing body weights varying from 50 through 600 gm., and that there was a significant linear relationship between the logarithm of the adrenal weight and body length or weight (Christian, 1954; Christian and Davis, 1955) . Finally, it is well known that there is a definite tendency for the larger animals to be dominant, therefore adrenal hypertrophy in smaller, subordinate rats would tend to make the adrenals of dominant and subordinate animals weigh the same. It is of considerable interest, however, that rats from colonies of mixed sex were appreciably larger than those from all-male colonies. In general the amount of sudanophilia in the zona fasciculata coincided with the weight data. Nevertheless, Barnett's results appear to agree with those established earlier as well as with the results of the experiments of other investigators. The above experiments warrant the general conclusion that in house mice and Norway rats adrenal weight tends to be inversely related to social rank in that dominant animals exhibit little or no increase in adrenal weight, while subordinate animals show a marked increase. A word of caution should be directed with regard to the interpretation of results with adrenal weights. A hyperactive adrenal with a loss of cortical lipids may weigh less than a less active gland containing a large amount of lipids. This has been shown to be the case in mice (Christian, 1955a, 1959b) and evidently is also true in Barnett's (1958) experiments in which the adrenals of his "interloper" 2. Endocrines and Populations 267 rats weighed somewhat less than those of subordinate rats, but the adrenals of the interlopers contained little or no lipid. The relationship between social dominance and adrenal activity is, however, not as clear cut as these experiments at first indicate and suggests that a great deal of work needs to be done on the factors which affect dominance-subordinance relationships and w^hat constitutes "social stress" in mammals. The adrenals of the dominant animal in a group do not always weigh the least and occasionally may be the heaviest, even though the average weight of the adrenals of the dominant animals is appreciably less than those of other ranks. Furthermore, the amount of fighting varies greatly from group to group. Finally, the amount of scarring on a mouse in a group is in a general way a measure of its rank. Observation has shown that it is generally safe to assume that the unscarred mouse in a group is the dominant animal, and yet, as we have shown, there is no relationship between the amount of scarring and absolute adrenal weight in groups of albino male mice although there was clearly a tendency for adrenal weight relative to body weight to increase with increased scarring (Christian, 1959d) . These results apparently indicate that fighting is a poor measure of social rank and is related only indirectly to it. These results appear to contradict the results of other experiments, although these differences would probably be reconcilable if more detailed information were available on social behavior in these animals. Rather rigid and simple criteria are used to determine rank in animals, such as physical dominance-subordi- nance relationships, and it is quite clear that social interactions are far more complex than this. However, the apparently contradictory results with relation to fighting and dominance in no way invalidate the conclu- sions that purely psychological social pressures are responsible for stimu- lating increased adrenocortical and decreased reproductive activity in groups of mice and rats and that fighting per se has little or no effect on the adrenal hypertrophy observed in groups of animals. One can speculate with some reason that a massive stimulation of the nervous system and adrenal medulla occurs in subordinate animals when they are suddenly confronted with a dominant, aggressive male. Observation shows that these animals are aware of their rank and cower in front of the dominant animal. When there is no escape from constant contact, it seems inevitable that the subordinate animals must suffer from emotional anxiety resulting from a desire to escape from the situation and the inability to do so. Chronic stimulation of the pituitary-adrenocortical system presumably results from the chronic continuation of such a situation. Admittedly this somewhat anthropomorphic interpretation of the situation is largely speculative, but observations of mice in groups inevitably lead one to such a conclusion. Finally, Mason (1959) has shown that when rhesus monkeys are kept in 268 /. /• Christian groups for prolonged periods of time there is a significant increase in their urinary tetrahydroxycorticoids, the metabolites of the carbohydrate-active corticoids, excreted by grouped monkeys is greater than their combined daily production of corticoids when individually caged. Furthermore, the production of corticoids remains high for the entire period of grouping. It has also been observed that when human bomber crews are housed as a group, their production of urinary corticoids is increased over the combined individual production of corticoids by the same men, paralleling the findings for monkeys (Mason, 1959) . In the case of monkeys and men there can be no question that the stimulus to increased corticosteroid production is psychological, resulting from social interactions. There can be little doubt that social pressures can increase pituitary- adrenocortical activity. We have also suggested that there is a depression of reproductive function in male mice, as indicated by the weights of the sex accessories, coinciding with increased adrenocortical function in relation to social factors. These results are in agreement with the earlier work of Crew and Mirskaia ( 1931 ) and Retzlaff ( 1938) , who showed that increased popu- lation density depresses reproduction in female mice. The reproductive performance of female mice was inversely related to population sizes in populations of 1, 4, 8, or 12 pairs. Retzlaff (1938) also indicated that repro- ductive performance was best in the socially dominant females in each population. He made several additional observations of interest in these experiments. He noted that there were aggressively dominant females that attacked and viciously fought introduced females or females which had been removed and were later replaced. The subordinate females suffered death or injury, and, of particular interest, any infections that they had were greatly exaggerated. This is one of the early experunental indications of decreased resistance to disease following social stress, and is further evidence that resistance is decreased primarily in the subordinate animals. He also noted that in the largest populations, 12 pairs of mice, there was a sufficient confusion among the mice to offer the subordinate animals partial protection from attack. Similar effects were later noted in populations of 32 male mice (Christian, 1955a, b). Finally, it was found that a reduction in environmental temperature of approximately 16° C. resulted in a signifi- cant decline in mean litter size for mice from populations of 1, 2, or 8 pairs, but not from populations of 4 or 12. The protection against a reduction in litter size by decreased temperature probably reflects huddling as a means of maintaining body heat and therefore diminishing the need for increasing thyroid activity. Retzlaff could not explain the reduction in populations of 8, but evidently it was due to severe social strife rather than the reduction in temperature. It is conceivable that severe strife prevented huddling due to mutual intolerance; so that both factors could play a causative role in 2. Endocrines and Populations 269 reducing reproductive performance. The preceding experiments usually- used populations consisting entirely of male or mixed male and female mice or rats (Crew and Mirskaia, 1931 ; Retzlaff, 1938; Barnett, 1958) . However, a depression of reproductive function occurs when only female mice are placed in groups (Andervont, 1944). In these latter experiments estrous cycles began at an earlier age, were more frequent, and lasted until a greater age in segregated female mice than in their littermates kept in groups of 8 each. Bullough (1952) showed that "overcrowding" mice (16 to a cage) for 3 weeks resulted in a 30% increase in the cross-sectional area of the adrenal cortex and an 80% increase in medullary area. These changes were accompanied by a 60% reduction in epidermal mitoses, which was attributed to an increased secretion of adrenocortical steroids. Finally, Chitty (1955) showed that liver glycogen was appreciably lower in voles maintained in the laboratory in groups than in those maintained under segregated conditions. 2. Adrenocortical and Reproductive Responses to Population Density The preceding experiments indicate that sociopsychologic factors in- volved in social interactions between mammals can elicit physiologic adaptive responses with increased pituitary-adrenocortical and decreased reproductive function in voles, house mice, both wild and albino, Norway rats, rhesus monkeys, and humans. However, with the exception of the experiments of Crew and Mirskaia (1931) and Retzlaff (1938) there was no indication that these functions were altered in relation to population density. Although an inverse relation between population size and reproduc- tive performance was shown in the experiments of Crew and Mirskaia (1931) and Retzlaff (1938), these authors did not investigate adrenocorti- cal function. If social competition, as a stimulus to increased pituitary- adrenocortical and decreased reproductive activity, is responsible for regu- lating the growth and decline of mammalian populations, then there must be a relationship between population density and the magnitude of the endocrine responses. The existence of such a relationship has been demon- strated in a variety of experiments. If male mice which have been segregated since weaning are placed to- gether in groups of 1, 4, 8, 16, or 32 per cage for a week, there is a hyper- trophy of the adrenal glands and atrophy of the gonads and sex accessories which progresses more or less linearly as the logarithm of the population increases (Christian, 1959b) . There is a decline in thymus weight from that of the isolated controls, but the decrease is not related to the population size. The increase in adrenal weight was found to result primarily from 270 /• J- Christian cellular hyperplasia and hypertrophy of the zona f asciculata, although the glands were not critically examined for medullary hypertrophy. The decline in the weights of the testes was a reflection of the generalized reduction in body weight in one series of experiments (Christian, 1955a), but in another series the testes declined in relative testicular weight as well as in absolute weight with increasing population size (Christian, 1955b). Body weight was significantly less in populations of 4, 8, and 16. These experiments were repeated using wild house mice raised in the laboratory in populations of 1, 3, 4, 6, 8, 9, and 17 with similar though more pronounced results (Christian, 1955b). The thymus weight of these mice decreased markedly as population size increased. The adrenocortical response was also much more pronounced in these mice than in the albino mice, although the mean weights of the adrenals of segregated albino and brown male mice were identical. The increase in adrenal weight of albino mice reached a maximum of 8% above the control levels in populations of 16, whereas that of the wild stock attained a maximum increase of 21% above the control levels in populations of 9. In populations of 32 albino mice and 17 wild mice the mean adrenal weight was less than in the next smaller population size in each case. This was found to be due to a loss of lipid and a marked decrease in the size of cells in the zona fasciculata al- though the degree of hyperplasia was greater than in the adrenals of mice from the preceding population size (Christian, 1959b). The wild mice are much more alert, reactive, and aggressive than albino mice, and the differences in adrenal reactivity probably reflect such behavioral differences. The decline in the weights of the accessory reproductive organs, seminal vesicles, and preputial glands indicated a diminished secretion of androgens from the testes with increasing population size, based on the assumption that these organs accurately reflect androgen levels (Burrows, 1949; Ren- nels ct al, 1953) . This conclusion is strengthened by the fact that relative testicular weight also declined in one group of experiments (Christian, 1955b) and absolute weight declined in all experiments with increased population size. Since all indications point to a decline in the secretion of androgens, the decline in thymus weight must therefore represent involu- tion by increased amounts of circulating corticoids. The progressive hypertrophy of the adrenals and atrophy of the thymus and reproductive organs do not reflect a diminished space per mouse per se, as the results were essentially identical where populations of 1, 4, 6, 8, and 17 each of male wild mice were placed in cages with 42 times the area of the cages used in the preceding experiments (Christian, 1959b). The similarity of the results from these two series of experiments with vastly different amounts of area per mouse also suggests that the amount of exercise or activity was not a factor in the observed endocrine responses. 2. Endocrines and Populations 271 It has been established that close confinement with adequate feeding can result in adrenocortical atrophy and lymphoid hypertrophy in a variety of species of mammals (Christian and Ratcliffe, 1952), but these limits of confinement evidently were not approached in the above experiments, as indicated by the adrenal weights in the large and small cages. These results apply to male mice. When female mice are grouped, there is evidence of increased adrenocortical activity, increased corticoids and androgens being secreted (Christian, 1960). The degree of hypertrophy is small, however being nowhere nearly the amount seen in grouped male mice or even in females from populations of mixed sex. The inference is that the cortical hypertrophy seen in females from populations of mixed sex must to a large degree reflect a situation created primarily by the males. 3. Food and Social Competition; Splenic Hypertrophy In all the experiments with mice so far discussed, food and water were provided ad libitum. Food was scattered over the cage and water was available from several sources in order to avoid competition for food which might result in inanition in the subordinate animals and might constitute stimuli to the endocrine adaptive responses. These precautions were taken even though observation had indicated that feeding and drinking were more or less random and on an individual basis, and that there was no observable competition for these items. Also Uhrich (1938) and Strecker and Emlen (1953) had indicated that a limited supply of food did not in- crease competition among house mice. Nevertheless, the question whether or not the location and amount of food was a major factor in eliciting the observed changes in grouped mice in the pituitary-adrenal and pituitary- gonadal systems was answered by specifically designed experiments. In one series of experiments, male mice, some in groups of four each and some segregated, were provided food either ad libitum or limited to 4.0 gm. per mouse per day for a 7-day experimental period. This amount of food re- stricted weight gain but did not produce weight loss. The food given the grouped animals, whether limited or ad libitum, was scattered for half of the populations and supplied from a feeder for the other half. Therefore food was given the mice in one of the four following ways: scattered and limited in amounts, from a feeder and limited, scattered and ad libitum, or from a feeder ad libitum. The experiment was repeated using groups of five each and a food limitation of 3.5 gm. per mouse per day, an amount which produced an appreciable weight loss in all the mice during the week of the experiment. This amount of food per mouse per day can therefore be said to produce inanition. It was found that neither the location of food, whether scattered or from a feeder, nor the amount of food had any effect 272 J. J. Christian on adrenal weight in the segregated or grouped mice. (Irouping produced significant adrenal and splenic hypertrophy along with atrophy of the thymus and reproductive organs, and these changes were not altered by the source or amount of food. The splenic hypertrophy produced in the albino house mice in these experiments by grouping paralleled the splenic hypertrophy in voles following social "stress" (Clarke, 1953; Chitty et at., 1956). However, restricting the amount of food resulted in an atrophy of the reproductive organs, thymus, and spleen which was related to the degree of food restriction. The source of food was without effect on the adrenals, thymus, spleen, or reproductive organs. Therefore the source or amount of food did not increase the level of social competition above that already present as a result of the establishment of a social order. The amount of food provided had no effect on the adrenal glands, therefore it was concluded from these and the experiments of others (Mulinos and Pomerantz, 1941; D'Angelo ct al., 1948; Baker, 1952) that inanition does not constitute a stimulus to the pituitary-adrenocortical system of house mice and rats. On the other hand, Frank's (1953) experiments with confined popula- tions of meadow voles (Microtus arvalis) suggest that a deficient supply of food may increase social competition in this species, as a marked increase in fighting occurred following the development of a food shortage. Whether or not a food shortage will increase competition very likely depends on the time relationships of the feeding behavior of the species. One would not expect to find increased competition among animals which feed randomly with respect to time, otherwise one would have to attribute to these animals the ability to predict, ahead of time, the development of a shortage, as there would be no appreciable increase in competition for food at any given moment. This consideration also implies that dominant and subordinate animals would lose weight equally in the presence of a deficient food supply. Such was actually the case in the experiments with house mice (Christian, 1959c) . On the other hand, an increase in competition would be expected to follow the development of a food shortage among mammals which habi- tually feed during the same period of time every day. In this situation one would not expect the dominant animals to lose weight to the same degree as the subordinate animals, if at all. Frank's (1953) results coincide with this latter situation. If these conjectures are correct, it is apparent that the temporal feeding relationship and behavior of any species will assume para- mount importance with respect to the production of competition and the physiologic responses to it, and should therefore be investigated critically for a variety of mammals. The experiments with house mice should be re- peated with voles and other species and any increases in competition deter- mined by observation and the accompanying adrenocortical responses. 2. Endocrines and Populations 273 Although inanition and starvation may not be stimuli to increased pituitary-adrenocortical activity in mice and rats, they may be in guinea pigs (D'Angelo et al., 1948) and white-footed mice {Pero7nyscus leucopus) (Sealander, 1950). However, a limited amount of food does depress repro- ductive activity in house mice as well as in other species which have been investigated (Lutwak-Mann, 1958), possibly as a resvilt of a protein de- ficiency, as it has been shown that a dietary deficiency of protein diminishes the secretion of gonadotropins (Srebnik et al., 1958; Lutwak-Mann, 1958). The striking declines in the weights of the preputial glands, and especially of the seminal vesicles, brought about by a limited amount of food (Chris- tian, 1959c) indicate that the secretion of androgens by the testes was markedly depressed. Whatever the mechanism by which a food deficiency depresses the secretion of gonadotropins, it was not by eliciting a generalized adaptive response involving the pituitary-adrenocortical system. These results lead to several conclusions, at least as far as mice are concerned. One is that when food is supplied ad libitum, competition for food is not a factor in eliciting pituitary-adrenocortical responses in relation to popula- tion. A second is that inanition and starvation per se are not stimuli to increased pituitary adrenocortical activity in mice or rats. The third is that food restriction depresses reproduction by dimmishing the secretion of gonadotropins without eliciting a more widespread response, and there- fore a limited supply of food can limit population growth specifically by depressing reproduction without operating through the pituitary-adreno- cortical system. However, we have seen that there is some indication that these relationships may not be universally true. Perhaps food supplies and social competition can act independently to limit population growth. Food conceivably may not be important to natural populations as long as sub- ordmate animals are free to move elsewhere. Calhoun (1949, 1950) has indicated that social competition is a more important factor than food supply per se for Norway rats. One fact is abundantly clear as a result of these experiments, and that is that sociopsychologic factors stimulate in- creased pituitary-adrenocortical function and depress reproductive func- tion in proportion to population density ; this reaction system is therefore active at all levels of population in the control of population growth, whereas a limitation in the food supply will exert its effects on reproduction only when it results in inanition in the members of a population. These considerations are of obvious importance to the investigator interested in the control and regulation of mammalian populations. The production of splenic hypertrophy in highly inbred albino mice by increased population density is especially interesting in view of Chitty's (1957) conclusion that the splenic hypertrophy in voles {Microtus agrestis and M . orcadensis) was due to inherited genetic factors. This conclusion 274 J. J. Christian was based on the fact that splenic hypertrophy, which had been observed previously only in natural populations of high density, had made its ap- pearance recently in laboratory stocks of these voles. The only factor which seemed to account for this appearance was the introduction into the labora- tory breeding population of voles from natural populations exhibiting splenic enlargement. The fact that a similar hypertrophj' was observed in response to increased population density in a highly inbred strain of mice, maintained under constant conditions for a good many years with no expo- sure to natiu-al conditions, makes a genetic explanation of the sort postu- lated by D. Chitty unlikely in such an inbred strain of presumptively gene- tically stable mice. Similarly, as was pointed out earlier, a comparable hypertrophy of the spleen was observed in a few inbred rats subjected to alarming stimuli. The hypertrophy, when examined critically, has been found to be due to increased hematopoiesis (Dawson, 1956), possibly in response to the increased stimulation of erythropoiesis by hormonal factors. It is also well known that splenic erythropoiesis can be stimulated by any stimulus that produces anemia. Therefore, conclusions regarding the causes of splenic hypertrophy, due to increased erythropoiesis, must be inter- preted with caution; although it does not seem likely that it is genetic in origin, at least in inbred albino mice with splenic hypertrophy following increased population density. 4. Reproductive Fuxctiox in Female Mice: Lactation, Reproduc- tion Female mammals have frequently been observed to respond to adverse stimuli with a reduction of reproductive function. When rats are suddenly moved from a temperature to which they have become accustomed to a different temperature, either higher or lower, there is retardation of growth and prolongation of the estrous cycle (Bohanan, 1939). Selye (1939) has listed a variety of agents which will inhibit o^'arian function and estrus. Reproduction is also depressed in female mice by increased population density. We have noted that Crew and Mirskaia (1931) and Retzlaff (1938) found that reproductive performance of female albino mice declined with increasing population density. In another series of experiments no young were produced and no females became visibly pregnant when mice were crowded 20 males and 20 females to a cage for 6 weeks (Christian and Le- Munyan, 1958) . It is not known whether there was a marked suppression of ovarian function with diminished ovulation, a failure of the ova to im- plant, or intra-uterine loss early in pregnancy, but more than likely all these factors were involved. When the population size was reduced to 10 males and 10 females, all the females became pregnant, but the number of 2. Endocrines and Populations 275 implanted ova was reduced significantly and only 7 of the 10 females delivered young. The remainder lost their progeny in utero during the early stages of pregnancy. The onset of pregnancy also was considerably delayed in these animals. Therefore there was decreased fertility, decreased im- plantation, and a marked increase in intra-uterine mortality. These results indicate that female mice respond to increased population density with a depression of reproductive function at all stages of the processes. These results correspond to those seen in males as indicated by the weights of their reproductive organs. Reproductive suppression was also observed when female mice were grouped without males (Andervont, 1944; Whitten, 1959; Christian, 1960). Chitty (1952) noticed that young voles from natural populations of high density were reduced in size and were unusually susceptible to increased mortality. He hypothesized that the young were adversely affected in utero by the physiologic derangements in the mothers which resulted from high population densities (Chitty, 1952, 1954). Later it was shown in a limited series of experiments that social "stress" diminished lactation in voles, as measured by the weights of progeny nursed by the mothers subjected to social pressures which had previously been shown to result in increased pituitary-adrenocortical activity (Chitty, 1955). These experiments were repeated on a larger scale using laboratory white mice (Christian and Le- Munyan, 1958) . It was found that progeny nursed by previously crowded mothers weighed appreciably less at weaning than those nursed by mothers which had always been segregated. The effect on the progeny was greater in the larger litter sizes, suggesting a quantitative rather than a qualitative deficiency in the supply of milk. When these young which had been nursed by crowded mothers were themselves bred, the progeny which they in turn nursed were significantly lighter at weaning than their controls. Again the defect was greatest in the larger litters, but the difference was not manifest until a larger litter size had been reached than in the preceding generation. These differences in the second filial generation cannot be attributed to grouping. Crowding depresses all the other reproductive functions, therefore it is not surprising that lactation is also suppressed, as it is to a large degree under the control of pituitary gonadotropins and sex steroids in addition to oxytocin, thyroxine, and growth hormone (Folley, 1956; Grosvenor and Turner, 1959a, b, c,). These results are consistent with others which show that lactation can be inhibited by a variety of stimuli which stimulate in- creased pituitary-adrenocortical activity and diminish increased reproduc- tion and growth (Selye, 1954) ; in fact, lactation can be limited by a defi- ciency of any one of a variety of hormones necessary for its fulfillment (Grosvenor and Turner, 1959a, b, c). Since the young mice in litters of small size were unaffected in the above experiments, it is unlikely that any 276 /. /. Christian substance, such as adrenal hormones, contained in the milk were responsible for the decrease in weights of the progeny. The mechanism by which these effects were carried over into the second generation of progeny is not known. Presumably the second generation of young may reflect the inanition suf- fered by the first generation of progeny as a result of deficient lactation. However, the fact that androgens can produce subsequent permanent sterility when injected into mice less than 10 days old suggests the possibil- ity that increased amounts of adrenal androgens may reach the nursing young via the milk and exert similar partial effects if some escape metabo- lism in the liver. The weights of the young at birth were unaffected by the earlier crowding of their mothers. Although the precise mechanisms are not understood, these results support and extend D. Chitty's results with voles and help in providing an explanation for the prolonged effects of high density on surviving young observed in natural populations, such as Chitty's (1952, 1954) observations on young voles from natural popula- tions. 5. Growth The effects of increased population density on growth have not been studied to the same degree as its effects on other aspects of endocrine physiology, although suppression of the secretion of pituitary growth hormone presumably is a part of the response to stimuli which also result in the increased secretion of ACTH (Selye, 1950) . However, there are a few experiments which clearlj^ indicate that the growth of house mice is de- pressed in response to increased population density (Vetulani, 1931; Christian, 1955b) . It has been shown also that there is suppression of growth in all but the dominant and second-ranking mice in a group of six (Christian, 1961). The degree of inhibition was related to rank. 6. Inflammation, Resistance to Infection, and Population Den- sity In earlier sections of this account the inhibition of the inflammatory re- response, granulation, and antibody formation, and therefore resistance to disease, by adrenal carbohydrate-active corticoids was discussed. Most of the experimental evidence cited was based on the results of injecting corti- cal hormones. A few examples of decreased resistance to infectious agents brought about by stimuli, such as cold, which stimulated increased adreno- cortical secretion were given. However, even though these experiments indicated that such effects might occm- under natural circumstances, they did not establish this possibility, and especially they did not show that increased population density could stimulate a sufficient increase in the 2. Endocrines and Populations 277 secretion of adrenal carbohydrate-active corticoids to inhibit inflammation, granulation, and antibody formation sufficiently to decrease resistance to disease, although Retzlaff (1938) had indicated that there was decreased resistance to infection in the subordinate mice in his population studies. Experiments have been conducted which do establish these points to a limited degree, but more experiments with more species are needed. An efficient method of inducing an inflammatory response and the forma- tion of granulation tissue in rats or mice is to implant subcutaneously cotton pellets moistened with turpentine (Meier et at., 1950; Christian and Wil- liamson, 1958). Later these pellets and the surrounding tissue can be re- moved and weighed. In this fashion the degree of the inflammatory response and formation of granulation tissue can be assayed under a variety of conditions. This technique has been used to show that ACTH and the adrenal carbohydrate-active corticoids suppress these responses (Meier ct al., 1950) . By this procedure it was found that when mice w^ere placed in groups of 5 each there was approximately a 20% reduction in the amount of granulation tissue formed in 1 week compared to the amount formed by the segregated control mice (Christian and Williamson, 1958). These experiments clearly indicated that increased population densit}^ is a suffi- cient stimulus to the pituitary-adrenocortical system to decrease signifi- cantly inflammation and granulation. Davis and Read (1958) conducted a series of related experiments in which they demonstrated that placing wild-stock house mice in groups markedly increased the susceptibility of the mice to invasion by the larvae of TrichincUa spiralis. Each mouse was infected parenterally with approxi- mately 125 embryonated Trichinella larvae. Each mouse was maintained in a separate cage, but from day 3 through 11 after infection 11 of the mice were placed in two groups, one of 5 and the other of 6 mice, for 3 hours a day, while 11 others were left segregated. The mice were sacrificed the 15th day after infection, the gastrointestinal tracts were digested, and the larval worms were recovered. Only 3 of the segregated mice were infected with an average of 9 worms apiece, whereas all the grouped mice were infected with an average of 32 worms each, a 250% increase. The experiment was re- peated with 6 segregated and 5 grouped mice, but they were not sacrificed until the 30th day post infection, and the encysted larvae were recovered. All the mice, segregated and grouped, were infected, but the grouped mice had 48% more encysted larvae than their segregated controls. In both experiments the differences in the number of worms between segregated and grouped mice were highly significant and in both experiments the mean adrenal weight was greater in the grouped than in the segregated mice, 8% iP < 0.20) in the first experiment and 20% (P < 0.01) in the second experiment. 278 /. /, Christian In earlier experiments it had been shown that either cortisone or ACTH increased the invasiveness of Trichinella larvae by suppressing the defen- sive inflammatory response of the host's intestinal wall and possibly by prolonging the sojourn of the adult females in the gut by suppressmg im- mune responses to the worms (Stoner and Godwin, 1953). Thus, these hormones decreased the resistance of mice to invasion by the larvae of Trichinella spiralis by inhibiting inflammation and possibly antibody formation. Grouping evidently stimulated a sufficient increase in the secre- tion of adrenal corticoids to produce similar effects. This conclusion is sup- ported by the demonstration that grouping was sufficient stimulus to pituitary-adrenocortical activity to diminish granuloma formation appreci- ably. These experiments with trichinosis in house mice have been repeated with albino mice with similar results, confirming the original results and demonstrating that albino and wild-strain house mice react similarly (Davis and Read, unpublished) .- The effects of crowding on trichinosis in mice is presumably primarily due to the effects of increased adrenocortical secretion on the inflammatory response to the worms. Therefore a similar series of experiments were per- formed which were more specificaUy designed to demonstrate the effects of grouping on antibody formation (Davis and Prudovsky, 1959). In this case mice were injected with tetanus toxoid and challenged 10 days later with 13 mouse MLD of tetanus toxin. The dosage of toxin was selected to cause death in 50% of segregated mice. Mice were placed in groups either 5 or 3 days prior to giving the toxoid and left in groups until 5 days after the toxoid. Control mice were left segregated in individual cages throughout the experimental period but otherwise were treated identically to the experi- mental animals. Grouping appreciably decreased resistance and increased mortality of mice to the challenge dose over the control levels. This effect was less marked when the mice were grouped 3 days before administering the toxoid. The effects of grouping resembled the effects of injected corti- sone at the appropriate times and in appropriate doses. These results indi- ^ A report was published recently which implied that cortisone or ACTH are without effect on the course of trichinosis in mice, but which showed that cortisone markedl}' increased mortality (Lord, 1958). These experiments require some critical comment. The procedure used to infect the mice was similar to that used by Davis and Read (1958), but injections of cortisone and ACTH were not begun until 6 days after infection. One would not anticipate that these hormones would affect the course of trichinosis at that late date, as invasion by the larval worms, the inflammatorj' response to them in the intestinal wall, and immune responses to them are fairly well accomplished facts by that time. Therefore one would not anticipate an alteration in the resistance to invasion by the worms. The doses of cortisone used in these experiments were extremely high pharmacologic doses: 76 mg. in 39 days, beginning with 3 mg. a day per mouse. It is not surprising that cortisone increased mortality. 2. Endocrines and Populations 279 cate that the adrenocortical response to grouping is sufficient to depress antibody formation as well as inflammation. From these results one can easily sec that behavioral factors associated with increases in population density, or grouping, can sufficiently increase adrenocortical activity to profoundly affect host resistance to infectious disease and parasites. The effects of hormones on miu-me tuberculosis are somewhat complex. Cortisone enhances tuberculosis infections m mice, especially by converthig a smoldering chronic infection into a fulminating acute process (Hart and Rees, 1950) . However, ACTH was without effect on the early development of tuberculosis in mice (LeMaistre et al., 1953). From these experiments it would appear that an increased secretion of endogenous adrenal corticoids was ineffective in enhancing tuberculosis in mice whereas injected carbohy- drate-active corticoids markedly enhanced the infection. Therefore, it is especially interesting that Tobach and Block (1956) were able to show that crowding significantly altered the courses of acute and chronic tubercu- losis m mice. Crowding after mfection decreased the survival time of mice of both sexes suffering from an acute tuberculous infection. Crowding after infection had essentially no effect on the course of chronic tuberculosis in female mice, whereas it enhanced the chronic disease in male mice. These experiments also indicate that crowding prior to infection may enhance host resistance. These experiments, although quite limited in number, all confirm the fact that crowding (increased population density) can reduce host resist- ance to disease. The evidence from experiments with increased popula- tion density is completely in accord with the results of experiments with injected corticoids. These results, considered in the light of the mass of this evidence on the effects of corticoids and ACTH on experimental infections, can only mean that increased population density sufficiently stimulates the pituitary-adrenocortical system to lower resistance to disease by inhibition of inflammation, granulation, and probably antibody forma- tion by endogenous corticoids. 7. Production of Mortality Directly In the preceding section the role of behavioral factors and increases in population density in decreasing resistance to disease was discussed. It therefore follows that grouping can increase mortality by this means and the more subordinate animals will be the ones most often affected. However, grouping is often followed in a very short tune by sudden death preceded by alternate prostration and convulsions of many of the animals (Christian, 1955b), and the greater the number which are placed together, the greater the number which succumb in this fashion. (J. J. Christian, unpublished). 280 J. J. Christian although there is considerable variation from population to population in the numbers which die in populations of the same size. The more reactive and aggressive wild-stock house mice are much more prone to succumb in this fashion than the usual albino mouse in the laboratory (Christian, 1955b). The proximate cause of sudden death in these animals has not been investigated, although its onset, behavior, and general symptomatology arc highly suggestive of hypoglycemic shock and closely resembles the deaths from "shock disease" observed in natural populations at peak densities (Christian, 1950b). Frank (1953) observed similar deaths in voles {Micro- tus arvalis) after placing them in groups, as well as in natural populations, and was able to demonstrate that glucose could prevent the fatal termina- tion of the syndrome, and also showed that the symptomatology of insulin hypoglycemia was identical to that observed in voles dying naturally following "crowding." Furthermore, he showed that the voles which were on the verge of dying had markedly decreased levels of blood sugar and liver glycogen. These results make it appear probable that the convulsions and death which follow shortly on the social strife produced by grouping mice are due to hypoglycemic shock. There is reason to suggest that a massive discharge of the adrenal medulla, with its subsequent exhaustion may lead to a failure to further mobilize glucose and the animals die in a hypoglycemic episode. However, this hypothesis requires further testing. In any event, social strife and the physiologic responses to it may result in mortality directly as well as by affecting host resistance. 8. Summary of Results from Populations of Limited Size Experiments with populations of fixed size have demonstrated that socio- psychologic interactions can and do stimulate increased pituitary-adreno- cortical and decreased reproductive activity and growth in mice, voles, and Norway rats. Increased adrenocortical activity is related to social domi- nance-siibordinance relationships, the more subordinate animals exhibiting a greater response than the dominant animals. These responses apparentl}' are unrelated to fighting per se. Fighting is evidently a sign of social interac- tion, just as is the endocrine response, and not a causative factor. There is a progressive increase in the pituitary-adrenocortical response and de- crease in reproductive function in male and female mice with increasing population size. All phases of reproductive activity are depressed, including fertility, implantation of blastulae, intra-uterine survival, estrus, lactation (with persistent effects for at least two generations) , and the size and activity of the male gonads and sex accessories. Inhibition of reproductive fimction apparently stems from a depressed secretion of pituitary gonado- tropins. Growth is also inhibited by increased population density. 2. Endocrines and Populations 281 In addition to these primary effects of physiologic adaptation to the social pressures associated with increased population density, there is a decrease in resistance to parasitism and infection. It was shown that in- creased density produced an inhibition of inflammation, granulation, and probably antibody formation. A decrease in host resistance to trichinosis and tuberculosis was observed which apparently was due to these factors. It was also shown that food was not a factor in these effects, either in- directly by increasing social competition or directly by inanition in the subordinate animals. A deficiency of food is not a stimulus to increased adrenocortical activity in mice, or rats, although it may be in other species. A food deficiency, however, does result in a marked suppression of reproduc- tive function, probably by decreasing the production of pituitary gonado- tropins. B. Freely Growing Populations 1. Introduction Experiments with populations of limited size, although indicative, do not establish that these same responses occur in freely growing populations. In the first place, experiments with limited populations were conducted for limited periods of time, usually too brief to permit adaptation to the situa- tion. Furthermore, in every case the experimental approach involved sud- denly placing strange animals together under rather artificial circum- stances. Therefore, these experiments provided no evidence that mammals which have been more or less in contact with each other from birth would respond similarly. House mice {Mus musculus) and voles {Microtus penn- sylvanicus, Microtus agrestis) from free growing populations show the same physiologic responses to increased population density as do mice from populations of fixed size but to an even greater degree. 2. Population Density and Adrenocortical Function Increased pituitary-adrenocortical activity has been related to increased population density in a number of experiments with freely growing popula- tions of house mice and voles (Christian, 1956: Louch, 1956; Christian, 1959a, b). A number of experimenters have shown that the growth of freely growing confined populations is self-limited in spite of the fact that food, water, nesting material, and nesting space were provided ad libitum and well scattered (Strecker and Emlen, 1953; Clarke, 1955; Southwick, 1955a; Christian, 1956; Louch, 1956; Crowcroft and Rowe, 1957; Christian, 1959b) . Competition for food or a lack of availability of food by particular individuals was not a factor (Christian, 1956; Crowcroft and Rowe, 1957). 282 /. /. Christian The growth form of these populations was approxunately sigmoid, indi- cating that an intrinsic damping factor was operating to regulate and limit the growth of populations throughout their histories. These populations were started by introducing a small number of animals of both sexes into confined quarters and allowing the population to grow of its own accord. The populations were either sacrificed, at maxunal and submaximal levels, to obtain organ weights and histologic material, or blood samples were taken for eosinophil counts to assess functional changes, especially of the adrenal cortex. The zonae fasciculatae of the adrenal cortices were hyperplastic and hypertrophic in house mice of both sexes from populations of maximum (asymptotic) size. The number and size of the cells of the fasciculata were increased. Adrenal weight reflected the fascicular hypertrophy by increases of 25% in the males and 14% in the females. The adrenal cortical hyper- trophy was approximately half as great in mice from populations of approxi- mately one half the maximiun size. The presence in mice of an adrenocortical X-zone which is involuted by androgens has been described. This zone complicates the interpretation of adrenal weight from immature or puberal male or nulliparous female house mice unless histologic studies accompany the data on weights. In the case of the freely growing populations of house mice there was a pronounced hump in the adrenal weights in relation to body weights for mice from the experimental populations in the 13-19.0-gm. weight range, even though the fascicular hypertrophy was proportionately constant for all weights. The curve of adrenal weight on body weight for the segregated control mice was more or less regular with no pronounced irregularities, although there is a tendency for the slope to decrease with increasing body size. This appar- ently excessive adrenal hypertrophy in 13-19-gm. mice from intermediate and high populations resulted from a failure of the X-zone to involute normally rather than from a true hyperplasia or hypertrophy. The width of the X-zone in segregated male house mice begins to decline in mice in the 10-12.9-gm. weight group, and involution is essentially complete by the time a body weight of 16 gm. is reached. The decline did not begin in the experimental animals until a weight of 16 gm. or more had been reached and was not complete until a weight of 19 gm. Therefore, along with a marked hyperplasia of the zona fasciculata, suggesting an increased secre- tion of corticoids with increased density, there was a delay in the onset of puberty, presumably with an insufficient production of androgens to in- volute the X-zone of male mice. A great variety of steroid hormones, in- cluding corticoids, have been tested for their ability to involute the X-zone in male house mice (McPhail and Read, 19-42b; Antopol, 1953; Allen, 1954; Christian, 1954) , but only those with pronounced androgenic activity (e.g., 2. Endocrines and Populations 283 testosterone) have been effective, although Delost (1954) has reported that cortisone involutes the X-zone in voles. This delay in androgen production presumably indicated an inhibited secretion of gonadotropins from the anterior pituitary, although there apparently were sufficient gonadotropins to maintain the X-zone, as luteinizing hormone presumably is responsible for maintaining this zone (Jones, 1949b, 1950, 1952). Thymic involution is effected by carbohydrate-active corticoids, estro- gens, and androgens, with variations in the mode of involution (cf . above) . Therefore thymic involution, as a measure of increased adrenocortical secretion, must be interpreted with caution if there is reason to suspect differences in the levels of circulating sex steroids. Such was the case in the experiments under discussion, but additional information makes it possible to state with reasonable certainty that the weights of the thymus reflect increased corticoid secretion. The thymuses of 13-19-gm. male mice from high populations weighed more than their segregated controls, whereas the mean thymus weight of 19-23-gram mice from the high populations was less than that of the segregated mice. The greater thymus weight coincides with the greater width of the adrenal X-zone in the experimental mice and probably, as in the case of the X-zone, represents inhibition of androgenic activity which is not overridden by the increased amounts of circulating corticoids. It has been shown that the natural adrenal secretory products of mice will produce thymic involution and lymphopenia (Bahn ct al, 1957; Wilson ct al, 1958) . However, depression of the thymus weight to below the control levels in the larger mice from high populations can only reflect increased adrenocortical activity. The mean thymus weights of mice from the intermediate populations were greater than those of the controls or experimental mice from high populations in the 16-19-gm. body weight range. Data from the X-zone indicate that the secretion of androgen (or at least its activity) was inhibited to the same degree in the intermediate and high populations, whereas adrenal weights and width of the zona fas- ciculata were less in the intermediate than in the high populations. There- fore the greater thymus weights in mice weighing 16-19 grams from the intermediate populations may have resulted from a less marked increase in adrenocortical activity than occurred in the high-density populations, whereas androgen secretion was depressed equally in populations of both sizes. These results might be interpreted to mean that at increased popula- tion densities the younger, and presumably subordinate, animals are the ones predominantly affected by increased density. Since these results are obtained by sacrificing an entire population at one time, such a conclusion would be valid if it were not for the fact that the evidence indicates that the increase in pituitary-adrenocortical activity involved all weight groups and therefore all ages. Nevertheless, as we shall see below, a few of the heaviest 284 /. /. Christian animals, probably including the dominant animals, were less affected by increased density than those in any other weight group. It was mentioned earlier than in response to stimuli which evoke in- creased adrenocortical activity there is often inhibition of growth resulting either from direct inhibition of growth by carbohydrate-active corticoids, by inhibition of the secretion of pituitary growth hormone, or both. Evi- dence has been presented indicating that there is inhibition of growth with increased population density. Therefore, one might question the comparison of organ weight data from mice from populations of high density with those from segregated mice, as mice from the high-density populations may be older than segregated controls for the same body weight. However, if it were possible to correct for age, the differences with respect to body weight between high-density populations and segregated controls would be even greater. Therefore, comparisons with respect to body weight will err on the conservative side. The zonae fasciculatae of female mice of all sizes from high populations were appreciably wider than their controls as a result of cellular hyper- plasia and hypertrophy, although the presumptive increase in adrenocorti- cal secretion was not indicated by the thymus weights. If anything, the thymuses of females from the experimental populations were heavier than those of the segregated controls, possibly a reflection of a diminished secre- tion of the sex steroids. On the other hand the preputial glands respond to stimulation by ACTH (Jacot and Selye, 1951; Hess et al, 1952, 1953; Rennels et al., 1953), and the preputials of female mice from high-density populations were heavier than those from their segregated controls. Therefore, it is possible that the increase in the weights of the preputial glands of these mice may have re- sulted from an increased secretion of ACTH. This problem will be discussed in more detail subsequently. The effect of increased population density on adrenocortical function of voles {Microtus pennsylv aniens) in freely growing confined populations has also been studied. The experimental procedure used for these populations was essentially the same as for the house mice except that eosinophil coimts were used to measure adrenocortical function in the three popula- tions of voles (Louch, 1956). The use of eosinophil counts has an obvious advantage over adrenal weight for assessing adrenocortical function in that the animals do not have to be sacrificed, especially when various factors contributing to variation in the counts are taken into consideration ( Louch et al., 1953) . In such long-term studies as this with repeated counts, there can be little doubt that the eosinophil counts reflect adrenocortical function rather than medullary. There was a significant negative correlation between 2. Endocrines and Populations 285 eosinophil counts and population density, indicating a progressive decline decline in the number of circulating eosinophils with increasing population density, but the correlation between eosinophil counts and population density was not significant in the third population. The latter population, however, never reached 30 animals in size. The published figures indicate a striking parallel between the rate of population growth and eosinophil counts for all three populations, and in all three there were significantly fewer circulating eosinophil when the populations of these voles were greater than 30 than when they were less than 30 (Louch, 1956). These results indicate that adrenocortical function increased progressively with increasing population density. The variability in Louch's data reflect to some extent the difficulties in obtaining precise eosinophil counts, even though he was fully aware of these problems and took every step possible to a\^oid the usual pitfalls (Louch et al, 1953; Louch, 1956). The problems involved in using eosinophil counts as indices of adrenocortical function have been dis- cussed fully elsewhere (Thorn et al, 1953; Louch et al, 1953; Rosemberg et al, 1954; Speirs, 1955; Visscher and Halberg, 1955; Louch, 1956; and earlier in this chapter) . Handling will cause an adrenal medullary and corti- cal discharge due to fear, excitement, and possibly rage in wild mammals and therefore can effect eosinophil counts (Southwick, 1959) . Conseciuently it is possible for variability to result from handling, as well as by individual and perhaps more importantly, by unknown factors, unless appropriate precautions are taken (Louch, 1958). However, in spite of these problems, eosinophil counts offer a promising means of investigating adrenocortical- population density relationships until simple, more direct tests become available. Probably the best procedure at the present time is to follow the population with eosinophil counts and to substantiate the changes with adrenal weights at the termination of the study. Louch's results provide evidence of increased adrenocortical function in voles with increased popu- lation density. Li a similar experiment, a marked increase in adrenal weight, as an index of cortical activity was found in both male and female voles (Microtus pennsijlvanicus) from a freely growing confined population which had reached its maximum size (Christian, 1959b) . The adrenals of mature male voles were increased 39.6%, and those of mature females 36.6% over their segregated controls. It was pointed out earlier that adrenal weight-body size relationships may vary with species and with sex; therefore, if animals covering a wide range of sizes are to be used, the correct relationship in these must be determined. It was found that in male voles over 115 mm long, adrenal weight did not vary with further increases in the size of the animal, therefore the absolute adrenal weights could be used for compara- 286 /. /. Christian tive purposes. However, in female voles adrenal weight increased with in- crease in body size; therefore for females it was necessary to use relative adrenal weights for purposes of comparison. 3. Reproduction a. Male. Reproductive function was depressed in proportion to increases in population size in both male and female house mice from populations of fixed size. The results of experiments with freely growing confined popula- tions of house mice and voles also show a progressive decrease in reproduc- tive function with increasing density. We have seen that there was a delay in the onset of puberty in male house mice from freely growing populations of high density, as demonstrated by the delayed involution of the adrenal X-zone and the development of the testes, seminal vesicles, and preputial glands. The size of the gonads and sex accessories was less than their con- trols from segregated mice of all but the heaviest body weight. Rapid de- velopment of the seminal vesicles and preputial glands did not begin until a body weight of 16 gm. was reached, which coincides exactly with the be- ginning of X-zone involution in animals. These results strengthen the con- clusion that androgen secretion was delayed. In the segregated controls, the sex accessories had begun rapid growth by the time the animals had reached a weight of 13 gm. These results were confirmed by histologic examination of the testes. The size of the testes primarily reflected the advancement of spermatogenesis and the development of the seminiferous tubules. Sperma- togenesis was inhibited to the same degree as the sex accessories (Christian, 1956) . Male mice from freely growing populations of intermediate size exhibited an inhibition of the reproductive organs which was approximately inter- mediate between that exhibited by the males from the high populations and the segregated controls (Christian, 1956). It is of additional interest that testes and sex accessories of male mice weighing 28 gm. or more, the heaviest weight group in the experimental populations, were about the same size as those of the isolated controls. Furthermore, there was no inhibition of spermatogenesis in these animals. In general, this weight group contained the dominant animals in the four high-density populations examined and was represented by a total of 21 animals. These mice represented the initially introduced males and those males from the first litter or two that had established their dominance early in the histories of the populations. These observations are confirmed by Crowcroft and Rowe (1957), who observed that the productive females in in confined populations of house mice were the introduced animals or those from their first few litters. Detailed observations relating the weights of 2. Endocrines and Populations 287 reproductive organs to specific animals were not made, but it is likely that these results parallel those from populations of limited size in which it was found that the weights of the reproductive organs were greatest in the socially dominant animals. We have indicated that the weights of the accessory reproductive organs appear to be the most sensitive indications of changes in population density as well as social pressures and differences in rank. This also appears to be the case in these experiments with freely growing populations. Reproductive function of male mice has not been examined in detail, usually not at all, but other investigators studying freely growing populations, although Strecker and Emlen (1953) did find all the males in a self-limited population with epididymal sperm 6 months after population growth had ceased. It might reasonably be asked why, during the 6 months or so that most of these populations lasted, there was not adaptation to the situation with a diminution of the effects of population density on the adaptive responses of the adrenals and reproductive organs. Brown (1953) and Southwick (1955b) have both pointed out that in a well-stabilized social hierarchy of mice there is a relatively low level of fighting, usually used as an indication of the amount of sociopsychologic pressure and interaction, but that when shifts or disruptions in the hierarchy occur, due to the maturation of new individuals or death of old ones, social pressures increase, as indicated by an increase in the amount of fighting. Southwick (1955b) has pointed out that these factors are constantly disrupting the social order in rapidly growing populations, therefore, as the population increases it is inevitable that social pressures increase apace. Comparable results have been observed in other freely growing populations, but there is not necessarily fighting (Christian, 1956, 1959a, b). Furthermore, female mice become particularly aggressive prior to parturition (Brown, 1953; Crowcroft, 1954), and so the total amount of aggressiveness contributed by females would tend to increase with the population. For these reasons it appears that the amount of social pressure in a population will increase with the size of population. It has been observed also that the self-limited maxunum size varies greatly from population to population (Southwick, 1955a, b; Christian, 1956) appar- ently as a function of the amount of social pressure within the population, the variation being contributed by individual differences, the stability of the social structure, and similar factors. For example, Southwick (1955b) has described the individual differences between males in the amount of territory they will fight over. Southwick ( 1955b) has discussed in consider- able detail some of the factors involved in the composition of social compe- tition between mice. One population has been observed in which the social order of the population was disrupted at about half the estimated maximum size by the death of an old, tyrannical male (Christian, 1956, and unpub- 288 /• /. Christian lished) . Severe fighting broke out in this population and the growth of the population ceased completely until social order was reestablished 6 weeks later. The cessation of growth resulted from a complete cessation of all aspects of reproductive activity. These considerations, plus the fact that the physiologic responses are equivalent in populations of maximum self- limited size irrespective of the number of mice (Christian, 1956), make it likely that the growth of populations of house mice, and possibly voles, is limited by the total amount of social pressure rather than by the number of animals. The reproductive competence of males has not been examined in detail for any species from freely growing populations other than house mice ; and no studies have adequately explored the problem. In most studies on popu- lation density the criteria of male fertility are position of the testes, gross size of the testes, visibility of the epididymal tubules, and occasionally the presence or absence of sperm in the epididymes (Strecker and Emlen, 1953; Brown, 1953 ; Southwick, 1955a; Crowcroft and Rowe, 1957) . These criteria are actually poor indicators of relative fertility and only suggest whether or not an animal is mature. Detailed morphologic studies provide more evidence of fertility (Christian, 1956), but they do not provdde conclusive evidence. No information on subtle changes in fertility is provided by any of these criteria. The ability of males to fertilize females with respect to population density has not, to my knowledge, been investigated. Many influences which depress reproductive activity cause striking degenerative changes in the germinal cells in the testes (Selye, 1947). The formation of giant cells from cells of the spermatogenic series is a common indicator of such changes (Selye, 1950; Steinberger and Dixon, 1959). Furthermore, influences which can produce severe degenerative changes or inhibit spermatogenesis completely can produce more subtle changes if the damaging stimulus is less severe (Steinberger and Dixon, 1959). It seems likely that the conspicuous changes that occur in the testes of house mice as a result of increasing population density [a delay in the onset of spermatogenesis, reduction in the number of mature spermatoza, and formation of giant cells (Christian, 1951, 1956)] can also be extended to include less obvious abnormalities of the sperm, such as decreased motility and viability. There also may be a decrease in the nmnber of sperm pro- duced, and therefore in the number of sperm in the ejaculate. All these factors presumably affect fertility (Chang and Pincus, 1951). To these must be added the likelihood of an altered medium for the sperm which would be suggested by the changes in the sex accessories associated with testicular changes, as indicated by the decline in their weights (Burrows, 1949; Lutwak-Mann et al., 1949; Leathem, 1950; Mann, 1954) . Atrophy of sex accessories carries the implication that their secretory products may be 2. Endocrines and Populations 280 abnormal, deficient, or decreased in amount, and that the composition of the ejaculate will in all probability not provide an optimal medium for sperm (Burrows, 1949; Lutwak-Mann et al., 1949; Cavazos and Melampy, 1954). Therefore it is possible that male fertility is depressed appreciably by increased population density, although the gross examination or rela- tively minor changes in weight would provide no indication of such a reduc- tion in male fertility. Male fertility is assessed in most studies on small mammals by (1) the position of the testes, (2) whether or not the epididy- mal tubules are clearly visible, or (3) possibly by epididymal smears to determine the presence or absence of spermatozoa (Southwick, 195oa; Louch, 1956; Strecker and Emlen, 1953; Crowcroft and Rowe, 1957). Degenerative changes can be detected in testicular smears (Christian, 1950a, 1951) , but with much less assurance than properly prepared, stained, and critically examined sections of the testes. Morphologic studies of the testes, if properly done, can be extremely revealing, but the weights of the testes and accessory organs, while providing a useful index of reproductive function in general, do not tell whether or not the male is actually fertile unless inhibition is severe. In the absence of good evidence to the contrary it is generally assumed that the males in a population are fertile — an as- sumption that may be misleading. Studies of male fertility in relation to population density are needed that make use of sperm counts, determina- tion of the motility and viability of the sperm, and possibly direct determi- nation of fertility by mating with proven females. Admittedly such a pro- gram would present problems, but they are by no means insurmountable. Furthermore, once the techniques are worked out for obtaining ejaculates from the males in populations of small mammals, it should be a valuable and useful procedure for routinely assessing male fertility and reproductive competence in freely growing populations of small mammals. But it is in- correct to assume that male fertility is not affected by increased population density, especially in view of the evidence indicating that the secretion of testicular androgens is extremely sensitive to changes in population density or to social rank. Southwick (1955a) observed a decrease in fertility in female mice from populations which were slowly declining from peak levels. He also noted, as have others (Southern, 1948; Calhoun, 1949), that in populations of high density or with poor social organization (Calhoun, 1949, 1950) that "copu- lation pressure" on females in estrus was high; that is, a number of males gathered around her and attempted to copulate although they were fre- quently pushed off by others, so that the mean copulation time per male was reduced. "Copulation pressure" was used as a possible explanation for the decline in fertility. This explanation overlooks several facts. The populations were progressively declining from peak levels and did so for six 290 J. J. Christian months, and so did pregnancy rates and fecundity rates (correspondence in the dechnes in these latter two was used as an argument against the possi- bility of increased intra-uterine mortality) . It is therefore unlikely that a steadily declining fertility can be explained by copulation pressure in a constantly decreasing number of animals. Male fertility was assessed by uncritical procedures and female fertility by performance. Assessing fer- tility by female performance of course does not provide a way to assess the possible role of depressed male fertility. It seems much more likely that both male and female fertility were depressed. Crowcroft and Rowe (1957) noted a decline in fertility in female house mice with increasing density as well as during the period of asymptotic stability in populations of house mice. These authors indicate the failure of population growth resulted en- tirely from inhibition of female reproductive function. Louch (1956) was unable to correlate diminished fertility with "copulatory pressure," al- though it was observed in his population of voles. We have seen that the females in extremely dense populations became pregnant but failed to bear litters and that recovery from the effects of chronically depressed fertility was extremely slow (Christian and LeMunyan, 1958). Increasing age may have been a factor in these freely growing populations, especially if fertility was already partially curtailed. This discussion is meant neither to be a criticism of the observations made by these investigators nor to provide the correct explanation for them. Rather, these examples have been used to indicate pitfalls in experi- mental procedures presently in general use to assess male fertility and the effects of various factors on fertility in populations of small mammals, and to call attention to reasonable and perhaps more probable explanations other than those usually provided. The literature contains many examples which could have been used. Finally, it should be noted that the popula- tions in Southwick's studies had reached peak densities and had been de- clining slowly for 6 months before the animals were examined, so it would be difficult to determine the effects of increasing density on fertility in mice of either sex. The results of those studies made during the period of increase of a population or at the time it reached maximum density are not com- parable to studies made so much later, and it is not correct to extrapolate from one to the other, as was done in several instances. The results of other experiments in which male fecundity was assessed during the period of population increase indicate that male fertility, in terms of the whole population, has a striking negative correlation with density (Christian, 1956, 1959a, b; Crowcroft and Rowe, 1957) . The secretion of gonadotropins is apparently depressed with increasing pituitary-adrenocortical activity in the greater proportion of subordinate animals associated with increases in density. Evidence has been presented which shows that increased adreno- 2. Endocrines and Populations 291 cortical activity in mice results in an increase in the secretion of weakly androgenic steroids, and that these can depress the secretion of gonado- tropms. h. Female. Reproductive competence of female mammals can be assessed grossly more easily than that of males diu-ing studies of growing popula- tions simply because the number of young produced can be counted. Some comments have been made about the relationships of female fertility and reproduction to population density in animals from freely growing popula- tions. Most of the pertinent evidence indicates that fertility and reproduc- tion in female mammals is depressed by increased density. Two kinds of information has been gathered on female productivity in relation to popula- tion density. In one case the number of young born at intervals throughout the history of the population has been determined, and in the other female fertility is assessed by external examination of the vagina, which is closed by a thin membrane during anestrus in many species, or by examination of the animals at autopsy. Information of both kinds is desirable, although neither is sufficient by itself. It has been shown in studies with house mice and voles in freely growing confined populations from which adequate data are available that the birth rate for mature or potentially mature females in the population declines steadily with increasing population size (Clarke, 1955; Christian, 1956, 1959b, 1961; Crowcroft, and Rowe, 1957). The decline in the number of young born per female appears to decline approximately linearly as the logio of the population increases (Christian, 1959b), The declines in productivity apparently resulted from suppression of all phases of reproductive functions. Crowcroft and Rowe (1957) showed there was complete suppression of estrus, as indicated by closure of the vaginal orifice, in an increasingly larger proportion of females as the size of a population increased. It was shown that closure of the vaginal orifice was a reliable index of fertility in female house mice in these experiments by the very high correlation between the condition of the vaginal orifice and the development of the reproductive organs. In these populations the majority of the young were produced by the introduced females initially or by females from the first few litters. These results correspond to those from populations of limited size in which it was indicated that the reproductive competence of female mice was related to their social status. Similar results were also observed in confined populations of Norway rats (Calhoun, 1949, 1950) . Reproductive function was completely suppressed in the majority of female born into these populations. These results are comparable to those from experiments with freely growing populations of house mice (Christian, 1956), thus indicating that reproductive function in female mice was depressed for all body-weight 292 J. J. Christian groups. In these experiments the weights of the preputial glands of mice from populations of high density were significantly greater than those from segregated controls. For their stimulation to full development and function, the preputial glands depend primarily on the more potent androgens (Bur- rows, 1949), but the weakly androgenic steroids (Huggins et al., 1955), ACTH (Jacot and Selye, 1951; Asling et al., 1951), and pituitary growth hormone (Huggins et al., 1955) all have a mild stimulatory action on the preputials. The evidence for the effects of estrogens on the preputials is conflicting. On the one hand, estrogens appear to have a mild stimulatory action (Burrows, 1949; Beyler and Szego, 1954) whereas other experiments indicate that they inhibit the preputials (Rennels et al., 1953). Since other evidence from the experiments with mouse populations indicates that the production of sex steroids by the gonads and growth hormone by the pitui- tary is inhibited at high densities, it seems probable that the increased size of the preputials in these intact females must have been due to increased ACTH and possibly increased adrenal C19 steroids. In any event the data on the preputials are strongly suggestive of increased pituitary-adrenocorti- cal function. Attention should be directed to the fact that the preputials were appreciably larger than those from segregated mice with full reproduc- tive competence. Therefore there is no reason whatsoever to implicate estro- gens in these effects ; so ACTH and adrenal androgens must be responsible for stimulating preputial development to well above the control levels. Presumably the levels of estrogens declined in these females as a result of a decreased secretion of pituitary gonadotropins in association with in- creased secretion of ACTH. These conclusions were supported by the fact that there was also (1) a marked increase in the proportion of females of adult size with infantile uteri and ovaries, and (2) a 20% decline m number of females with mature reproductive organs that were also preg- nant, (3) a 13% decrease in the mean number of viable embryos per pregnancy, and (4) a 58% increase in the number of resorbing embryos per pregnancy. Thus there was diminished fertility and increased losses between o\'ulation and implantation, and implantation and birth. Decreased fertility was shown in some animals by a total inhibition of reproduction and in others by a markedly diminished number of viable embryos per pregnancy. These results agree with those of Crowcroft and Rowe (1957). The same phenomena apparently occurred in populations of voles (Clarke, 1955; Louch, 1956; Christian, 1959b) . Birth rates declined steadily as the popula- tions increased for house mice and voles (Christian, 1959b, 1961). There- fore it seems that reproductive function is inhibited in female mice and voles in proportion to population density, either in terms of the proportion of reproductively competent adult females in a population or of the degree of reprodu(•ti^'e function in individuals. Stated another way, reproductive 2. Endocrines and Populations 293 function in female mice and voles is reciprocally related to population density. The degree of inhibition apparently may vary from none to com- plete in the females of a given population, within limits depending on social relationships of the particular individuals. We have already criticized the concept of "copulation pressure" which has been used to explain the decline in female fertility seen in populations of high density. As an explanation it is inadequate because it does not coincide with the facts, even in those cases in which it has been used as an explanation (Southwick, 1955b). Furthermore, no correlation could be shown between "copulation pressure" and fertility in other studies (Louch, 1956) . In the light of those studies in which female reproductive function was more precisely assessed, it appears that reproductive function was at least partially inhibited in those populations in which "copulation pressure" was used to explain the decline in fertility, and that the means used to assay female fertility were not sufficiently sensitive. "Copulation pressure" con- ceivably could have an effect on female reproductive performance, but until the problem is reexamined more critically it must remain an unaccept- able concept, especially in view of the preponderance of evidence indicating that reproductive function is inhibited, either individually or on a popula- tion-wide basis, as part of the adaptive responses to increased density. A broad view of this evidence suggests considerable variability from popula- tion to population in the degree of reproductive inhibition with respect to the numbers of females involved as well as to the magnitude of inhibition in particular individuals. These variations are evidently related to social factors, and this aspect of the problem needs examination in greater detail than heretofore. Prenatal mortality of the fetuses was an appreciable factor in reducing the number of births in dense populations, presumably largely owing to a suppression of gonadotropins, but also possibly to the effects of increased adrenal corticoids and androgens. There seems to be some kind of "dual response" to density in depressing female productivity. Judging from the results described in this and preceding sections, it appears that the least "dose-response" effect occurs when fertility is partially diminished, as by decreased numbers of ova and increased losses between ovulation and birth, without a total suppression on the ability to bear young. A greater effect apparently is total inhibition of estrus and reproduction in potentially mature animals. Delayed attainment of maturity probably reflects partial inhibition. The possible mechanisms involved in producing intra-uterine mortality have been discussed in an earlier section. c. Litter survival. A marked decline in litter survival with increasing population density was observed in all but a few experiments with freely growing populations of house mice or voles (Rtrecker and Emlen, 1953; 294 /• /• Christian Brown, 1953; Clarke, 1955; Southwick, 1955a, b; Christian, 1956; Louch, 1956). Litter survival apparently declines approximately linearly as the logarithms of the population increases (Christian, 1959b). However, litter mortality is not always a factor in diminishing the rate of population growth. Crowcroft and Rowe (1957) found very little mortality of young mice in their populations and furthermore were able to attribute all the observed mortality to interference on their own part in making routine censuses. The decline in productivity in their populations was due almost entirely to prenatal loss or complete inhibition of all reproductive activity. It has been suggested (cf. above) that diminished fertility probably was more of a factor than was realized in several other investigations; neverthe- less litter mortality has been an unportant factor in many populations. Decreased litter survival may be due to diminished lactation (Christian, 1956; Christian and LeMunyan, 1958) or to behavioral factors (Brown, 1953; Strecker and Emlen, 1953; Southwick, 1955b). Partial inhibition of lactation with increased density was described earlier. The results suggested that lactation, controlled by complex endo- crine mechanisms, was partially inhibited owing to inhibition of gonado- tropin secretion and a resultant diminished production of estrogens and progestins. Lactation therefore reflected population density in a similar fashion to other reproductive functions. It was also pointed out that the progeny nursed by mothers subjected to increased density were profoundly affected by the inhibition of lactation. Experiments with freely growing populations of house mice suggest that deficient lactation may be an im- portant factor in decreasing litter survival (Christian, 1956). These young were stunted and were weaned early. At autopsy their stomachs contained little or no milk. Calhoun (1949, 1950) suggested that the socially sub- ordinate rats in freely growing confined populations were incapable of raising then* young, even though they were protected from disturbance. He indicated that physiologic and psychologic disturbance in the sub- ordinate females affected the young through either poor fetal nutrition or a breakdown of maternal instincts. Dimmished lactation may have been an appreciable factor in reducing the survival of young in the above experiments, and diminished lactation is a logical consequence of a generalized inhibition of reproductive function presumably due to diminished gonadotropin secretion. Decreased litter survival was attributed entirely to social or behavioral factors in a number of experiments with freely growing populations of house mice or voles. Brown (1953), Southwick (1955b), and Louch (1956) related litter survival to the type of nest constructed and maintained. Brown and Louch each noted that litter survival was good so long as the female mice or voles were able to maintain covered or bowl types of nests, 2. Endocrines and Populations 295 but that this was frequently impossible because of destruction of the nests and interference with the attempts of the females to maintain or reconstruct them. Only 49 of the 72 attempts to build and maintain either of these two types of nest were successful in these populations (Brown, 1953). South- wick (1955b) noted a similar relationship between the type of nest and litter survival, but he also found that litter survival was good in bowl or covered nests regardless of the number or sex of the adults which were also present. Litter survival was zero with no nests. These and Brown's (1953) results imply that not all the females were prevented from maintaining proper nests and nourishing then* litters irrespective of the conditions and interference. These results are revealing, as they suggest strongly that more is involved in litter mortality in these experiments than simple interference or the type of nest maintained. Similar results were noted in other experi- ments (Christian, 1956) except that in this case even those with no nests sometimes survived. In these latter experiments it was also noted that if litter mortality occurred when the populations were less than one-half of maximum density, it occurred within the first four postnatal days and might be attributed to interference which resulted in too much movement of the litter by the mothers. Of additional importance is the fact that litter survival declined regularly with increasing density and that this began to occur well before interference could be significant. If the young survived the first 4 days at these lower densities, they almost always were success- fully weaned. However, at higher densities the increased litter mortality usually occurred after the young were 10 days old. Until this age survival equaled that seen at lower densities. These facts suggest that the defect was primarily nutritional, even though there still were some deaths of young less than 4 days old attributable to interference. The age of death of the young is not known for most of the reported experiments, so that this distinction was not possible. However, the fact that crowding and inter- ference was not a factor in litters with proper nests suggests that perhaps the behavioral changes which resulted in poor nest maintenance may be based on an underlying alteration in maternal behavior, possibly due to endocrine changes. Admittedly this is speculative, but the available evi- dence suggests some such explanation. The problem certainly must be investigated m greater detail. It is possible that the capacity to lactate properly and the abilitj^ to maintain proper nests are closely related by a common causal basis. However, until evidence for or against such a hy- pothesis is available, it must be assumed that postnatal litter mortality at high population densities may result from (1) inhibition of lactation, (2) interference by other animals, or (3) changes in maternal behavior, which apparently decreases with increasing population density. We are inclined to the view that interference of various sorts probably 296 /. ./. Christian plays a more or less constant, probably unimportant, role in causing litter mortality at all levels of population density, whereas inhibition of lactation and changes in maternal behavior are density dependent and probably reflect physiologic (endocrine) responses to changes in population density. Southwick (19o5b) noted that aggressiveness, as indicated by fights per mouse per unit of time, was reciprocally related to litter survival at high densities, but that this relationship did not necessarily hold at lower densities. On the other hand, there was a correlation between fighting and density in only one of three populations of voles (Louch, 1956). The be- havioral changes observed in relation to litter survival may be outward manifestations or "symptoms" of more profound physiologic changes at higher population densities. A final consideration of importance is that fecundity and litter survival are sufficiently sensitive to changes in the population to be responsive to a variety of different circumstances affecting density. Litter survival was markedly increased in a population of house mice in which there was an appreciable mortality of adults (Christian, 19o9b). The growth form and eventual size of the population were comparable to those of populations without appreciable adult mortality. The loss of adults in this population was compensated for by increased litter survival. Similar relationships were observed in three populations of voles (Louch, 1956). There was a signifi- cant correlation between fertility and population density in one population of voles in which there was no correlation between density and adult mortality. In a second population there was a good correlation between density and adult mortality, but none between density and fertility. The third population was intermediate between these two. Therefore, there appears to be sufficient flexibility in the physiologic adaptive responses to compensate for losses of adults from populations of voles or mice. This compensation apparently can occur at any stage of the reproductive pro- cess from ovulation to weaning. d. Effects of food supply. It is often assumed without question that food shortage is responsible for limiting population growth. However, we have seen that the growth of a population may be entirely self-limited without a shortage of food. The role of a limited food supply in the regulation of population growths has been investigated (Strecker and Emlen, 1953; Strecker, 1954). Clarke (1955), Christian, (1955b, 1956, 1959b), South- wick (1955a, b), and Louch (1956) have emphasized the fact that in their experiments food was always abundant and usually scattered so that any animal could obtain food irrespective of other animals present. Further- more, experiments with populations of fixed size indicated that inanition was not a stimulus to increased adrenocortical activity in house mice, nor did it constitute a factor for increasing competition when it (food) was 2. Endocrines and Populations 297 limited either in source or amount (Christian, 1959c). These results are consistent with those from experiments with freely growing confined populations of house mice or voles in which competition for food in every case was rare or absent (Strecker and Emlen, 1953; Louch, 1956; South- wick, 1955a, b; Christian, 1956). Strecker and Emlen (1953) provided two confined populations with a limited amount of food but the growth of only one of these was limited by the limited food supply. Growth of this popula- tion was rapid and ceased abruptly when the limit set by the food supply was reached. Growth ceased because reproduction stopped abruptly with involution of the reproductive organs, especially of the females, all of which were reproductively quiescent at autopsy, although the animals otherwise appeared to be in excellent condition and usually excessively fat. Several points of interest emerge from these experiments. One is that population growth ceased very abruptly with a truncated growth curve, indicating that a limited food supply does not act as a damping factor, but exerts its effects at one point on the growth curve. Therefore, it is unlikely that a typically sigmoid growth curve would result from a food shortage. The second point of interest is that reproduction was so sharply limited by the limited food supply. These results agree with those from populations of fixed size and indicate that the food limitations completely inhibited re- production, probably by suppressing the secretion of gonadotropins, with- out producing increased activity of the pituitary-adrenocortical adaptive system. The last point is that the population immediately adjusted to the supply and the general condition of the mice was unaltered by the limitation in food. The inhibition of reproductive activity in all the females contrasts sharply with the results of other experiments conducted on self-limited freely growing populations of mice or voles supplied with an excess of food. In the latter populations there were always some reproductively active females, although the actual proportion in the population varied with each population. Data on adrenal activity were not collected in these experi- ments on the efTects of food limitation on freely growing populations. It is probable that there would have been density-dependent increases in adreno- cortical activity, but the effects of food limitation were independent of any density-dependent effects. In another series of experiments, the food supply was limited similarly, but egress from the population was allowed (Strecker, 1954) . In these populations there was a low constant rate of egress until the food limitation was reached and then a high rate of egress began and continued until the experiment was terminated three months later. The egress apparently involved all segments of the population except the youngest. Reproduction continued at a good rate in this population in sharp contrast to the confined population without egress. The implications of these experiments are clear: f1) food limitation can limit population 298 J- J- Christian growth by inhibiting reproduction, but the growth curve becomes sharply truncated; (2) if egress from a population is permitted, food limitation has no effect on reproduction; (3) feeding must be random and food cannot have been a factor increasing competition, otherwise all the mice would not have been affected equally. Extrapolating from these results to natural populations, it is evident that a limited supply of food will not affect repro- duction or otherwise affect the population so long as emigration is possible, but if emigration becomes impossible, owing to a complete saturation of the available habitat, reproduction will cease without any other apparent effect. Whether or not there is competition for food in species other than house mice must be determined, as increased competition would increase pituitary-adrenocortical activity with all its sequelae. There may be in- creased competition for food in voles (Frank, 1953), although it seems un- likely that in general there will be an increase in competition over that already present due to social factors (cf. above) . However, the usual result of emigration from a population is increased mortality: the animals which leave enter strange territories and very rapidly become mortality statistics (Errington, 1943, 1954b; Calhoun, 1948; Davis, 1953). Physiologic adap- tive mechanisms apparently are always operative in relation to population density and therefore would reflect the relative density whether or not the growth of a population was limited by food, and a distinction between food- limited and self-limited populations should be possible by comparing the reproductive activity of the populations and the general conditions of the individual animals. Adrenal weights and other parameters of increased pituitary-adrenocortical activity should also differentiate between the two unless a population was food-limited at a point close to its maximum self- limited size. These statements and conclusions are based on the results of experiments with house mice and seem fairly conclusive for this species, possibly even for voles, but it is difficult to believe that food is not a competitive factor for all species and for all populations. The results of experiments to date with populations of fixed size or freely growing indicate that food is not even a competitive factor within the existing social structure, as all anmials are apparently equally affected irrespective of their social rank (Strecker and Emlen, 1953; Christian and LeMunyan, 1958; Christian, 1959b). It should be remembered that if ever and when ever food becomes an object of competition, shortages then necessarily will act through the generalized physiologic adaptive responses and limit population growth in a density- dependent fashion just as does purely social competition. The net conclu- sion from these results is that a shortage of food per se probably rarely limits population growth as the peculiar combination of effects which result from a food shortage is seldom seen. However, this statement is not 2. Endocrines and Populations 299 to be interpreted to indicate that acute starvation cannot ensue in local populations or that a limited food supply is not at times important. The relationships between food, competition, reproduction, and the growth of populations require much more investigation, especially for different species. Until additional critical information is available, any conclusions regarding food and population growth must remain tentative. 4. Growth In a recent experiment with a freely growing population of house mice, it was shown that there was appreciably inhibited growth in all but the mice originally introduced and those from the first litters (Christian, 1961) . In this experiment all mice were toe-clipped so that their ages were known. In general the results from the reproductive organs and adrenal glands confirmed those of earlier experiments and were even more pro- nounced because the results could be equated with age rather than body- weight categories. 5. Summary of Results from Freely Growing Experimental Popu- lations We have seen that, for the most part, freely growing populations of house mice and voles are self-limited, primarily as a result of a density- dependent activity of physiologic adaptive mechanisms. The activity of these mechanisms is reflected in both sexes by a progressive inhibition of reproduction and stimulation of the pituitary-adrenocortical activity with increasing population size. The results agree with those obtained from populations of fixed size. Diminished reproductive function in the female may be apparent at any one or all phases of reproductive activity : inhibi- tion of estrus, increased intra-uterine mortality, reduced nvmibers of im- planted ova, increased postparturient mortality due to suppression of lactation, and possibly by diminished maternal behavior. Inhibition of male reproductive ability is shown by decreases in the weights of the sex acces- sories and depressed spermatogenesis, although the problem of male fertility needs further investigation. The decreases in reproductive function in both sexes apparently stem from decreases in the secretion of pituitary gonado- tropins with a secondary decline in the production of estrogens, progestins, and androgens. Evidence for and against the role of "increased copulation pressure" in diminishing the fertility of female mice and voles was dis- cussed. Without much more conclusive evidence, it is likely that "copula- tion pressure" is an unimportant factor and that fertility is depressed by increased density operating through sociopsychologic and physiologic path- ways. Increased adrenocortical activity was shown by increased adrenal 300 J' J- Christian weights, eosinophil counts, and histologic studies. Thymus weights re- flected these changes. Increasing infant mortality with increasing density may be due to diminished lactation, but may also result from social and behavioral factors. Food limitation may restrict population growth by completely inhibiting reproduction, but is without any other apparent effects. Finally, it is evident that the growth of confined populations of mice and voles is regulated and limited by density-dependent physiologic responses which are activated by sociopsychologic pressures. Whether or not these relationships hold for all species remains to be determined. C. Natural Populations Evidence gathered in the laboratory relating physiologic adaptive mecha- nisms to changes in population density cannot prove that these responses occur in natural populations. Even for freely growing confined populations in the laboratory, the environmental conditions are quite altered by the removal of the effects of climatic and seasonal variability from those found in natural situations. Preventing egress is another artificially imposed condition; although it seems more likely that confinement parallels the situation when populations reach densities where egress into neighboring areas becomes possible. Clearly, evidence from natural populations is neces- sary before any conclusions are justified regarding the role of physiologic adaptive mechanisms in the regulation of mammalian populations under natural conditions. Conclusive results are much more difficult to obtain from natural populations than from confined populations, as might be expected, due to the complexity and variability of these populations and techincal difficulties in collecting the required data. Adequate controls and proper assessment of environmental factors are often severe obstacles, and ob- taining samples of adequate size from populations at very low densities is intrinsically very difficult. Nevertheless, evidence has been obtained to indicate that the density-dependent physiologic responses in natural popu- lations are similar to those seen in experimental populations. Finally, social strife has been implicated (Kalela, 1957) as an important factor in producing the effects associated with increased density ; territorial mutual intolerance increases greatly with sexual maturity in Clethrionomys rufocanus, which serves to increase tension even with decreased density (Kalela, 1957). Therefore behavioral factors again appear to be unportant. 1. Adrenocortical Activity The available evidence relating adrenocortical activity to changes in population density has been obtained largely from studies on populations 2. Endocrines and Populations 301 of Norway rats, both urban and rural, and voles {Microtus sp.), although suggestive results have been obtained for a few other species. Adrenal weight in urban Norway rats of both sexes was shown to be related to population "density" in a study of 21 populations in Baltimore, Md. (Christian and Davis, 1956). Each population was confined to a city block, the latter acting as an island (Davis, 1953). The capacities of the blocks for rats varied considerably, as did the sizes of the populations them- selves, which resembled confined freely growing populations of house mice in this respect. Therefore, the populations were categorized by their posi- tion on their own growth curves at each sampling. A hypothetic growth curve was divided into low stationary, low increasing, high increasing, high stationary, and decreasing, the progression from low increasing through decreasing being a progressive increase in relative density, although the "density" status of low stationary is equivocal (Christian and Davis, 1956) . Each time a sample was collected, the population from which it came was put in one of these categories. "Density" is obviously not strictly in terms of area, but in relation to the carrying capacity of the block and the social characteristics of the population. As populations increased in relative density from low increasing to decreasing, the mean adrenal weight was increased with each relative density; so that rats of both sexes from de- creasing populations had 19% heavier adrenals than those from low, in- creasing populations. Thymus weight was reciprocally related to adrenal weight in female rats, but there was no apparent relationship between thymus weight and adrenal weight, with respect to population density, in male rats. The weights of the pituitary glands of male rats were positively related to the adrenal weights. That is, changes in adrenal weight were re- flected by changes in pituitary weight in the male rats (Christian and Davis, 1956) . However, the functional significance of these changes in the weight of the pituitary glands is not known. The weights of the pituitaries of fe- males and thyroid glands of both sexes bore no apparent relationship to population density. The data from the low stationary populations are difficult to evaluate. The adrenals of female rats were almost as light as those from low increasing populations, and their thymus glands were the heaviest found in any category. On the other hand, the adrenals of male rats were heavier than in any other category. Low, stationary populations are extremely difficult to evaluate, as the actual numbers of rats are so small that even proportionately large changes are difficult to detect. How- ever, these difficulties with their inherent errors in properly assigning populations to a category do not explain the divergence in the male and female adrenal weights, nor do they alter the fact that these populations were at very low levels of density. It should be pointed out that the de- creasing populations were at maximum "density" because they were de- clining naturally and therefore were at or above the environmental capa- 302 /. J. Christian city. It should also be emphasized that food was available in excess of needs for all populations and from numerous sources ; so that food cannot be con- sidered to be an imprtant factor with respect to these populations. Some of the variability between urban populations of rats may be ex- plained by the fact that the rat population in each block is divided into several discrete colonics when the total population is at a relatively low density (at high density these colonies coalesce and the population evidently becomes a single unit throughout the block). The colonies comprising several of the block-populations were evaluated individually with respect to relative density in the same way as the populations for the entire blocks (Christian and Davis, 1956). Relative density values were assigned and compared with the adrenal weights of the rats from these colonies. A sug- gestive correlation between adrenal weights and relative population den- sities of these colonies was found, although the differences were not signifi- cant, probably owing to the small number of samples. The sample size was limited by the relatively few colonies from which a sufficient number of rats were collected for comparative purposes. Although adrenal weight is greatest in naturally declining populations (Christian and Davis, 1956) , it was shown in another study that artificially reducing populations of rats produces an immediate and proportional reduc- tion in adrenal weight (Christian and Davis, 1955). Adrenal weight in both sexes of rats from three populations was reduced 38% by intensive trapping. The adrenal weights were maintained at this level for 5 months by main- taining the populations at the reduced level. In another study a rural population of Norway rats was followed by monthly sampling for two years (Christian, 1959b). An index of the size of the population was obtained each time a sample was collected by using a standardized trapping procedure. The weights of the adrenals, pituitaries, and thyroids were determined for each sample. There was a highly signifi- cant correlation between adrenal weight and population index for both sexes, and an even more significant correlation between pituitary and adrenal weight for both sexes for the 24 monthly samples in the two-year period. The functional significance of the pituitary changes is not known; it can only be inferred from data on weight. Evidently changes in the rate of ACTH secretion, as indicated by adrenal weight, are accompanied by parallel changes in pituitary weight. Changes in thyroid weight and in thymus weight were not correlated with changes in the population size, adrenal weight, or pituitary weight. The results of the foregoing experiments indicate that adrenocortical activity in Norway rats from natural urban or rural populations is related directly to changes in population density and that both sexes respond in the same way. Therefore it appears that physiologic adaptive mechanisms are 2. Endocrines and Populations 303 operative in natural populations of Norway rats, just as they are in freely growing confined populations of house mice or voles. Another series of experiments with populations of rats produced results which at first glance appeared to contradict the foregoing conclusions. Alien rats were introduced into stationary and increasing populations to verify earlier observations that such a procedure profoundly affected the popula- tion (Calhoun, 1948). When stationary populations of rats were increased 20% by adding alien rats of one sex or the other, the populations declined abruptly to about three-fifths their original values. When large numbers of rats were substituted (native rats were removed and replaced by an equal number of aliens) into increasing populations, the populations promptly ceased growing. These procedures presumably produced severe social strife with a marked increase in mortality (Calhoun, 1948; Davis, 1953). How- ever, the adrenal weights of rats taken at regular sampling intervals failed to reflect the increased strife and closely followed the course of the popula- tion size. The explanation of this apparent paradox is clear. The introduced rats were, of course, aliens — hence subordinate rats — in a strange environ- ment (see Clarke, 1953; Barnett, 1955, 1958) and therefore became mor- tality statistics. The native rats which succumbed were probably subordi- nate animals in the original population. The adrenal weights were only from survivors and therefore probably from dominant animals. It already has been pointed out that adrenal weight is least in dominant animals, and so the increase in adrenal weight which might have been anticipated from a superficial examination of the situation obviously and simply failed to appear. Had the adrenals of the rats that died been obtainable, they un- questionably would have exhibited profound changes. Natural populations of voles (Microtus) have also been studied to deter- mine the relation between adrenal function and population density. Adams, Bell, and Moore (Christian, 1959b) periodically collected frequent samples from a natural population of Microtus montanus in Montana for four years to obtain indices of population density, adrenal weights, and data on re- productive activity. The number of males collected was inadequate for valid comparisons. However, population density and the adrenal weights of female voles were closely correlated. The population was at peak densities in late summer of 1952 after which there was a continued general overall decline in the population until the summer of 1955. The adrenal weights of females were maximum in the late summer of 1952 and then underwent a gradual overall decline, generally following the population. However, within each year there were marked seasonal changes in the population which were reflected by equally marked changes in adrenal weights. The population reached its annual maximum density in late summer or early fall and then declined sharply to very low levels where it remained until late winter or 304 /. ,/. Christian early spring when breeding recommenced and the populations increased sharply. Changes in adrenal weight closely followed these animal cycles in population density. Peak adrenal weights were found in early fall and coin- cided with a cessation of reproduction and the beginning of the autumnal decline in the populations. Adrenal weights were minimal by November and remained there until March, ^ when the population again began to in- crease. Adrenal weights were maximum in the last summer of 1952, aver- aging about 15% greater than in any other year for a comparable time of year. The mean weights in winter were roughly 60% less than the maxi- mum. These results indicate that the supposedly severe winter conditions of the Rocky Mountain Region of Northern Montana do not impose physio- logic hardships on voles. Climatic conditions, if they affected the animals at all, apparently were unimportant compared to changes in population density. The sharp declines in the population every fall evidently were due to a cessation of breeding and continuing random mortality, not to a de- clining environment, otherwise the adrenal weights would not have de- creased so spectacularly (Christian, 1959b). It is possible that physiologic responses to high densities in late summer contributed to the annual de- clines in population density, but it seems unlikely except in 1952, In that year it is probable that physiologic adaptive responses were at least partly responsible for the decrease in the size of the population. It is noteworthy that the rapid decline from peak densities in the late summer and early fall of 1952 was not caused by increased mortality from disease (Adams et al.; cited in Christian, 1959b). Adrenocortical-density relationships were studied by Louch (1958) in two natural populations of voles (Microtus pcnnsylvanicus) . He used eosinophil counts, supplemented by adrenal weights, as indices of adreno- cortical activity. Relative adrenal weights were high and eosinophil counts remarkably low in one population at peak density. Following a sharp de- cline in this population, indicated by an 85% drop in the population index, the eosinophil counts rose sharply about 500% and continued to rise more gradually for the subsequent nine months of the study. Adrenal weight averaged 59% lower during the period of low density than during the pre- ceding period of high density: 14.5 mg./lOO gm. compared to 23.0 mg./lOO gm. The size of the second population remained low tliroughout the experi- mental period. The eosinophil counts began high and gradually rose to higher levels. Adrenal weight declined about 27% (from a mean of 19.4 to a mean of 15.2 mg./lOO gm.) in the second population over the same period 3 Subsequent work has suggested that the low winter adrenal weights are partly due to sexual inactivity and regression, although not entirely as a number of the voles were not sexually regressed. In other words the adrenal weights should be low due to density factors (cf. October), but these were too low [see Christian (1961, 1963b)l. 2. Endocrincs and Populations 305 as the 59% decline in the first population. However, the decline was not nearly so great and the initial weight was 19% less than in the first popula- tion. The lower adrenal weight was reflected by a higher mean eosinophil for the same period of time. Even though the reason for the lower adrenal weight in the second population during the second period is not known, adrenal weight and eosinophil counts in these studies generally reflected differences in population density (Louch, 1958). Methods for estimating most natural populations of mammals are at best relatively crude, insensitive, and subject to many errors. At best they can detect only relatively large changes in population density. The catch per trap-night or any comparable index of population density obtained by some sort of uniform trapping effort is probably as good an index as any readily usable procedure. The catch per unit of time was used in these studies of vole populations by Louch (1958) and Adams et al. (Christian, 1959b) , as well as in the studies of rural populations of Norway rats (Chris- tian, 1959b) . Errors in estimating population density in this fashion may account for most of the observed discrepancies. If the existence of physio- logic responses to population density is established for a variety of species, it is likely that the magnitude of these responses will provide a much more precise index of relative population density (the important figure for practi- cal purposes) than any existing indirect method for determining population size.^ Limited studies with natural populations of other species have been made. A 68% decline in the index of the size of a population of white-footed mice {Peromyscus leucopus) from one July to the next was accompanied by a 58% decline in their mean adrenal weight (Christian, 1959b). Similar, but less conclusive, results have been obtained with natural populations of short-tailed shrews [Blarina) (Christian, 1954, and unpublished). Beer and Meyer (1951) studied the seasonal changes in the endocrine and i-eproductive organs of muskrats and found a marked peak in adrenal weight in adults of both sexes in early fall and a second minor peak in March and April, especially in adult females. These seasonal changes are similar to those we have noted in Microtus montanus and may be related to behavioral and social changes. Preliminary work on the relationships of the weights of deer adrenals to " The persistence of immature zonation in the adrenals of males and lack of hyper- trophy due estrogenic stimulation in females may explain some of the discrepant re- sults with Microtus, and possibty Lemmus, as these would seriously confound adrenal weight relationships if the population under study is composed of an appreciable per- centage of sexuallj' immature, regressed, or otherwise sexually inactive animals. Winter or high-density populations will consist largely of such animals [see Christian (19(il, 1963b)]. 306 J- J- Christian various factors indicates that adrenocortical physiology in this species, as in others, reflects environmental changes, and the adrenal was therefore said to be an indicator of conditions as in any other species. (Hughes and Mall, 1958). However, sika deer (Cervus nippon) respond to changes in population density in a manner quite similar to that seen in rats (Christian et al., 1960) . A 60% decline in the population of these deer was accompanied by a proportional decline in adrenal weight. The decline of this population was brought about by a mass mortality which apparently was due to metabolic disturbances resulting from the prolonged adrenocortical hyper- activity associated with a high density of the population. There is evidence that potassium deficiency resulting from cortical hyperactivity may have contributed directly to the mortality. Marked stunting of growth was also seen during the period of high density and especially during the year of die-off. Other possible causes of the die-off, such as malnutrition, could be ruled out. More experimental work is needed to relate adrenal function with popula- tion density for a number of species in natural populations. The problems are numerous and not the least of these is being able to rule out extraneous factors or else to assess their role in producing the measured effects. 2. Reproductive Function A large number of studies suggest that reproductive function is depressed with increasing density of natural populations, but studies sufficiently discriminative to attribute changes in reproductive function to changes in density per se without additional complications are few. Therefore a great deal of the evidence is circumstantial and tentative at best. The present discussion is limited to those studies which have been conducted with suflficient care and attention to a variety of details so that one is confident that the factors have been properly considered which possibly might affect reproduction. However, a brief discussion of various problems involved in evaluating reproductive function is in order before considering the evidence implicating physiologic responses to population density in the suppression of reproductive function. First there is the problem of the food supply of the experimental popula- tion. As we have seen, there is ample evidence that food deficiencies can curtail reproductive function independently of other adaptive mechanisms. However, the effects of food and of increased density on the reproductive system and growth are so similar that unless careful assessments are made of the food supply (preferably these should be accompanied by an evalua- tion of adrenocortical and other adaptive fvmctions, no separation can be made between the effects of food and of density, especially at relatively 2. Endocrines and Populations 307 high population densities. Furthermore, it is very likely that the adaptive reactions to density and their effects may overlap food shortages, so that their effects are mutually augmentive at critical densities. However, the aim of the present discussion is to assemble the evidence that adaptive reactions to density occur irrespective of whether or not the effects of in- adequate food or other environmental factors are superimposed. The growth of populations unquestionably can be limited by environmental factors which may either act through the physiologic adaptive mechanisms or in- dependently of them, especially in localized populations. However, the basic concept of physiologic adaptation to population density is that these mechanisms are always operative, and will regulate and can limit popula- tion growth. Finally, limitations of enviroimiental factors, even of food, may increase competition directly and therefore indirectly produce in- creased activity of the physiologic adaptive mechanisms. Pitelka's (1957b) statement that "the interest in the stress mechanisms has led some students to overlook the point that such a mechanism does not evolve without linkages to critical variables extrinsic to the population" bear repeating and is emphasized and supported by an immense amount of work with rat populations (Davis, 1953). Nevertheless, it is extremely miportant to dis- tinguish between the direct action of environmental variables on popula- tions and their indirect action through sociopsychologic and physiologic mechanisms; and experimental evidence to date emphasizes the general importance of the latter mode of action. Evidence of the direct action of food shortages in depressing reproduction in natural populations of Pero- myscus boylii and P. maniculatus is cited by Jameson (1953, 1955), and population declines evidently followed the shortages as a result of con- tinuing normal mortality in the presence of a lull in reproductive activity with no recruitment into the populations. The evidence presented by Jame- son, supported by the controlled experiments previously described, strongly favors the interpretation that inadequate food supplies were directly re- sponsible for the inhibition of reproduction. However, the possibility that the shortages induced increased competition and increased activity of adaptive responses were not ruled out completely. Davis (1951c), in a study of Norway rats from natural populations, provided definitive evi- dence that a deficient food supply can inhibit reproduction under natural circumstances. However, w^hether the effects were direct or produced by increasing competition with stimulation of generalized physiologic adaptive response is unknown. It was determined later that the adrenals of these rats were responsive to changes in population density (Christian, 1959b). Other examples could be cited, but the majority could serve only to empha- size the fact that discrimination between the effects of food and other factors is usually not attempted. 308 /. J. Christian Another, perhaps more serious problem in evaluating the effects of density on reproduction is the lack of adequate criteria to determine the age of most small mammals; so that weight and length measurements are usually used as criteria of age. Since one of the major effects of increased activity of physiologic adaptive responses is diminished growth, as well as inhibition of reproductive function, there is no valid way to separate normal immature animals from older animals which should be mature but in which both growth and reproductive maturity are inhibited. Several serious misinterpretations can result from this situation : ( 1 ) a shift of age composi- tion of the population toward greater age will be obscured; and (2) repro- ductive competence is usually assessed on the basis of the prevalence of pregnancy, prevalence of lactation, and similar criteria in those animals which are obviously mature, therefore total suppression of reproductive activity with a delay in the onset of puberty will be missed altogether. Of course in such a situation, the reproductively active and obviously mature animals represent only the portion of the population which is least affected by density factors, a situation to which attention has been called earlier. The studies of Crowcroft and Rowe (1957) offer a clear illustration of this situation in controlled populations in which the ages of the animals were known. How would the nonreproductive mice in these populations have been classified in the usual studies of natural populations with trapped animals? Kalela's (1957) studies on the effects of population density on Clethrionomys rufocanus from a natural population are of singular value because (1) he had a means of determining the age of the animals by the rooting of their molars and was therefore able to state with certainty that growth and maturity were totally inhibited, and (2) he eliminated the possibility that food was an etiologic agent in producing these phenomena. Of course, all gradations of these effects may occur to further confuse the situation. Most studies which evaluate changes in reproductive function of small mammals, for which there is no adequate way of determining age, in relation to density in populations must be viewed with considerable skepti- cism. It has already been pointed out that the usual means of determining reproductive competence do not detect changes short of almost total inhibition, especially in males. A third problem, less frequent in its occurrence, is the failure to take into consideration changes in age composition when evaluating changes in litter size, although this frequently results from the inability to determine age. Hamilton (1937) reported that litter size in Microtus pennsijlvanicus in- creased with increasing population density and yet there was increased intra-uterine mortality at the higher densities. It is well known that litter size increases with parity for the first few litters and that there usually is a direct relationship between body weight and litter size for most litter- 2. Endocriues and Populations 309 bearing mammals (Watt, 1934; Hoffman, 1957; Flick et at., 1959). There- fore it is entirely possible that the apparent increase in litter size noted by- Hamilton was a result of a shift in age composition, and even if this is not the case, the point is generally valid and is well illustrated by Hamilton's data. These data bring up another point which often proves confusing; that is there is no word in use to designate an in utero group of embryos. "Litter" used for both postpartum and antepartum young with the result that ''litter size" is frequently determined from embryo counts and conclu- sions drawn therefrom regarding litter size at birth. Although the authors are themselves usually quite clear on these differences, their descriptions in the literature often are not, and the reader will arrive at false conclusions or else be unable to make any at all. This situation can be corrected by the use of the collective noiui gravidum to describe the in utero counterpart of "htter" (Snyder and Christian, 1960). Finally, there is a wide divergence in the descriptions of the effects of population density on reproduction. It seems clear from experimental and field data that the reproductive processes can be inhibited at a number of different points, evidently depending on the severity of the stimulus, dura- tion of the stimulus, age at which the stimulus was first effective, the posi- tion of any given animal or groups of animals in the social structure, prob- ably individual physiologic and psychologic differences, as well as other unknown factors. The details of these various relationships are not known, but experimental results suggest that the smallest stimulus inducing an in- creased adaptive response with inhibition of reproduction in mature ani- mals will affect lactation, increase litter mortality, and possibly depress fertility; a greater stimulus will result in increased intra-uterine mortality and an even greater stimulus will totally suppress reproductive function. It is suggested that as the alarming stimulus increases in severity there is a progressively greater suppression of the secretion of gonadotropins. It is equally evident that young mammals reaching maturity are far more sus- ceptible to a given alarming stimulus than an animal which has already reached maturity. It is known that immature rats and mice are many times more sensitive to suppression of gonadotropins by steroids than the mature animals (Byrnes and Meyer, 1951). The results of experiments discussed in the preceding sections show that these statements apply to the effects of population density. The effects of vitamin and other nutritional deficiencies follow a similar pattern; furthermore, the earlier in the process of reproduction the deficiency begins, the more profound is its effect on the developing fetuses (Lutwak-Mann, 1958). Usually a deficiency beginning at the start of pregnancy or earlier will produce a very high percentage of resorptions. These decrease the later the deficiency begins. It is noteworthy that only "borderline" deficiencies appear to produce congenital anomalies. 310 J. J. Christian So it appears to be with population density. Only those female mice which were moderately affected by density produced young which were then permanently affected by reduction in lactation, whereas those mice more seriously affected failed to produce at all and exhibited 100% resorption of embryos (Christian and LeMunyan, 1958). Therefore, when one considers the enormous number of variables affecting a population, it is not sur- prising that there is so much variation among individuals and among populations wdth respect to the effects on reproduction. Reproduction should include the entire process of producing young from maturation of the parents to weaning when discussing or measuring the effects of physiologic adaptive mechanisms and the effects on the endocrine organs. In spite of these problems, a number of studies on natural populations of small mammals have been sufficientlj'' detailed and critical to permit exami- nation of the relationships between population density and reproduction. The most conclusive of these have been carried out on Norway rats (Rattus norvegicus) and voles {Microtus sp. and Clethrionoimjs) , but there have been others on muskrats (Ondatra), cotton rats {Sigtnodon) , woodchucks {Mar- mota) , and hares (Lepus americanus) . Most of these suffer to one extent or another from a lack of dependable criteria for determining age, as dis- cussed above. The reproducti^'e performance of Norway rats from increasing, de- creasing, and stationary populations was investigated (Davis, 1951a). These rats have a major reproductive season in late winter and early spring and a secondary minor peak in reproductive activity in the fall. Increasing populations have a higher prevalence of pregnancy than either decreasing or stationary populations. These differences are especially marked in the spring breeding season when the prevalence of pregnancies was 41.6% in increasing, 25.3% in decreasing, and 14.4% in stationary populations. The incidences of pregnancy were, repsectively, 6.1, 6.3, and 3.8 per year. However, there were no apparent differences in litter size and the prevalence of lactation Avas essentially the same in all three categories although the data on lactation could not be analyzed separately for the two breeding seasons. However, an analysis of lactation by seasons could not account for the similarity of the overall figure and one must conclude paradoxically that, although the pregnancy rate was highest in increasing populations, there was also a greater parturitional mortality and at the same time a better survival of those young which were not lost soon after birth. Similar results were obtained when reproductive performances of Norway rats from a rural population were compared at two different relative popula- tion densities. The pregnancy rate was 48.3% a month after artificially reducing the population a third, compared to 14.4% before the reduction. 2. Endocrines and Populations 311 These results indicate that reproductive performance is inversely related to population density in Norway rats, at least for increasing and stationary populations. The status of decreasing populations is equivocal and may represent a partial recovery of reproductive function in declining popula- tions, although decreasing populations are presumably at maximum den- sity. However, we already have noted that adrenocortical hypertrophy is greatest in populations spontaneously decreasing from asymptotic levels. These results represent a large number of populations and carry consider- able weight; nevertheless in another experiment in which three urban populations of Norway rats were artificially reduced about 50% there was no corresponding increase in the rates of pregnancy (Davis and Christian, 1958). Two factors may have obscured such an occurrence. One was that the populations were increasing and therefore had a fairly high pregnancy rate at the time of the reduction (30.2%) , and the other was that the main breeding season was declining at the time the next samples were collected (April, May, and June) from which a mean pregnancy rate of 32.2% was obtained. Experiments designed to analyze reproductive function in relation to density of populations of rats suffer from the inability to determine the age of the animals, therefore attainment of maturity and other reproduc- tive end points are based on the sizes of the animals. There is evidence to indicate that rats in increasing populations grow faster, and so are larger at a given age, than rats from stationary populations (Davis, 1951b). Therefore inhibition of growth in populations of high density may tend to obscure evidence of partial inhibition of reproductive function, such as delayed puberty, since it is likely that reproductive function and growth are equally inhibited. Thus, these results are evidence to support the earlier comments regarding the desirability of determining age in mammals when evaluating reproductive function. One of the more conclusive studies to date on the relationship between density of population and reproduction was conducted by Kalela (1957) on red-backed voles {Clethrionomijs rufocanus) in Finland. A major factor contributing to the value of this study was the ability to determine and approximate age of the animals by the root development of the first molars. These molars are rootless at the end of September of the year of birth, but the roots are visible by the following spring and continue to develop further (Zimmermann, 1937; Kalela, 1957). The question might be raised whether the growth and rooting of the molars would be suppressed along with sup- pression of growth, but molars were rooted in animals in which growth and maturity were definitely suppressed (Kalela, 1957) ; so that any suppression of molar growi^h and rooting would make the results even more dramatic. []This and other means of estimating age in voles has been more fully re- 312 /. /. Christian viewed by Bourliere (1951).] Kalela also determined that mature sperma- tozoa are present in the testes of these voles when the testes are seven or more millimeters long and defined maturity on this basis. Females which were pregnant or parous were defined as fecund. During the first summer of Kalela's studies in 1954, moderate population densities were achieved after a spring characterized by a very small popula- tion which had overwintered from the preceding fall. Males and females from the litters born early in the breeding season matured without excep- tion. Four-fifths of the mature females of late summer were young of the year. A large number of the young of the year which reached maturity had two litters and some even had thi-ee during their first summer. The old overwintering females had as many as four litters. The following spring, 1955, the population started with a much larger number of overwintering animals. The rate of growth of this population at first was as high or higher than the rate of growth of the population in the preceding year, but it rapidly declined as the density of the population increased. Peak densities were reached in this year. A good many of the males born in the first part of the breeding season reached maturity, but males with enlarged testes were rarely found in August, and there was an accumulation of immature males weighing between 20 and 24 gm. at this time (mature red-backed voles normally weigh more than 24 gm., usually between 30 and 40 gm.). This weight range represents the maximum size achieved by male or fe- male red-backed voles which fail to mature, irrespective of their age. There was no accumulation of voles in this weight category during the preceding year of low population densities. Female young of the year exhibited the same cessation of growth and failure to mature, except for those born early in the breeding season. Less than half of the mature females in late summer were young of the year and there was a marked accumulation of immature females in the 20-24 gm. M^eight class. Furthermore, the pregnancy rate fell sharply and had fallen to well below the 1954 levels by mid-August. The overwintering females had up to three litters, but none had four litters. Those young of the year which reached maturity had no more than two litters and only a few had this many. One area (Malla) had twice the density of the others under study at this time, and none of the young of the year, male or female, attained sexual maturity or grew beyond the 20-24 gm. category. The population had undergone a major decline in numbers by the spring of 1956 and was well below the 1954 levels for the same period, and yet the rate of growth of the population was extremely slow. The overwintering animals, as well as the young of the year, were distinctly smaller than normal. Reproductive performance was essentially identical to that of the preceding summer of 1955 when the density of the population was extreme. 2. Endocrines and Populations 313 The rates of fecundity, pregnancy, and other measurements of reproductive competence were unchanged from the preceding year. There was no appar- ent change in htter size or intra-uterine mortaUty throughout the period of the study of this population. There was no shortage of food at any time during these studies, and especially not during periods of active reproduc- tion. Therefore, the changes in reproductive function are not attributable to ^'arying food supplies. Climatic factors, although variable, did not corre- late with the functional changes and were probably noncontributory in producing functional changes. This study shows, beyond reasonable doubt, that the shifts in reproduc- tive function were reciprocally related to the density of the population in 1954 and 1955 and that increased density was the factor responsible for the decline in reproductive function (with a total suppression of reproduc- tion in the young of the year in one area) and attainment of maturity in 1955. It also shows that the primary effect of increased density was to in- hibit maturation so that large numbers of immature animals accumulated by late summer. At the same time, growth beyond a general level of 20-24 gm. was suppressed in both sexes. The data from the area of extreme density, in which no animals matured are especially convincing. No direct measures of endocrine function were made, but these occurrences in natural populations of Clethrionomys rufocanus conform with the results from the more highly controlled experiments with populations of mice or voles in the laboratory. The apparently paradoxical failure in 1956 of reproduction to return to the 1954, or higher, levels, together with the apparent stunting, also fits the conclusions discussed earher. The effects of increased density on lacta- tion and subsequent growth of the young and in turn their inability to lactate adequately were discussed earlier, and attention was called to the profound long-range effects of increased density on the animals experiencing the increase as well as two generations of their progeny (Chitty, 1955; Christian and LeMunyan, 1958) . The red-backed voles which overwintered until the spring of 1956 had been subjected to increased density and had experienced its effects. It was noted that these voles were unable to mature in the year of their birth and were stunted. The following year their repro- ductive performance and that of their offspring reflected a similar situation, closely resembling the effects of increased density on laboratory popula- tions. The population dechne was consequently due to the high mortahty of those young born during the period of maximum density and probably reflects decreased resistance to a variety of stimuli coincident with increased activation of adaptive mechanisms. A very high rate of infant and juvenile mortality was a major factor in the cessation of growth in laboratory popu- lations, but in these there was no appreciable mortaUty of the adults. 314 J- J- Christian There is a continuous high rate of mortality of all age groups in natural populations of these small mammals so that a failure of reproduction and a sharply increased mortality rate of juvenile animals make a collapse of the population easily understood. The prolonged recovery from this decline also can be attributed to the effects of increased density, apparently through defects in lactation as well as other endocrine reproductive functions, al- though the details of these mechanisms require much more investigation. It should be noted in these populations; that while all phases of reproduc- tion were affected the particular functional aspect which was most severely affected appeared to depend on the level of density and on the age of the animals involved — the young being most severely affected, as was the case in laboratory populations. It appears that the responses of this natural population to density were identical in every respect to those seen in labora- tory populations with the exception of the ever-present mortality which occurs in the wild. Reproductive function e\ddently is inversely related to density in natural populations of red-backed voles {Clethrionomys) , and the inhibition of re- production and growth probably resulted from a suppression of the secre- tion by the anterior pituitary of gonadotropins and growth hormone. There is no other explanation evident which fits the known facts, even though there was no direct assessment of pituitary function. The apparent paradox of a low population exhibiting a marked inhibition of reproduction and growth following a decline appears to result from the prolonged effects of high population densities on these animals. These conclusions derived from Kalela's studies carry particular weight, as food, and apparently other environmental factors, appear not to have been causative agents. Kalela (1957) discusses the social problems in these populations. A quite similar study was conducted on Microtus montanus (Hoffmann, 1958) with comparable results. This population was followed for 3 years and there was a peak between the second and third breeding seasons which was followed by a marked decline in the size of the population. The popula- tion density was moderate in the spring of 1952, increased during the sum- mer and early autumn, and was followed by the annual decline in density subsequent to the annual cessation of breeding. The population in the spring of 1953 began moderately and increased sharply until September. The spring population of 1954 was higher than in 1953, but the population declined rather than increased during the breeding season and was at a very low level in the spring of 1955. Thus the history of this population of Microtus montanus was in many respects similar to that of Kalela's popula- tion of Clethrionomys. The published data indicate that Microtus montanus may differ from most other small mammals in that litter size remains constant with respect to age, weight, and parity (Hoffmann, 1958) . There- 2. Endocrines and Populations 315 fore changes in mean litter size apparently do not need to be corrected for these variables. During each breeding season of the study there was an appreciable decline in litter size as measured by embryos and uterine im- plantation scars and this decrease was also paralleled by a decline in the number of corpora lutea. There was also an increase in the general level of the population for comparable months from 1952 to 1953. This general in- crease coincided with an overall decline in mean litter size which, however, was not significant. These changes were inversely related to the annual increase in population density for the first two years. However, the popula- tion declined sharply from spring to fall in the third year and yet the mean litter size also declined. Prenatal mortality was directly related to population density in the first breeding season, inversely in the third and bore no conspicuous relationship in the second. Prenatal mortality was greatest after the population had declined in September 1954. The mean prevalence of pregnancy also de- clined with each successive year. The peak of the population was evidently in September of 1953, and the decline followed shortly thereafter. Hoffmami noted that at this time the proportion of fertile males began to decline and at the same time 24% of the mature females weighed less than 33 gm. This figure increased to ap- proximately 45% in June and July of the following season. The proportion of mature males weighing less than 35 gm. also rose to reach a maximum of 33% in July of 1954. These morphologic functional changes resemble those observed by Kalela and probably reflect suppression of growth at high densities. The fact that there was a decline in male fertility as well as in the incidence of pregnancy further supports such a conclusion. Hoffman called attention to the fact that prenatal mortality was lowest at peak densities and highest the following year. However, examination of his data reveals that the proportion of multiparous females rose steadily throughout the 1953 season to reach 100% in September, undoubtedly accounting for for the low proportion of prenatal losses for two reasons: (1) it is likely that the older parous females suffer less prenatal loss at any time; and (2) more important, they probably represent the dominant animals and there- fore those least affected by high densities in accordance with the results of laboratory experiments (Retzlaff, 1938; Christian and LeMunyan, 1958). The age of the animals could not be determined in these studies ; immature animals were classed as such and were not further divided into those old enough to have matured and young animals. Had it been possible to deter- mine age, it is likely that these results would have been more decisive. There was a low mortality of weanlings and juveniles during the period of build-up in this population, but apparently there was a marked increase in mortality in all age groups during the decline. 316 /• /• Christian These data, like those from the preceding study, indicate that the effects of high densities on reproduction and growth persist for some time after the peak has been reached and passed. It should be remembered that all animals beginning the breeding season after a peak are sur^-ivors from the peak densities. Although the highest numerical size of Hoffmann's popula- tion was in September of 1953, the actual peak could just as easily have been the relatively high spring population of 1954. The data suggest this to be the case, as there was a brief period at the beginning of the 1954 (June) breeding season in which prenatal and infant mortality were lower than usual and then climbed sharply. Hoffmann concluded that ovulation rate and Utter size tend to vary inversely with population density and thus to run counter to the cychc trend of the population, except during the crash decUne period in Microtus montanus, when lowered Utter size may contribute to the drop in density. He also concluded that speed of attain- ment of reproductive maturity remained rather constant despite changes in density, which is quite the reverse of Kalela's results and conclusions. This conclusion is, however, based on the assumption that there is no inhibition of growth or that it is totally independent of changes in reproduc- tive function. Since the age of these voles could not be determined, age was assumed to be reflected in body weight. In view of the likelihood that inhibition of growth and reproduction are not independent, but rather are two manifestations of one reaction, as we have seen for Clethrionomys as weU as for Mus in experimental populations, the conclusion is not justified that the speed of attainment of maturity remains constant in the presence of changes in density. Furthermore, Hoffman's figures indicate that a high proportion of mature animals were much smaller in peak and declining populations than usually found at lower densities. Of course these data could be interpreted to indicate an early attainment of maturity with respect to size, but this interpretation is most unUkely in view of the other data on reproduction and the results of other experiments. This problem could be settled by determining the age of these animals; a problem ah-eady discussed at some length. Chitty (1952) also studied a population of voles {Microtus agrestis) and obtained results similar to those of Kalela. During the peak breeding season of 1937 he found that young males did not increase in weight above 22.2 gm., whereas normally adult males seldom weigh less than 22.3 gm. after May. Young females weighed more than 22.2 gm. only while pregnant; otherwise the heavier females in this population were old adults with a few exceptions in September and October. The prevalence of pregnancy in the peak year was apparently less than in other years and appeared to be due mainly to a failure of maturation in the young of the year, as older animals exhibited a uniformly high pregnancy rate. In one area all age groups ceased 2. Endocrines and Populations 317 breeding in August of the peak summer and the survivors did not breed the following spring after the population had declined. Other populations which were at peak density the following year continued to breed from May to October and survivors bred again the following year, after the dechne, although no recovery in population occurred. D. Chitty concluded that lowered fertility was not invariably associated with a decline in num- bers. The decreases in size in all these populations primarily was due to an excessive juvenile mortality before August which was attributed to some adverse effect of high population density on the ability of the young to survive. Hoffmann (1958) also studied a population of Microtus calif ornicus and noted a general inverse relationship between density and reproductive function which occurs on a seasonal basis. In other words, the annual in- crease in the population also has density effects on its members. Fitch (1957) noted a decline in litter size in Microtus ochrog aster with progression of the breeding season and increase in the population, as noted by other authors, but he attributed this to an increasing number of young of the year reaching maturity and having small first litters. However, this explana- tion does not account completely for the observed progressive decline in the population. A similar relationship has also been noted in muskrats (Ondatra zibethica) (Errington, 1948, 1951, 1954a). Errington (1954a, 1957) has also shown that reproduction may be depressed during the low years following high densities and increase during an increasing phase of the population. The depressed reproduction probably is another example of the prolonged effects of high population densities on succeeding generations. The pregnancy rate was high early in breeding season during the peak year in a population of voles (Microtus montanus) studied by Adams, Bell, and Moore (Christian, 1959b) , but dropped precipitously after June so that the percentage of pregnancy was below 30% for August and September — months of peak breeding activity in subsequent years with lower popula- tion densities. Hamilton (1937) reported an increase in litter size with increasing popu- lation density and a decrease in litter size during the decline. He also re- ported increased intra-uterine mortality. However, although the ages of these animals were not determined, it is probable that the age composition of the population shifted so that it is consisted of a higher proportion of older animals as the peak approached. The litter size of Microtus pennsyl- vanicus increases with parity (Hatfield, 1935; Martin, 1956; Fitch, 1957) differing from M. montanus in this respect; so that the increase in mean Utter size could reflect such an occurrence. The decline in litter size during the decrease in population size is consistent with the preceding studies. Odum (1955) also reports a greater mean Htter size for Sigmodon in 318 /. /. Christian "high" density years than in "low" density years. Once again weight was used as an age criterion and so the possibihty exists that Odum's figures for age composition in "low" versus "high" density populations may reflect complete suppression of reproduction and growth in young animals at high densities, rather than a shift in age composition toward younger animals as his figures suggest. Tanaka (1956) reported complete inhibition of reproductive function in Anteliomys smithii {Clethriononiys smithii) irrespective of the age or sex of the voles during a season of peak densities. The reproductive organs were in a condition of complete quiescence. The possibility that a deficiency of food may have been instrumental in producing these effects cannot be ruled out. However, Tanaka (1956, 1957) points out that maximum den- sities, or vole "outbreaks," may occur either in concurrence with or inde- pendently of widespread flowering of bamboo grasses. The fact that the voles apparently were equally numerous and showed similar reproductive inhibition regardless of whether they were living in areas of living or areas of dead bamboo strongly suggests that the inhibition of reproduction was density dependent. Lemmings, because of the conspicuousness of their population cycles, have been the subjects of study by a number of investigators. Lenimus trimucronatus has been reported to experience a complete suppression of reproduction during periods of peak densities of their populations (Rausch, 1950) . In the spring of 1949, prior to a precipitous decline in their popula- tion, there was an absence of young animals and no evidence of reproduc- tive activity: none were pregnant, there were no uterine implantation scars, few females had perforate vaginas, and the testes of the males were small and incompletely descended. Similar results were obtained by Barkalow (1952) in a study of the tundra mouse (Microtus oeconom.us) and lemmings (Lemmus trimucronatus and Dicrostonyx groenlandicus) at Barter Island, Alaska. Barkalow in summarizing the results of his and other studies on vole and lemming populations in the Arctic states that cessation of breeding prior to and during a cyclic decline is in his opinion a population character- istic and that large litters are characteristic of the build-up phase of a population cycle, especially in its early stages. Rausch (1950) stated that although there was a reduction in the tundra vegetation there was no sug- gestion that the decimation of the population resulted from a deficiency of food. Thompson (1955) takes the view that exhaustion of the supply of food and cover is the important factor, and well it may be in a local situa- tion. However, the bulk of the evidence suggests that a limited supply of food is not usually the factor limiting population growth. Lemmings have an annual decline in reproduction with the annual increase of density, espe- cially in prepeak or peak years of density similar to that seen in the other 2. Eudocrines and Populations 319 microtines discussed (Pitelka, 1957b). Pitelka (19o7a, b) also makes the point that the cessation of reproduction at peak densities may occur and produce a decline in the lemmings before their predators have a chance to exploit the lemming population. Lemming populations have not been studied for a long enough period of time or with sufficiently detailed evalua- tion of the various factors which might inhibit reproduction to warrant any conclusions at present. However, it is apparent that there can be inhibition of reproduction with increased density, but the extent to which food sup- plies may also contribute has not been sufficiently appraised. The evidence presently available suggests that failure of reproduction in response to ex- treme densities is the major cause of the cyclic declines in lemming popula- tions. Many studies indicating a decline in reproduction with high population densities in other species, such as hares (Preble, 1908; MacLulich, 1937), but in none of these is it possible to ascribe the alteration in reproduction solely to density factors, even though it may well be that such is the case. Many other studies could be listed which illustrate the same sort of thing, but no useful purpose would be served by doing so here. More recent studies with Microtus pennsylvamcus indicate that in this species the annual re- productive cycle is governed by population density, but this does not appear to be true for Peromyscus manicidatus (Christian, 1961). The main point of interest is that reproduction does respond to changes in population density in natural populations of voles and rats and probably in other .species as well. In some studies there was a reciprocal relationship between adrenocortical and reproductive function, in others only one or the other of these general responses was studied, but the results conform to this general relationship. It seems undeniable, especially in the light of studies on laboratory populations, that physiologic adaptive responses are operative in natural populations and are reflected by curtailment of repro- duction and growth and stimulation of increased pituitary-adrenocortical activity in natural populations. However, detailed and well correlated studies on a variety of species still are required and for a variety of different populations in order to assess the relative importance of these mechanisms in curtailing free-for-all population growth. 3. Disease Resistance and Mortality One of the major points of the hypothesis that physiologic mechanisms could control population growth as a feedback system acting in response to changes in density was that the sudden mass mortality seen at the end of a build-up of populations to peak densities could be accounted by exhaustion of the adaptive responses (Christian, 1950b). It was suggested that the 320 /. /. Christian symptoms so frequently observed (Hamilton, 1937; Green and Larson, 1938 ; Green, et al., 1939) were the result of hypoglycemic shock as a result of pituitary-adrenocortical exhaustion. The subject remains at that point to- day, except that Frank (1953) has succeeded in showing that hypoglycemic shock, which is uncorrected by epinephrine but is corrected by glucose in- jection, occurs in Microtus. Frank (1953) also succeeded in producing mass mortality from hypoglycemic shock by crowding voles in enclosures. How- ever, he believes that in addition to increased density alone, which sets the conditions for a mass mortality, a trigger, such as competition for food must also be present. This seems a reasonable suggestion which perhaps can be modijfied to be included in density-dependent factors. On the basis of Frank's and other experimental data it appears that competition for any factor is also a matter of relative population density and inseparable from it. In this case it seems that the voles were reducing the environmental capacity at high densities and were therefore themselves setting up the conditions for increasing competition among themselves above the level that was already present. It has been mentioned that mass mortality in sika deer was probably a result of electrolyte imbalances brought about by prolonged adrenocortical hyperactivity. There were indications of a prominent role of the zona glomerulosa, presumably with increased secretion of aldosterone, to explain the evidence of potassium deficiency (Christian et al., 1960; Christian, 1963). Frank (1953) was able to eliminate infectious disease and climatic factors as causative agents in precipitating the mortality in these animals, as were Adams, Bell, and Moore (Christian, 1959b) in Microtus montanus. Rausch (1950) also indicated that neither parasitism nor infectious disease could account for the sudden decline in the lemming population he was studying. In a study of mortality in an experimentally induced epidemic in Norway rats, Davis and Jensen (1952) found that mortality rate was not significantly changed and probably would be so only under special circimi- stances. A precipitous population decline due to mass mortality from hypo- glycemic shock is probably only one of several mechanisms which may operate to reduce population density drastically and it may be a rather special occurrence. Our knowledge of the physiologic mechanisms involved in invoking "shock disease" in natural or experimental populations is little better understood now than previously. It was originally postulated that adrenocortical exhaustion was the cause, but it is just as likely, if not more so, that readily mobilizable sources of glycogen and glucose become totally exhausted with continued overstimulation of the adrenal medulla and cor- tex. There may be exhaustion of other parts of the responsive system, such as the pituitary, hypothalamus, or of the adrenal medulla. None of these 2. Endocrines and Populations 321 possibilities has been explored and in retrospect the idea of attributing hypoglycemic shock solely to adrenocortical exhaustion seems naive. That the hypoglycemic shock syndrome does occur cannot be denied, but its physiological causes remain to be determined. Such indirect evidence as is available indicates that it is a very complex affair. Mice and voles have been observed to die of hypoglycemic shock shortly after being placed placed together in groups (Frank, 1953; Christian, 1955a), but if moribund animals are removed from their cagemates, they recover (Frank, 1953; J. J. Christian, unpublished) . The rapidity with which this occurs suggests some- thing other than cortical exhaustion, perhaps medullary exhaustion or exhaustion of readily available glycogen reserves. In addition, there is evidence that adrenal cortical exhaustion may not occur per se, but may be an apparent result of exhaustion elsewhere in the adaptive system (Ro- senfeld, 1958). At the present time it appears that a failiu-e in reproductive function may account for a decline in a population much more frequently than shock. It has been observed in several species that the young born during peaks of density appear to be much more susceptible to various mortality factors, and their deaths largely account for precipitous population declines (Green and Evans, 1940a, b, c; Chitty, 1952, 1954; Godfrey, 1955). This dispro- portionate mortality of young animals may result from three different factors that have already been discussed: (1) they are the subordinate animals in a population and therefore, as we have seen, are much more severely exposed to sociopsychologic pressures than older and more domi- nant animals; (2) they appear to be more sensitive to these pressures and respond accordingly; and (3) they are adversely affected by deficient lactation on the part of their mothers, and then- progeny in turn are affected. The combination of these factors would be expected to have pro- found effects on the young, and we have already seen that their reproduc- tive function is severely depressed. Excessive stimulation of the adaptive responses in these animals would also be expected to result in exhaustion and shock. Frank (1953) has shown that socially inferior voles are the ones primarily affected and that succumb to shock. In addition to these effects of social pressure and increased activity of physiologic adaptive responses, one would anticipate a marked decline in resistance to infection, parasitism, or other harsh environment experiences. It is not surprising that epidemics are frequently observed following peak densities and a general decrease in host resistance. It is particularly signifi- cant that a variety of agents may be found to produce death in a given population, apparently as a result of decreased resistance (Chitty, 1954) . It is not the intent of this account to dwell on the causes of mortality in natural populations except insofar as a decreased resistance may result from 322 J- J' Christian increased physiologic adaptation to increased density. A causal relation- ship between population density and parasitism in hares is suggested by the studies of Erickson (1944). Parasites were scarce when population densities were low and maximiun parasitism was found in populations of hares at peak densities. The hare populations declined but the parasites remained abundant in the surviving animals. There was no evident correlation between shock disease and the parasites in these hares other than that parasitism was at high levels when the population began to decline owing to shock. Similarly, a close correspondence between the level of parasitism of rabbits by Eimeria stiedae and population density was found in New Zealand (Whittle, 1955) and it was suggested that the differences in the incidence of severe infections were correlated with differences in host re- sistence, which in turn may have been a function of host density (Bull, 1955, 1957, 1958). It is of interest that young rabbits were the ones pri- marily affected in these populations (Tj^ndale-Biscoe and Williams, 1955; Bull, 1958). In a study on parasitism by lice on populations of Microtus penrisylvanicvs and Peromyscus maniculatus it was found that the level of parasitism varied with season in both the voles and the deer mice, but that the size of the louse population changed significantly with season only in the male voles (Cook and Beer, 1958). It was suggested that the spring maximum in the louse populations on the male voles came at the period of greatest "stress" and therefore the increase in the louse population at this time resulted from decreased host resistance. The evidence for a decrease in host resistance to specific diseases or parasitism in natural populations is not conclusive, but is certainly sugges- tive. However, there can be little (luestion that there are severe physiologi- cal derangements associated with high population densities which result in high mortality rates in voles, lemmings, and hares (Green and Evans, 1940b; Elton, 1942; Rausch, 1950; Chitty, 1952, 1954; Frank, 1953; God- frey, 1955), and that this mortality cannot be accounted for by infectious disease, even though the prevalence of infection and parasitism may be increased. It is equally evident that young animals are more severely af- fected than older animals and that the effects are prolonged and account for continued declines in populations for appreciable periods following a sharp reduction in population density (Chitty, 1952, 1954, 1955; Christian and LeMunyan, 1958; Christian, 1959a, b). In summary, there is much indirect evidence indicating that a decline of a population from peak densities may be caused by a density-dependent activation of physiologic adaptive mechanisms and exerting their effects in one or all of several ways: 1. There may be direct mass mortality due to physiologic exhaustion following prolonged, excessive stimulation of the adaptive mechanisms. 2. Endocrines and Populations 323 2. There may be increased mortality due to parasitism or infectious disease due to decreased host resistance (presumably from suppression of inflammatory and immune defense mechanisms by increased adreoncortical activity) . 3. There may be partial or complete inhibition of reproductive function, especially in the younger animals and with prolonged effects on the next generations of progeny, apparently initiated by deficient lactation on the part of mothers subjected to mcreased density, but also owing to the fact that the young probably are most severely affected by increased density. It is assumed that in the absence of mass mortality normal or moderately increased mortality rates can produce striking declines in density when reproduction is partially or wholly suppressed. The bulk of evidence in the literature indicates that this is more usually the case than mass mortality. Furthermore, food shortages, epidemics, or predation may be the immediate cause of the mortality, although it is equally clear that the mortality still occurs when these factors are absent (Elton, 1942; Rausch, 1950; Chitty, 1954; Godfrey, 1955; Pitelka, 1957a, b). It is also possible that some pre- cipitating factors may act through the physiologic adaptive mechanisms by increasing intraspecific strife, as was shown to be the case in experimental populations of voles (Frank, 1953). 4. Summary: Natural Populations There is considerable evidence to indicate that there is a density-de- pendent increase in the activity of physiologic adaptive mechanisms in natural populations of Norway rats, voles {Microtus, Clethrionomys, Dicro- stonijx, Lemmus, Ondatra), hares (Leptis), rabbits {Onjctolagus) , white- footed mice (Peromijscus) , and probably other species. A relationship be- tween population density and adrenocortical activity has been demon- strated for Norway rats, meadow voles {Microtus niontanus and M. pennsylvanicus) , white-footed mice (Peromyscus leucopus), and sika deer (Cervus nippon). An inverse relationship between density and reproductive function exists for Norway rats, red-backed voles (Clethrionomys) , meadow voles {Microtus agrestis, M. montanus, M. californicus, M. pennsylvanicus), muskrats {Ondatra), cotton rats {Sigmodon), and hares (Lepus). However, in few of these studied were reproductive function and adrenocortical func- tion correlated in the same population. Furthermore adequate assessment of other envu-onmental factors has not been made. In many investigations there were no adequate means of determining age, so that a true indication of the degree of inhibition of reproductive function was not possible, espe- cially with a simultaneous suppression of growth. Determinations of age should be possible in a variety of species if a concerted effort is made to find the proper criteria. There is evidence that, as in the laboratory, 324 /. /. Christian there is suppression of lactation, as well as of other reproductive functions, with increased density which may account for the prolonged effects of high density on the young. However, the effects of high density may also be exerted on the young animals directly. There is also evidence that resistance to disease and parasites is decreased, especially m the young, at high popula- tion densities. In extreme cases, there may be mass mortalities of popula- tions due to hypoglycemic shock, presumably following exhaustion of some part of the entire physiologic mechanism or of the reserves of readily available necessary metabolites or both. None of the data from natural populations is conclusive evidence that density-dependent responses of physiologic adaptive mechanisms are active in the regulation and control of the growth of mammalian populations. However, when the available evidence is viewed in the light of the results obtained from carefully controlled studies on laboratory populations, there is sufficient reason to conclude that these mechanisms are operative in natural mammalian populations, and more precisely in populations of rodents and lagomorphs. It is equally apparent that sociopsychologic pres- sures are the stimuli to the various physiologic responses involved. There- fore, there is a wide range in responses in the individuals of a population, the subordinate, and therefore younger, animals being the most severely involved. Finally, it appears that these sociopsychologic-physiologic mecha- nisms are basic controlling factors in populations of mammals and other factors are secondarily important in most cases. There is a great need for a coordinated study on a small rodent for which there are criteria for determming age in which adrenocortical function, re- productive function, resistance to disease, mortality, social factors, and enviroilmental factors, can be adequately studied for a complete cycle of the population. Until the results of such a study are available, conclusions regarding density-dependent physiologic mechanisms must lean heavily on extrapolations from data gathered from experimental populations in the laboratory. There are in addition to the general problem many specific problems that need investigation. Many of these have been mentioned m the course of the discussion, but a few have not. A major problem is what factors determine where the reproductive process will be affected in a particular population. For example, why is it intra-uterine mortality in one case, total inhibition of reproductive function in another, and depressed lactation in a third? The explanations are largely conjectural at present, but that these differences exist cannot be questioned, yet all represent a common mechanism and effect: inhibition of reproduction. The answer to another question may provide the answers to those already asked : how do social pressures affect the individual members of a population? 2. Endocrines and Populations 325 III. Conclusion The first part of this chapter reviewed briefly the endocrine adaptive mechanisms which are of unquestionable importance in enabling mammals to meet and adapt to their constantly changing environment and the visic- situdes of daily existence. The mechanisms discussed are by no means the only adaptive responses which are evoked by environmental exigencies, but they are the better known ones and at the present time those which are most Hkely to be of interest to mammalogists, ecologists, and students of mammalian population dynamics. The first part of the chapter was in itself a summary review of these responses; so no useful purpose would be served by further condensing and .summarizing at this point. However, it should be emphasized that one is not justified in regarding any single response, for example increased adrenocortical activity, as an isolated phenomenon complete unto itself and independent of any other changes. Any adaptive response initiates and is a part of an extremely complex series of physio- logic changes which probably involve every aspect of the host's physiology and metabolism. Furthermore, the adaptive responses are not static affairs, but a system of dynamic changes in the nature of feedback mechanisms which operate to maintain a constant internal environment and life. As stated earlier, these mechanisms are undoubtedly constantly active and responding to even minor changes encountered in daily life. Emphasis is lent to this statement by the hypoactive physiologic state observed in closely confined, inactive, and overfed mammals. Therefore one should regard the adaptive responses that are customarily studied and reported merely as quantitative deviations from "normal" daily experience. Finally, we should regard physiologic adaptations as flexible in that the available evidence indicates that qualitatively different stimuli probably do not elicit qualitatively similar responses even though cursory examination may seem to contradict this statement. The components of the responses prob- ably differ proportionally from each other with differing stimuli. It is true that certain organ systems are primarily responsive to the demands of external change, but their responses appear not to be identical, either quantitatively or qualitatively, to all stimuli. For example, we have seen that heat and cold elicit quite different responses, while emotional stimuli evoke a third and different set of reactions, although all three may have certain features in common. Therefore a plea is again made to examine adaptive responses in the light of the specific stimuli by which they were elicited. Generalization serves an extremely useful purpose conceptually, but it may be misleading in the interpretation of results from critical studies designed to explore physiologic adjustments to specific stimuli. 326 J- f- Christiau iMiuill}', what has been presented here only represents a selected stopping point in a very rapidly advancing field of research and must, perforce, be used as such and modified in the light of newer developments. The second part of this chapter attempted to review critically the evi- dence from the laboratory and from the field relating physiologic adaptive responses to changes in population density, largely in response to poorly defined sociopsychologic factors. There seems to be little doubt that endo- crine adaptive responses to sociopsychologic pressures are of basic import- ance in the regulation of population growth, at least for a limited number of species. It also is obvious that a great many gaps remain to be filled before the evidence for the physiologic regulation of natural populations can be considered conclusive one way or the other except for a few species of rodent. These gaps have been pomted out in the appropriate portions of the foregoing discussions. Nevertheless, considerable support has been derived in the last ten years for the original hypothesis that factors inti- mately related to population density are stimuli to physiologic feedback mechanisms and that population growth and decline are largely controlled by changes in density. It has also become evident that "density" in terms of mammalian populations is related only indirectly to numbers of mammals per unit of area, being more directly related to intraspecific competition, social strife, sociopsychologic pressures, or whatever other comparable designation one may choose to use for the interactions between mammals in the same population. It is obvious that these factors require a great deal more study in order to define them precisely. Figure 1 is presented as a schematic summary of the physiologic feedback n^gulation of population growth as it is envisioned today in the light of the available experimental evidence. It should be re-emphasized that this is a dynamic and flexible system and that the importance of various compo- nents may vary with respect to each other. The broad ascending arrows on the left of the figure indicate that as population size increases, social pres- sures increase accordingly. The dotted lines above and below the arrow for population increase serve to indicate that the actual population size may vary considerably from population to population for a given degree of social pressure, which we see hypothetically as the fundamental growth-regulating and growth-limiting factor in all mammalian populations and the factor to which physiologic adaptive mechanisms respond. However, that this factor is always present and always operative does not necessarily imply that it is always the factor which limits population growth. Environmental factors probably operate through this mechanism by increasing or decreasing social pressures, although conclusive evidence for this statement presently is lacking. There is good e^'idence, howe\^er, that the social factors will limit population growth despite an abundance of all environmental requirements and that the degree of social density is related to the behavioral composition 2. Endocrines and Populations 327 i lie O * E < Itul o z 5 w O" O ; = < <= 2 - z • c £ 2 < o z ^ c ^ "- < -o - 328 /• J- Christian (A the population. As social pressure increases, it acts as a progressively stronger stimulus to physiologic adaptation via the mechanisms on the right of the broken vertical line. These in turn act to decrease reproduction and increase mortality, and therefore the rate of population growth declines with increasing density and eventually ceases, as indicated by the"reproduc- tion" and "mortality" arrows on the left. We have already seen that repro- duction may cease altogether at maximmii densities and that mortality may achieve precipitous proportions. An alteration in age composition of the population is assumed to be inherent m these effects. The details of the various mechanisms have been discussed earlier, and will not be discussed further here. However, it is hoped that this diagram will help in visualizing the dynamic mterrelationships between the endocrine responses in the members of the population to changes in the population as a whole. It will be observed that a food deficiency has been shown as decreasing directly the production of gonadotropins, but, as we have discussed earlier, it may serve to increase competition and therefore effective density under some circumstances. Theoretically it seems unlikely that a food deficiency would reach proportions in natural populations which would enable it to exert its effects dhectly on the pituitary without competitive factors first becoming operative. This diagrammatic hypothesis appears to fit the facts available for a Imiited number of studies on a few species of rodent, and undoubtedly it will be necessary to modify it as information from more critical studies become available. It is of primary importance to obtain results from careful studies on ungulates, similar to those already conducted on rodents, before regulation of population growth of ungulates by sociopsychologic-physio- logic feedback mechanisms can be considered to be more than hypothetical. However, at present it is very probable that these mechanisms are basically important in regulating the growth of populations of rodents and lago- morphs. An attempt has been made ui this chapter to point out the areas where critical data are lackuig and some of the problems and pitfalls which may be encountered in investigating these physiologic phenomena in relation to population density. It is hoped that it will serve as a useful guide for further research by investigators who wish to explore the mechanics of population dynamics. References Ackerman, N. B., and Arons, W. L. (1958). The effect of epinephrine and norepinephrine on the acute thyroid release of thyroid hormones. Endocrinology 62, 723-737. Agate, F. J., Jr. (1952). The possible role of the adrenal cortex in fluid shifts in the ham- ster following renal damage. Ann. N. Y. Acad. Sci. 55, 404-411. Albert, A., Tenney, A., and Ford, E. (1952). The effect of cortisone and corticotropin on the biologic decay of thyroidal radioiodine. Endocrinology 50, 324-326. 2. Endocrines and Populations 329 Allen, J. C. (1954). 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(1937). Die markische Rotenmaus. Analyse einer population. Markische Tierewelt 3, 24-40. Zweifach, B. W. (1952). Functional deterioration of terminal vascular bed in irreversible hemorrhagic shock. Ann. N. Y. Acad. Sci. 55, 370-380. Zweifach, B. W., Shorr, E., and Black, M. M. (1953). The influence of the adrenal cortex on behavior of terminal vascular bed. Ann. N. Y. Acad. Sci. 55, 626-633. Zwemer, R. L. (1936). A study of adrenal cortex morphology. A7n. J. Pathol. 12, 107-114. Zwemer, R. L., Wooton, R. M., and Norkus, M. G. (1938). A study of corticoadrenal cells. Anat. Record 72, 249-264. Author Index N umbois ill italics indicate the pages on which the complete references are listed. Abrams, G. D., 242, 253, 329 Ackerman, N. B., 233, 328 Agate, F. J., Jr., 244, 328 Albert, A., 232, 328 Allen, J. C, 196, 282, 329 Allen, J. M., 196, 201, 213, 329 Alpert, M., 194, 196, 329 Altzuler, N., 227, 335 Amiot, L. W., 97, 187 Amromin, D., 209, 254, 351 Anderson, C. H., 202, 203, 204, 209, 213, 329, 338 Anderson, E., 206, 212, 218, 257, 258, 283, 285, 329, 3U, 348 Andervont, H. B., 269, 275, 329 Angevine, D. M., 256, 331 Angrist, A. A., 208, 210, 346 Anigstein, L., 210, 256, 352 Antopol, W., 282, 329 Arons, W. L., 233, 328 Aronson, S. M., 210, 256, 349 Asling, C. W., 196, 292, 329, 341 Austin, C. R., 222, 333 Axelrod, A. A., 238, 343 Aycock, W. L., 221, 328 Ayres, P. J., 200, 329 Bachman, R., 193, 329 Badrick, F. E., 233, 235, 329 Baeder, D. H., 209, 241, 349 Bahn, R., 212, 218, 283, 329 Bahn, R. C, 203, 206, 207, 208, 209, 212, 218, 219, 283, 329, 335, 352 Baker, B. L., 209, 211, 222, 242, 253, 254, 257, 272, 329, 330 Baker, J. R., 221, 330 Baldridge, G. D., 256, 344 Ball, W. C, Jr., 204, 335 Barber, J. K., 204, 330 Barkalow, F. S., Jr., 318, 330 Baiker, S. B., 229, 330 Barnett, S. A., 131, 185, 257, 265, 266, 269, 303, 330 Barraclough, C. A., 221, 330 Barry, M. C, 249, 330 Bartter, F. C, 201, 202, 203, 204, 330, 344, 346 Bascom, W. D., 213, 348 Bastenie, P. A., 232, 330 Bates, R. W., 240, 285, 331, 348 Bauman, E. J., 227, 345 Beer, J. R., 305, 322, 330, 334 Beetham, W. P., Jr., 223, 226, 339 Bell, G. H., 223, 224, 225, 330 Bell, J. F., 225, 253, 320, 340 Bell, W. R., 215, 334 Benfey, B. G., 214, 215, 348 Benua, R. S., 196, 197, 330, 342 Berry, M. M., 235, 351 Berson, S. A., 232, 330 Bethune, J. E., 223, 226, 339 Beyler, A. L., 292, 330 Biglieri, E. G., 202, 203, 204, 330 Bing, R. J., 244, 331 Birdsell, J. B., 97, 99, 185 Birmingham, M. K., 216, SS/ Black, M. M., 209, 353 Bloch, E. H., 206, 244, 331, 344 Block, H., 257, 279, 351 Boas, N. F., 240, 331 Bogdanove, E. M., 230, 232, 331, 341 Bogoroch, R., 235, 331 Bohanan, E. H., 257, 274, 331 Bois, P., 238, 255, 331, 349 Boring, W. O., 256, 257, 331 Borris, J. J., 206, 207, 208, 209, 212, 218, 219, 283, 352 Botkin, A. L., 233, 331 Bourliere, F., 312, 331 Bourne, G. H., 193, 194, 331 Bradlow, H. L., 206, 207, 219, 249, 331 Braidwood, R. J., 97, 99, 185 Bridgman, R. M., 242, 253, 329 Brimblecombe, R. W., 233, 235, 257, 329, 355 356 Author Index Broadbent, D. E., 70, 1S5 Brobeck, J. R., 213, 345 Broderick, C. B., 100, 187 Brown, D., 215, 351 Brown, R. Z., 287, 2S8, 294, 295, 331 Brownell, K. A., 193, 194, 198, 223, 224, 227, 228, 261, 341 Brown-Grant, K., 231, 232, 233, 234, 235, 236, 331 Bruce, H. M., 239, 331 Bull, P. C, 322, 331, 332 Bullough, W. S., 198, 210, 269, 332 Burks, R., 215, 351 Burn, J. H., 225, 332 Burrill, M. W., 259, 340 Burrows, H., 211, 218, 219, 258, 270, 288, 289, 292, 332 Bush, I. E., 206, 207, 208, 212, 219, 332 Butt, A. J., 209, 349 Byrnes, W. W., 211, 212, 220, 257, 258, 259, 309, 332 Cain, A. J., 195, 332 Caldwell, T. M., 82, 184 Calhoun, J. B., 4, 6, 26, 32, 39, 43, 44, 81, 82, 87, 92, 93, 97, 101, 132, 138, 140, 148, 150, 161, 165, 168, 185, 273, 289, 291, 294, 298, 303, 332 Cannon, W. B., 224, 332 Cantarow, A., 234, 235, 350 Caplan, R., 230, 351 Carlson, L. D., 228, 234, 342, 352 Carpenter, C. R., 90, 91, 185 Casby, J. U., 4, 6, 26, 39, 43, 44, 81, 165, 185 (::asper. A., 204, 335, 346 Cater, O.B., 195, •1\:^,332 Cavazos, 289, 332 Cervantes, L. F., 100, /57 Chang, M. C, 288, 332 Charipper, H. A., 272, 273, 334 Chart, J. J., 199, 2m, 388 Cheek, W. R., 215, 2X^,340 Chitty, L)., 89, 179, 185, 242, 251 , 2(\\ , 264, 272, 273, 275, 276, 313, 316, 321, 322, 323, 332, 333 Chitty, H., 222, 242, 261, 2o4, 272, 333 Christian, J. J., 189, 197, 202, 210, 220, 221, 222, 225, 226, 242, 244, 246, 247, 250, 251, 255, 257, 25S, 259, 260, 2(i2, 264, 265, 266, 267, 268, 269, 27.), 271, 272, 273, 274, 275, 276, 277, 279, 280, 281, 282, 285, 286, 287, 288, 289, 290, 291, 292, 294, 295, 296, 297, 298, 299, 301, 302, 303, 304, 305, 306, 309, 310, 311, 313, 315, 317, 319, 320, 321, 322, 327, 333, 334, 349 Christianson, M., 195, 334 Chu, J. P., 239, 334 Clarke, J. R., 242, 251, 263, 272, 281, 291, 292, 294, 296, 303, 334 Clayton, G. W., 213, 215, 216, 334, 340 Cohen, A. I., 206, 331 Cole, D. F., 204, 334 Collias, N. E., 96, 186 Collins, J., 234, 235, 240, 341 Cook, E. F, 322, 334 Cornfield, J., 285, 348 Crabb, E. D., 255, 344 Crew, F. A., 268, 269, 274, 334 Critchlow, B. v., 257, 334 Cronin, M. T. I., 244, 347 Crowcroft, P., 221, 281, 286, 287, 288, 289, 290, 291, 292, 294, 308, 334 Curley, F. J, 221, 334 Cun-ie, A. R., 198, 205, 217, 248, 351 DahllxMg, B. L., 95, 96, 185 D'Angelo, S. A., 231, 232, 233, 234, 257, 258, 272, 273, 334, 350 Davidson, C. S., 212, 213, 219, 334 Davidson, J. N., 223, 224, 225, 3,30 Davis, D. E., 247, 257, 264, 265, 266, 277, 278, 298, 301, 302, 303, 306, 307, 309, 310, 311, 320, 333, 334, 335 Davis, J. O., 202, 203, 204, 335, 352 Davis, M. E., 210, 259, 335 Dawson, J., 242, 274, 335 Deane, H. W., 194, 195, 198, 201, 217, 248, 335, 340, 343 Deanesly, R., 196, 197, 334 DeBodo, R. C, 227, 335 Deevey, E. S., Jr., 97, 185 Delea, C. S., 202, 203, 204, 330 Delea, C, 204, 330 Delfa, E., 239, 343 Delost, H., 196, 336 Delost, P., 196, 197, 218, 219, 220, 283, 335, 336 Dempsey, E. W., 195, 198, 217, 238, 248, 253, 336 Deeney, R., 163, 186 Author Index 357 Denison, iM. E., 238, 239, 257, SS6 Desaulles, P., 255, 277, 346 Desclin, J., 219, 336 Despointes, R. H., 223, 224, 339 Dixon, W. J., 288, 350 Dobriner, K., 207, 249, 330, 331 Dorfman, A., 209, 336 Dorfman, R. I., 206, 207, 208, 209, 212, 218, 219, 250, 253, 259, 336, 347 Dougherty, T. F., 208, 209, 210, 211, 249, 250, 254, 255, 256, 336, 348 Doyle, D., 235, 347 Drager, G. A., 214, 336, 347 Duff, W., 99, 186 Duncan, L. D., Jr., 204, 330 Duncan, L. E., 202, 203, 204, 344 Eberhard, T., 235, 347 Egdahl, R. H., 213, .350 Ehrich, W. E., 209, 210, 238, 242, 253, 259, 260, 336, 349 Eidinoff, M. L., 249, 330 Eik-nes, K., 265, 336 Eisenstein, A. B., 200, 222, 336, 341 Elias, H., 194, 195, 196, 337 Eliot, T. S., 244, 344 Elmadjian, F., 223, 226, 227, 244, 337 Elton, C, 82, 186, 322, 323, 337 Emlen, J. T., 271, 281, 284, 285, 287, 288, 289, 293, 296, 297, 298, 345, 350 Engel, F. L., 209, 244, 337 Erachkoo, ()., 198, 225, 227, 337 Erickson, A. B., 322, 337 Ermans, A. M., 232, 330 Errington, P. L., 298, 317, 337 Ershoff, B. H., 234, 337 Evans, C. A., 321, 322, 339, 340 Evans, E. S., 228, 337, 349 Evans, H. M., 199, 227, 228, 346 Everett, J. W., 257, 258, 337, 345 Fainstat, T. D., 210, 221, 259, 338 Farrell, G. L., 199, 202, 203, 204, 206, 20s, 209, 213, 215, 329, 337, 338, 350 Feldman, J. D., 195, SS5 Finerty, J. C., 237, 270, 284, 292, 341, 347 Finland, M., 208, 209, 210, 211, 255, 256, 343 Fitch, H. S., 317, 338 Fleming, R. B., 202, 203, 209, 213, 338 Flexner, L. B., 195, 338 FHck, S., 309, 338 Flueckiger, E., 232, 338 Flyger, V., 306, 320, 332 Foenss-Bech, P., 209, 213, 344 FoUey, S. J., 275, 328 Foot, E. C., 289, 343 Ford, E., 232, 328 Fortier, C., 213, 215, 216, 257, 338, 341 Frank, F., 225, 253, 272, 280, 298, 320, 321, 322, 323, 338 Eraser, F. C., 210, 221, 259, 338 Fredericson, E., 47, 186 Fredrickson, D. S., 227, 338 Freedman, H. H., 234, 238, 338 French, L. A., 213, 350 Fruit, K., 21^,345 Furth, J., 206, 212, 218, 283, 329 Gaddum, J. H., 223, 224, 225, 226, 227, 338 Gallagher, T. F., 206, 207, 218, 219, 249, 330, 331, 338 Gann, P. S., 203, 204, 330 Ganong, W. F., 338 Gaunt, R., 199, 201, 338 Gersh, I., 194, 196, 339 Gerwing, J., 236, 237, 339 Geschwind, I. I., 209, 213, 344 Gierlach, Z. S., 235, 341 Giroud, C. J. P., 199, 200, 202, 339, 350 Glaubach, S., 210, 259, 339 Glazer, N., 103, 186 c;iick, D., 196, 339 (iodfrey, G. K., 321, 322, 323, 339 Godwin, J. T., 278, 350 Goldberg, R. C, 232, 339 Goldfien, A., 223, 226, 339 Goldstein, M. S., 209, 223, 347 Goodkind, M. J., 204, 335 Goodman, H. M., 227, 339 Gordon, A. S., 211, 234, 238, 249, 251, 252, 254, 256, 272, 273, 334, 338, 339 Gordon, R. S., Jr., 227, 338 Gorski, R. A., 221, 330 Gould, R. P., 200, 329 Gowenlock, A. H., 201, 350 Grad, B., 240, 339 Grant, J. K., 198, 205, 217, 248, 351 Gray, G., 228, 342 Gray, I., 223, 226, 339 Gray, S. J., 242, 253, 339 358 Author Index Green, J. D., 213, 214, 339 (iiven, R. G., 225, 253, 320, 321, 322, 83.9, 340 Greene, R. U., 259, 340 Greep, R. ()., 195, 198, 201, 217, 232, 248, 335, 339, 340 Greer, M., 230, 351 Greer, M. A., 232, 234, 257, 258, 340, 352 Griffin, A. C, 213, 352 Grollman, A., 194, 195, 196, 338, 339 Gross, F., 199, 201, 340 Gross, J., 231, 341 Grosvenor, C. E., 258, 275, 340 Guettirigor, R. C, 95, 96, 185, 186 Guillemin, R., 213, 215, 216, 334, 340, 348 Hagen, P., 223, 340 Halberg, F., 285, 352 Halkerston, I. D. K., 257, 331 Hall, C. E., 202, 284, 341, 348 Hall, C. S., 89, 186 Hall, 0., 284, 341 Hallowell, A. I., 98, 186 Halmi, N. S., 230, 232, 331, 341 Hamilton, W. J., Jr., 308, 317, 320, 341 Hammond, J., Jr., 257, 341 Hamolsky, M. W., 235, 341 Hardin, G., 77, 186 Harris, G. W., 213, 231, 232, 233, 234, 235, 236, 331, 341 Harrison, R. G., 194, 195, 196, 332, 341 Hart, P., 279, 34I Hartcroft, P. M., 200, 336, 341 Hartman, F. A., 193, 194, 198, 223, 224, 227, 228, 261, 341 Hatfield, D. M., 317, 341 Hauser, E. A., 209, 349 Hayashida, T., 209, 213, 344 Haymaker, W., 257, 329 Hayne, D. W., 81, 186 Hearn, W. R., 215, 216, 340 Hellman, K., 234, 235, 240, 341 Hellman, L., 218, 219, 338 Hess, M., 237, 239, 270, 284, 292, S4I, 347 Hill, R. T., 220, 341, 342 Hoffmann, R. S., 314, 317, 342 Hofmann, F. G., 206, 309, 342 Hollander, V. P., 206, 209, 347 Holman, J., 204, 335 Holmes, W. M., 196, 197, 342 Holzhauei', M., 223, 224, 225, 226, 227, 338 Hope, J. M., 223, 226, 227, 244, 337 Hopsu, v., 225, 227, 337 Horn, E. H., 238, 342 Housholder, D. E., 215, 216, 3^0 Howard, E., 195, 196, 197, 212, 217, 330, 342 Hsieh, A. C. L., 228, 342 Hudyma, G. M., 238, 349 Huggins, C, 292, 342 Hughes, E., 306, 342 Hume, D. M., 216, 342 Hungerford, G. F., 209, 213, 344 Hurst, v., 235, 240, 342 Hutchinson, G. E., N., 77, 186 Ingalls, T. H., 221, 329, 334, 342 Ingle, D. J., 208, 209, 211, 253, 257, 329, 330, 342 Irving, J. T., 210, 342 Isler, H., 238, 343 Ivy, A. C, 259, 340 Jacot, B., 213, 284, 292, 343 Jaffe, H., 233, 235, 352 Jameson, E. W., Jr., 307, 343 Jenkins, D., 285, 351 Jennings, H. H., 154, 186 Jensen, E. V., 292, 342 Jensen, H., 235, 341 Jensen, W. L., 320, 335 Jones, G. E. S., 239, 343 Jones, I. C, 193, 195, 196, 197, 199, 200, 201, 206, 207, 208, 209, 213, 215, 217, 218, 219, 254, 261, 283, 334, 343, 347, 352 Josimovich, J. B., 195, S.^5 Kaljat, C., 96, 186 Kalas, J., 241, 349 Kalela, O., 221, 300, 308, 311, 314, 343 Kalter, H., 210, 221, 259, 338, 343 Kappas, A., 218, 219, 335 Kass, E. H., 208, 209, 210, 211, 255, 256, 343 Katonah, F., 208, 210, 346 Katsh, G. F., 256, 339 Kedda, L., 206, 212, 218, 283, 329 Kelsall, M. A., 255, 344 Kemp, C, 233, 235, 352 Author Index 359 Kendrick, M. I., 208, 210, 211, 255, S4S Keuning, F. J., 211, 255, 344 Kew, M., 99, 186 Kirschner, L., 232, 233, 250, 346 Kligman, A. M., 256, 344 Kliman, B., 203, 204, 336, 352 Knigge, K. M., 194, 196, 206, 344, 348 Knisely, M. H., 244, 344 Knobil, E., 227, 339 Kraatz, C. P., 239, 344 Kracht, J., 235, 344 Kraintz, L., 232, 233, 250, 346 Kramer, J., 209, 344 Kuhl, W. J., Jr., 232, 344 Kurlents, E., 216, 331 Kurzok, R., 346 Ladman, A. J., 195, 343 Laidlaw, J. C, 285, 351 Lamson, E. T., 223, 226, 227, 244, 337 Lanman, J. T., 195, 344 Laqueur, G. L., 215, 257, 258, 338, 344 Larson, C. L., 225, 253, 320, 340 Leathern, J. H., 288, 344 Leblond, C. P., 238, 240, 339, 343 LeMaistre, C. A., 210, 279, 344 Le Munyan, CD., 257, 258, 260, 274, 275, 290, 294, 298, 313, 315, 322, 333 Leopold, A. S., 24, 186 Leslie, P. H., 242, 261, 264, 272, 333 Levy, A. C, 227, 344 Li, C. H., 199, 209, 211, 212, 213, 219, 227, 257, 292, 329, 330, 344, 346 Lichtlen, F., 199, 201, 340 Liddle, G. W., 202, 203, 204, 330, 344 Lieberman, S., 206, 212, 219, 351 Lillie, R. D., 253, 344 Lipner, H. J., 230, 341 Lipscomb, H. S., 213, 215, 216, 340 Lipsett, M. B., 218, 219, 338 Long, D. A., 236, 237, 339 Long well, B. B., 206, 347 Lord, R. A., 278, 344 Lostroh, A. J., 199, 209, 212, 213, 219, 289, 344, 345 Louch, C, 284, 285, 345 Louch, C. D., 252, 281, 284, 285, 290, 292, 293, 294, 296, 297, 304, 305, 345 Lundgren, M. M., 209, 210, 256, 343 Lutwak-Mann, C, 222, 259, 273, 288, 289, 309, 310, 345 Lyons, W. R., 209, 213, 344 McCain, R., 24, 186 McCally, N., 202, 203, 204, 209, 213, 329, 338 McCann, S. M., 213, 214, 257, 258, 344, 345 McCarthy, H. H., 209, 344 McDermott, W., 210, 279, 344 McDonald, R. K., 215, 345 Mac Lulich, D. A., 319, 345 Mc Nutt, S. H., 196, 352 McPhail, M. K., 196, 197, 217, 282, 345 Mahler, R. F., 201, 350 Manly, B. M., 257, 330 Mann, T., 288, 289, 345 Mall, R., 306, 342 Magsood, M., 238, 345 Marine, D., 227, 345 Markee, J. E., 257, 258, 345 Marmorston, J., 215, 348 Marrian, G. F., 222, 257, 345 Martin, E. P., 317, 345 Martorano, J. J., 253, 345 Mason, J. W., 244, 253, 267, 268, 346 Meier, R., 255, 277, 346 Meites, J., 235, 347 Melampy, R. M., 289, 332 Melby, J. C, 213, 350 Menkin, V., 254, 346 Merrill, P., 232, 233, 250, 346 Meyer, R. K., 211, 212, 220, 252, 258, 259, 284, 285, 305, 330, 332, 345, 350 Meyers, V. M., 209, 344 Miller, R. A., 196, 346 Mills, I. H., 202, 203, 204, 330, 346 Mirskaia, L., 268, 269, 274, 334 Money, W. L., 232, 233, 234, 237, 250, 346 Moon, H. D., 199, 209, 212, 213, 219, 227, 334, 344, 346 Moore, W. W., 257, 258, 346 Mora, P. M., 97, 187 Moreno, J. L., 154, 186 Morgan, B. B., 196, 352 Morin, G., 228, 346 Morse, A., 195, 335 Mosier, H. D., 195, 346 360 Author Index Moss, M.L., 210, 211,3-^6 Mulinos, M. G., 257, 272, 346 Nalbanov, A. V., 257, 258, 346 Nelson, D. H., 206, 207, 208, 346 Nelson, D. M., 216, 348 Nelson, M. M., 222, 257, 260, 273, 350 Nezamis, J. E., 255, 348 Nichols, J, 202, 346 Noble, R. L., 208, 346 Norkus, M. G., 247, 353 Norton, H. W., 257, 258, 346 Nowell, N. W., 215, 216, 346 Oastler, E. G., 198, 205, 217, 248, 351 Ochs, M. J., 196, 339 O'Donnell, U. J., 198, 205, 217, 248, 351 Odum, E. P., 317, 346 Palmer, J. G., 216, 348 Parkes, A. S., 222, 257, 345 Parmer, L. G., 208, 210, 346 Parsons, F. M., 292, 34^ Paschkis, K. E., 234, 235, 347, 350 Patric, E. F., 67, 85, 186 Pauly, J. E., 194, 195, 337, 347 Pearson, O. H., 218, 219, 338 Pearson, O. P., 175, 186 Pechet, M. M., 204, 335 Peron, F. G., 206, 347 Perry, W. F., 232, 347 Peterson, R. E., 203, 204, 335, 352 Philbrook, F. R., 221, 342 Phillips, J. G., 195, 352 Piletta, P., 199, 200, 33i> Pillsbury, D. M., 256, 344 Pincus, G., 288, 332 Pitelka, F. A., 307, 319, 323, 347 Pitt-Rivers, R., 236, 237, 339 Plotz, E. J., 210, 259, 335 Poindexter, H. A., 257, 347 Pollard, M., 210, 256, 347 Pomerantz, L., 257, 272, 346 Poore, W., 206, 209, 347 Porter, J. C., 214, 215, 347 Preble, E. A., 319, 347 Price, D., 288, 289, 345 Pronove, P., 204, 330 Prudovsky, S., 278, 335 Pruitt, R. L., 215, 348 Puntriano, G., 235, 347 Raeisaenen, L., 198, 227, 337 Rail, J. E., 229, 230, 231, 238, 347, 351 Ramey, E. R., 209, 223, 225, 227, 344, 347 Ramey, C. G., 242, 253, 339 Rand, M. J., 225, 332 Randall, H. T., 244, 347 Ransom, R. M., 221, 330 Ranson, S. W., 82, 185, 186 Ratcliffe, H. L., 202, 225, 244, 250, 271, 333, 347 Rausch, R., 318, 320, 322, 323, 347 Rauschkolb, E. W., 199, 202, 203, 208, 209, 213, 338 Rawson, R. W., 229, 230, 231, 232, 233, 238, 250, 346, 347, 351 Read, C. P., 257, 277, 278, 335 Read, H. C., 196, 197, 217, 282, 345 Rebell, G., 256, 344 Reed, C. A., 97, 99, 185 Rees, R. J. W., 279, 341 Reichlin, S., 231, 232, 233, 234, 235, 236, •2-il,331,347 Reif, A. E., 206, 347 Reinhardt, W. O., 209, 213, 344 Reineke, E. P., 237, 238, 345, 352 Reinhardt, W. O., 292, 329 Reiss, J. M., 233, 235, 329 Reiss, M., 233, 235, 257, 329, 331 Rennels, E. G., 214, 270, 284, 292, 34I, 347 Renzi, A. A., 199, 201, 338 Retzlaff, E. G, 268, 269, 274, 277, 315, 347 Richards, J. B., 215, 3^5 Richardson, H. C, 213, 352 Richardson, J. A., 223, 348 Richter, C. P., 195, 198, 202, 348 Riesman, D., 163, 186 Riney, T., 24, 186 Ring, G. C., 234, 348 Rioch, D., 257, 258, 344 Robert, A., 255, 348 Robinson, H. J., 210, 254, 256, 348 Roby, C. C., 196, 343 Rogers, P. V, 195, 198, 202, 348 Rosasco, E. M., 80, 85, 187 Rosemberg, E., 257, 258, 285, 344, 348 Rosenberg, L. L., 349 Rosenfeld, G., 213, 253, 321, 348 Rothballer, A. B., 214, 348 Rowe, F. P., 221, 281, 286, 288, 289, 290, 291, 292, 294, 308, 334 Author Index 361 246, 248, Royce, P. C, 199, 202, 203, 208, 213, .338 Rumsfeld, H. W., Jr., 214, 215, 347 Runfret, A. P., 213, 3S3 Sacks, J. G., 82, 185 Saffran, M., 214, 215, S^S Sakiz, E., 218, 348 Salter, W. T., 230, 348 Samuel, L. T., 216, 348 Sandberg, A. A., 216, 3^5 Sanders, R. D., 96, 186 Santisteban, G. A., 208, 211, 250, 348 Sawyer, C. H., 257, 258, 334, 337, 345 Sayers, G., 195, 197, 198, 215, 243, 248, 348, 351 Sayers, M., 195, 197, 198, 243, 246, 348 Scarborough, H., 223, 224, 225, 330 Schaefer, E. S., 143, 155, 162, 186 Schairer, M. A., 257, 329 Schally, A. V., 214, 215, 348 Schapiro, S., 215, 348 Scharrer, B., 214, 348 Scharrer, E., 214, 345 Schindler, W. J., 194, 206, 348 Schmidt, L. H., 256, 349 Schmitenloew, C. G., 224, 349 Schneebeli, G. L., 208, 209, 210, 254, 256, 336 Schneirla, T. C., 89, 186 Schorger, A. W., 96, 186 Schreiner, L. H., 257, 258, 344 Schuler, W., 255, 277, 346 Schwartz, H. S., 229, 330 Scott, J. C., 242, 261, 264, 272, 333 Scudder, J., 244, 349 Sealander, J. A., Jr., 273, 349 Seifter, J., 209, 210, 238, 241, 242, 253, 260, 336, 349 Seligman, A. M., 194, 335 Selye, H., 192, 208, 209, 211, 212, 213, 220, 236, 238, 242, 243, 244, 250, 254, 255, 256, 257, 258, 260, 261, 274, 275, 276, 284, 288, 292, 331, 349 Share, L., 216, 349 Shaw, J. H., 195, 201, 335 Shipley, E. G., 211, 212, 220, 257, 258, 309, 332 259. 217, 253, 264, 343, 259, Shipley, R. A., 206, 208, 212, 218, 219, 250, 259, 336 Shiras, G., 96, 186 Shorr, E., 209, 353 Shwartzman, G., 210, 256, 349 Sideman, M. B., 209, 213, 344 Simay, Kramer, M., 209, 344 Simpson, M. E., 199, 222, 227, 228, 257, 260, 273, 346, 349, 350 Simpson, S. A. S., 200, 329 Sloviter, 239, 331 Slusher, M. A., 215, 216, 248, 349 Smelser, G. K., 240, 349 Smelser, J., 346 Smith, A. L., 210, 254, 256, 348 Smith, E. K., 220, 349 Smith, J. D., 213, 215, 216, 340 Smith, R. W., Jr., 257, 348 Snyder, R. L., 309, 349 Sobel, H., 215, 348 SoUman, T., 229, 230, 231, 238, 349 Sonenberg, M., 230, 231, 238, 347 Southern, H. N., 89, 179, 185, 289, 349 Southwick, C. H., 252, 265, 281, 285, 287, 288, 289, 293, 294, 295, 296, 297,' 3.50 ' Spalding, M. H., 195, 343 Speirs, R. S., 211, 252, 285, 350 Spirtos, B. N., 230, 341 Squires, W. L., 256, 349 Srebnik, H. H., 222, 257, 260, 273, 350 Stachenko, J., 199, 200, 202, 339, 350 Stack-Dunne, M. P., 195, 213, 332 Stadler, J. B., 216, 3^5 Stanbary, S. W., 201, 350 Steinberger, E., 288, 350 Stevens, C. E., 234, 350 Strecker, R. L., 271, 281, 287, 288, 289, 293,296,297,298,350 Stewart, J. O., 97, 186 Stoner, R. D., 278, 350 Story, J. L., 213, 350 Sturgis, S. H., 258, 350 Sundberg, R. D., 211, 350 Sunderman, F. W., 234, 350 Swanson, H. E., 228, 229, 234, 350 Sweat, M. L., 206, 350 Swift, E., 96, 186, 187 Sydnor, K. L.. 215, 351 Symington, T., 198, 205. 217. 248, 351 Szego, CM., 292, 330 362 Author Index Tait, J. F., 200, 339 Tamura, Y., 196, 198, 351 Tanaka, R., 318, 351 Tata, J. R., 229, 351 Taubenhaus, IM., 208, 209, 210, 254, 351 Tenney, A., 232, 338 Tevis, L., Jr., 24, 186 Tew, J. T., 233, 331 Thomas, L., 210, 254, 255, 256, 351 Thompson, D. Q., 318, 351 Thorn, G. W., 285, 351 Thorn, N. A., 241, 351 Timiras, P., 235, 331 Tobach, E., 89, 186, 257, 279, 351 Tompsett, R., 210, 279, 344 Traum, R. E., 231, 232, 233, 234, 257, 258, 334 Turner, C. W., 235, 240, 258, 275, 340, 342 Tyler, F. H., 216, 348 Tyndale-Biscoe, C. H., 322, 351 Uhrich, J., 271, 351 Uotila, U. U., 238, 336 Vander Laan, W. P., 230, 351 Van der Slikke, L. B., 211, 255, 344 Vande Wiele, R., 206, 212, 219, 351 Van Middlesworth, L., 235, 351 Venning, E. H., 200, 339 Verzar, F., 232, 338, 352 Vetulani, T., 276, 352 Vidovic, v., 232, 352 Visscher, M. B., 285, 352 Von Elder, C, 231, 331 Von Elder, U. S., 223, 234, 236, 352 Von Foerster, H., 97, 187 Wagner, H. N., Jr., 215, 345 Walker, D. L., 256, 257, 331 Wallach, D. P., 237, 352 Waring, H., 196, 197, 352 Warner, L., 244, 344 Watt, L. J., 309, 352 Weaver, J. A., 211, 249, 250, 352 Webb, W. L., 32, 80, 82, 85, 185, 187 Weber, A. F., 196, 352 Welch, A. D., 223, 340 West, C. D., 218, 219, 338 Wexler, B. C, 213, 352 Whitney, D. M., 210, 256, 352 Whitten, W. K., 275, 352 Whittle, P., 322, 352 Whyte, W. H., 163, 187, 198, 205, 217, 248, 351 Wiese, V. K., 215, 345 WiUiams, R. H., 233, 235, 352 Williams, R. M., 322, 351 Williamson, H. 0., 255, 257, 277, 334 Wilson, B. R., 210, 256, 347 Wilson, H., 206, 207, 208, 209, 212, 218, 219, 283, 329, 352 Wolff, F., 232, 339 Woodbury, D. M., 213, 216, 352 Woods, E. F., 223, 348 Woods, J. W., 231, 232, 233, 234, 236, 341 Woodward, P., 213, 345 Wooton, R. M., 247, 353 Wright, A., 195, 343, 352 Yalow, R. S., 232, 330 Yamada, T., 234, 352 Yankopoulos, N. A., 203, 204, 335, 352 Yatsu, F. M., 202, 203, 209, 213, 338 Zalesky, M., 196, 353 Zarafonetis, C. J. D., 241, 349 Zarrow, M. X., 238, 239, 257, 336 Ziff, M., 232, 344 ZUeli, M. S., 223, 226, 339 Zimmerman, C. C, 100, 187 Zimmermann, K., 311, 353 Zippin, C, 26, 187 ZuRhein, G. M., 257, 331 Zweifach, B. W., 209, 244, 353 Zwemer, R. L., 247, 353 Subject Index AAF, 216 Aborigines Australian, 99 ACTH, 197, 200, 209, 214, 220, 232, 243 assajdng, 248 basal release rate, 215 A-1 fraction, 203 endogenous, 249 exogenous, 249 inhibiting the release, 215 mice, 237 rabbits, 237 rats, 237 regulation of the release, 213 release, 216, 217 release fraction, 215 secretion, 237, 258 secretion of ADH, 241 secretion of aldosterone, 202 sj-nthesis, 216 Activity hyperactivity, 9 minimal, 9 normal level, 16 normal nocturnal period, 16 24-hour rhj-thm, 9 endocrine glands of, 192 evolutionary, 123 Adaptive mechanisms, 190 atrophy, 244 Adaptive responses measurements of the endocrine, 242 Adenohypophysis, 214, 233 arterial supply, 213 ADH, 201, 214, 241 Adirondacks, 55 Adjustment learned, 89 Adrenal androgen, 206 effect on nursing young, 276 atrophy, 238 ascorbic acid, 248 depletion, 192 Callothrix nrgentata, 196 cat, 195 Cerropithent^, 195, 196 chimpanzee, 195 cholesterol, 192, 193, 248 circulation, 195 Ciiellus tridecemlineatus, 196 Cleihriononiys glareolus, 196 colobus monkej', 196 Colohus polykomos, 196 cortex, 191, 192, 193, 217, 245, 246 hormones, 199 human beings, 212 lipid vacuoles, 194 measurements of increased function, 245 Microsorex hoyi, 246 parenchjina, 195 Sorex cinereus, 246 Sorex dispar, 246 Sorex fumeus, 246 Sorex palustris, 246 secretorj' activity, 248 sex steroids, 219 sex steroidal activity, 218 sudanophilia, 197 X-zone, 217 X-zone of mice, 282 zona fasciculata, 194 zona glomerulosa, 194, 199 zona reticularis, 194 zonation of, 194 demeduUation, 228 cow, 196 Crocidura, 196 gland, 192 effects of h\T5ophysectom\- on, 196 fetal zones of the, 195 general morphology of, 193 ground squirrels, 196 hamsters, 196 histologic measurements, 247 histology, 195 humans, 195, 196 hypertrophj', 238, 246 lipid content, 193 Loris, 196 Macaca mulatta, 195 macaque, 195, 196 marmoset, 196 363 364 Subject Index Adrenal — continued medulla, 193, 198, 223, 224, 245, 246 hypertrophy, 199 Microsorex hoyi, 246 Sorex dispar, 246 Sorex fumerus, 246 /Sorex cinereus, 246 Sorex palustris, tumors, 199 Mesocricetus auratus, 196 mice, 196 Microtus agrestis, 196 Microtus arvalis, 196 monkeys, 195, 196 Ornithorhynchus, 195 Orydolagus, 195 Pan, 195 Perodicus potto, 195 pituitary, 197 Pilymys, 196 potto, 195 primates, 195 rabbits, 195 laboratory rabbit, 195 rats, 195, 196, 198 Norway rat, 195 wild rats, 195, Rattus alexaadrinus, 195 Rattus norvegicus, 195 regulation of hormones, 213 reticularis, 198 samples, 247 slow loris, 196 Sorex araneus, 196 starvation, 196 steroids, 219 steroid secretion, 192 androgenic metabolites, 219 synthesis, 219 Tachyglossus, 195 transplantation, 21 X ungulates, 196 vascularization, 195 weight, 192, 245 factor, 216 fighting, 264 variation, 246 X-zone, 196 Adrenalectomized animals, 201 Adrenocortical activity indices, 21 1 in natural populations, 300 sudanophilia, 248 Adrenocortical-gonadal interrelationships, 218 Adrenocorticotropin, 196, 197, 205, 213, 220, 222 release, 216 secretion, 215 secretion of aldosterone, 202, 205 inaccuracy of determining, 308 Age determination by teeth, 311 Alarm stimulus, 192 Alberta, 54 Albino mice {see also mice) trichinosis, 278 Aldosterone, 199 release, 217, 243 secretion decrease in blood volume stimulates, 204 and pulse pressure, 204 stimulation by decrease in blood volume, 204 regulation, 202, 203 renal hemodynamics, 204 stimulation of, 203 Aliesterase, 200 Alley emotional activity, 177 Alouaita palliata, 90 Alpha individuals, 59 central, 59 Amines pressor, 225 Amine oxidases, 223 Androgen, 217 adrenocortical, 219 cortical, 220 precursors, 206 Androgenic steroids house mice, 220 man, 220 rats, 220 Androstenedione gonadotropic activity, 220 Animal {see also specific animal names), 239 laboratory, 262 .4 ntelioinys sni ithii inhibition of reproductive function, 318 Subject Index 365 Antibody formation, 255, 278 inhibition, 210 Antibodies stored, 21 1 Antidiuretic hormone, 201 Antigonadotrophic activity, 211 Area determination, 84 Ascendency dominant, 55 psychological, 55 Ascorbic acid, 217, 237 adrenal, 216, 248 factor, 216 Associations intraspecific, 64 Audition, 38 Australian aborigines, 97 Avoidance of a strange field, 17 Awareness of self, 150 AWF, 216 Bainbridge cardiac reflex, 230 Balance electrolyte, 192 fluid, 192 Barter Island, Alaska, 318 Basic group size, 113, 125 Basic number, 3 Bats (see also generic names such as My Otis), 193 Behavior, 15, 158 alterations, 94 cultural origin, 124 exploratory, 175 genetic origin, 124 Behavioral sink, 93 development by Norway Rat, 92 Beta individuals, 59 Bivariate normal distribution, 20 function, 4, 39 Blarina, 29, 30, 31, 32, 36, 38, 52, 61, 64, 66, 68, 69, 72, 75, 76, 78, 80 population, 305 Brain subcortical portion, 15 British Columbia Indians of, 99 Broadbent's theory, 70, 72 Brown fat, 194 Cages "life-space," 179 Callothrix argentata, 196 Capture cumulative probability, 21 Carbohydrate-active corticoids suppressive effects, 209 Cl9 steroids, 206, 217, 219 ketosteroids, 205 Caribou, 122 Catch comparative, 29, 30, 31, 32 decline, 56 Huntington WildUfe Forest, 29, 30 Maine (1950) and Maryland (1953), 31 Peromyscus and Clethrionomys, 32 Cattle, 194 Cells inflammatory-, 210 Census 30-day, 53 Central nervous system, 191 integrative role, 242 memory store, 134 Cercopithecus, 195, 196 Cervus nippon, 323 population density, 306 Chadwick Woods, 76 Changes environmental, 190 liver, 260 pancreas, 260 parotid, 260 visceral degenerative, 260 Chimpanzee, 195 Chromaffin cells, 198 tissue, 195, 223, 225 Circulatory collapse, 244 Citellus tridecemlineatus, 196 Clethrionomys, 27, 30, 31, 32, 33, 34, 35, 36, 52, 53, 54, 55, 61, 67, 68, 69, 70, 75, 78, 80, 83, 85, 88, 314, 323 inhibition of growth and reproduction, 316 366 Subject Index Clethrionomys — continued relationship between population densitj' and reproduction, 310 reproductive function, 314 Clethrionomys glareolus, 196 Clethrionomys rujocanus, 311 population density, 308, 313 territory, 300 inhibition of reproductive fun(^tion, 318 Close confinement effects of, 271 Codominants, 67 Cold adaptation, 228 exposure, 234 Colobus polyl'omos, 196 Colony compact, 86 evolution of, 88 Howler monkeys, 90, 92 Norway rat, 92 formation, 87 stability, 89 Communication, 38, 125 low frequency, 59 Communication reduction, 67 vocal, 70 Communication constant, 133 Communication function (/*), 126 Community, 2, 8, 32, 35, 49, 55, 74, 78 Blarina: Peromyscus, 73 one-species, 73 psychological apex, 79 small-mammal, 75 Sorex: Clethrionomys, 73 subordinate member, 78 Competition, 78 food and social, 271 social, 262 "Competitive exclusion," 77 Configuration active rejection of new, 179 physical nonsocial, 183 seeking of new, 178 Conformity, 162 Constellation, 85 adjoining, 60 derivation of compact colonies from, 86 expected viability in, 61 formation, 57 individuals forming, 63 loosely knit, 88 number of individuals forming, (il periphery, 60 theoretical, 62 Contact between individuals, 105 decrease of responsive-responsive, 107 encounters, 106 frequency, 38, 106, 139 frequency of responsive-responsive, 106 individual, 106 refractory, frequency of, 105 responsive-refractory, 103 responsive-responsive, 103 social perception, 136 variables determining, 101 Copulation pressure criticized, 293 Cortex {see also adrenal cortex), 72 adrenocorticotropin, 197 cellular hj^perplasia, 213 fasciculata, 198 h^-pertrophy, 213 Cortical glomerulosa, 216 Cortical hormones relationships, 212 Cortical hyperplasia cortical, 218 Cortical mass increase, 135 Cortical stroma carnivores, 194 rodents, 194 Corticoids carbohydrate-active, 220, 245 secretion, 222 Corticosteroids release, 213 Corticosterone, 205, 206 mice, 208 rats, 208 Corticotropin peptides, 200 Corticotropin-releasing factor, 214 Cortisone, 196, 197, 205, 232 tetratogenic effects in mice, 210 Cotton rat, {see also Sigmodon), 323 Cow, 196 Creativity, 162 Crocidura, 196 Subject Index 367 Crocidura russula, 197 Cultural disturbance, 99 Cynomys ludovicianus, 122 Cytochrome, 230 Cytochrome oxidase, 223, 230 d-gene, 134 differentiation in a similarity rank hierarchy, 142 dominant, 128, 141 recessive, 128, 141 transformation of recessive, 159 DCA, 205 DOC, 205 DOCA, 205 Deer adrenals, 305 Northern Wisconsin, 95 white-tailed, 95 yarding, 95 Deer mice (see also Peromyscus), 322 Dehydroepiandrosterone, 206, 212 Density actual, 53 high, 53 increase, 138 low, 53 low spring, 54 Density function, 4, 6, 44, 45, 47 Cartesian coordinates, 4 Deoxycorticosterone, 196, 199 Diabetes, 241 Dicrostonyx {see also lemming) 323 Dicrostonyx groenlandicus population cycles, 318 Diestrus, 239 Differences morphologic, 190 Diffuse motor activity (DMA), 175 Digestive organs effect of stimuli, 253 Diiodotyrosine, 230 Disease resistance in dense populations, 319 Distance between neighbors, 44 methods of calculating data, 44 Distribution spatial, 58, 59 uniform, 81 Dog adrenal medulla, 225 dominant, 265 hypophysectomized, 233 release of radioiodine, 233 subordinate, 265 secretion of aldosterone, 203 Dominance psychological, 74, 75, 77, 79 Effector, 134 Eimeria stiedae, 322 Electrolyte balance, 201 ll-Deoxycorticosterone, 205 ll-Deoxy-17-hydrocorticosterone, 205 IIB-Hydroxy testosterone, 211 11-0H4AD, 206, 211 Elk, 122 Embrj^o resorption of, 310 Emotional activity alley, 181 Encounters, 106 Endocrine adaptive mechanisms, 191 adaptive responses, 189 function inhibition, 221 organs relationships, 227 Endogenous corticosteroid seci-etion, 2 1 1 Environment abnormal, 108 external, 190 impact on, 43 of all individuals, 44 initial hyperactivity in a strange, 15 internal, 190, 261 optimum uniform utilization, 60 shifts, 190 structured, 11 two-dimensional, S Environmental factors, 190 Eosinopenia, 252 Eosinophil as index of adrenocortical activity, 211 counts, 252, 285 as index of population density, 284 Epinephrine, 209, 216 action, 215 effects, 223, 224 secretion, 226, 227 368 Subject Index Estradiol, 208 Estrus, 239 changes, 258 Evolution, 51 cultural, 98, 122 of a new species or genus, 87 of compact colony, 88 of a filtering device, 134 probable cause, 74 man's social, 184 social, 3, 137 P^acilitation, 151 Factor communication-inhibiting, 112, 139 contact-Winding, 112, 139 Families human, 100 F:B ratio monkeys, 206 mice, 206 rabbits, 206 rats, 206 Feedback mechanisms physiologic, 190 Female asexual, 88 estrus, 89 Ferguson activity allc}', S, 18 Fertility density, 290 female, 239 male, 239 mouse, male, 290 Fetus congenital defects, 210 growth and development, 259 prenatal mortality, 293 resorption, 95 Fighting as a measure of social rank, 267 as form of stress, 264 Filter Broadbent, 71 neural, 71, 74 system, 77 Food limiting population growth, 298 Food scarcity, 98 Food supply effects on population growth, 296 Frequency of meeting of responsive individuals, 112 of meeting of responsive-nonresponsive individuals, 112 Frustrations optimum, 119 FSH, 259 Functions interaction, 113 Gene d-, 128 frequency, 125 mutant, 125 Gene pool, 125 Gamma individuals, 59 Gastrointestinal tract effect of stimuli, 253 integrative role, 242 Glomerular filtration rate, 201 Glomerulotropin, 203, 205 depression, 204 secretion, 204 Glucagon, 240 Glucocorticoids, 245 Glucose utilization inhibition, 209 Glj'cogen exhaustion, 253 showshoe hares, 253 voles, 253 levels factors altering, 253 Glycosuria, 209 Gonadal endocrine cells steroids, 219 Gonadectomy, 219 Gonadotropin, 217, 219 inhibition, 211, 220 production, 211 secretion suppression, 257, 309 Granulation effect of corticoidson, 254 Subject Index 369 Gravidum, 309 Ground squirrels thirteen-lincd, 196 Group dynamics formulation, 101 Group size basic, 3 change, 125 effect on reproduction, 91 optimum, 2 saltatorial changes in the basic, 122 satisfaction and frustration as a function 116 Growth, 254 effects of increased population density, 276 house mice, 299 population, 1S9 Guinea pig harderian glands, 240 hydrocortisone, 236 medullary hypertrophy, 227 pituitary-adrenocortical activity, 273 Guinea pig pneumococcal infection, 256 streptococcal infection, 256 thyroid activity, 236 tuberculosis infections, 256 Habitat, 42 marginal, 45 one-dimensional, 8 unstructured one-dimensional, 9 unsuitabilitj', SO Hamster, 196 golden, 194 poliomj-elitis, 256 sudanophilia, 248 Hare (see also Lepus), 319, 323 mortality, 322 population density and parasitism, 322 relationships between population den- sity and reproduction, 310 Harvest mice, 6 Hematopoiesis, 251 Hibernating gland, 194 Hierarchical situation, 263 Hierarchy formation reductions in velocity of, 153 Histamine, 216 Homeostasis circulator}', 192 electrolyte, 202, 205 fluid, 202, 205 Home range, 20, 25, 36, 38, 42, 164 behavioral origins of the bivariate normal, 8 bivarate normal, 4 center, 4, 23, 39, 42, 43, 47, 57, 58, 72 actual, 64 "ideal" interval between, 45 optimum interval, 51 uniform distribution, 59 clumping, 67 contracted, 54 enlargement, 76 expansion, 68, 79 fixed, 77 inhibition, 53, 78, 80 intraspecific differences in size of, 75 mutual inhibition of, 79 overlapping, 67 periphery, 51 reduction, 70 relative, 165 relative, of constellation members, 166 schematic for Blarina, 65 for Peromycus, 65 for Pitymys, 66 sigma, 5, 6 size, 53 social inhibition, 70 travel-path, 24 Homo sapiens, 57 Hormone antidiuretic, 241 anti-inflammatory, 208 fascicular action, 208 regulation of secretion of the fascicular, 213 Host resistance decrease, 210 effect of crowding, 279 infectious disease, 279 parasites, 279 370 Subject Index House mice {see also mice, mouse, Mus), 140, 148, 180, 197, 251 ACTH and gonadotropin relationship, 260 adrenals, 206 adrenal cortex, 217, 282 adrenal weight, 266 albino, 269 birth rates, 292 competition, 271 competition for food, 297 crowding mortality, 280 decrease in reproduction, 286 food, 296 growth, 276 inanition, 272 inhibited growth, 299 intra-uterine mortality, 221 litter survival, 294 nests, 294 pituitary-adrenocortical activity, 273 resorption of the embryos, 221 responses to increased population den- sity, 281 responses to sociopsychologic factors, 269 self-limited populations, 299 social pressure, 288 spermatogenesis, 288 splenic hypertrophy, 272 trichinosis, 278 wild, 269 wild-stock, 280 Howler Monkeys, 90, 121 Humans, 196 Humans dominant, 132 hyi)othyroidism, 238 responses to sociopsychologic factors, 269 thyroid, 232, 236 Hum field, 41, 50 Humoral substance, 16 Huntington Forest, 27, 61, 82 Hyaluronidase, 209 Hydrocortisone, 205, 236 Hydrocortisone cats, 206 ferrets, 206 guinea pigs, 206 humans, 206 mice, 20^ monkeys, 206 rats, 208 sheep, 206 HjTJeractivity, 175 in a strange environment, 16 Hyperglycemia, 209, 224, 226 Hyperthyroidism, 239 Hj^pertrophy cortical, 216 Hypoglycemic shock, 320, 321 Hypophysectomy secretion of aldosterone, 202, 203 Hypothalamic centers, 216 Indians Kunghit Haida, 99 Individuals alpha, 59, 61, 165 beta, 59, 165 gamma, 59, 165 Infection resistance to, 256 Inflammation effect of corticoids on, 254 Inflection point arithmetic, 121 Inhibitory influence, 38 Input rates, 56 Insulin, 240 Intensity of action, 112 Interaction constant, 115 frequency, 108 frustrating, 119 intensity, 115 maximum frequency, 114 positively affective, 112 refractory, 109 responsive, 109 variables determining, 101 Interconstellation matrix, 60, 68 Intraspecific competition, 263 Intrauterine mortality, 259 Invasion induced, 80 Iodine, 230 Iraq, 99 Islets of Langerhans, 240 Subject Index 371 Isolation spatial, 69 Isolation cage, 17 Jarmo site, 99 Kendall's compound A, 205 B, 205 E, 205 F, 205 Lactation failure, 260 inhibition, 294 Lemming (see also Dicroslonyx and Lemmus), 320 populations cj'clic decline, 319 mortality, 322 population cycles, 318 Lemmus, 305, 323 Lemmus trimucronalus population cycles, 318 Lepus (see also hare), 323 Lepus americanus relationships between population den- sity and reproduction, 310 Life-space quadrants shifts into the second and fourth by rats, 159 Lipid mobilizing factor, 241 Lipogenesis, 209 Litter mortality factors causing, 295 mice, 294 size, 239 survival effect of increasing density on, 295 effect of nests on, 295 factors, 294 mice, 293, 294 voles, 293, 296 Liver, 260 glycogen, 252 LMF, 241 Loris, 196 Lymph nodes weights, 249, 250 Lymphocytes as indices of adrenocortical activity, 21 1 criteria of stress, 251 counts, 251 Lymphocytolysis, 211 Lymphocytopoiesis depression, 211 Lymphocytopoiesis depression, 211 Lymphoid organs nucleic acid content of, 255 Lymphoid tissue growth, 250 involution, 250 Macaca mulatia, 195 Macaque, 196 Maine, 32, 54 Male dominant, 89 rats, pansexual, 162 reduction of, 90 territorial, 161 Mammals {see also specific names) adrenalectomized, 208 European, 196 Man {see also human) 121, 173, 194 anestrus, 220 basic numbers for, 97 corticosteroid production, 268 ovarian atrophy, 220 ^Marking with red dye, 76 Marmoset, 196 Marmota, 193 relationships between population den- sity and reproduction, 310 Marmota monax, 122 Maryland, 32 Montgomery County, 69 Meadow mouse (see Microtus) Medulla {see also adrenal) adrenal, 198 basophilic granules, 198 chromaffin cells, 198 Medullary hyperplasia mice, 198 ungulates, 198 Mesocriceius auratus {see also hamster), 194, 196 Metestrus, 239 372 Subject Index Mice {see also house mouse, AIus, white- footed mice, mouse), 26, 148, 170, 193, 196, 19S, 212, 218, 222, 257, 264, 277, 293, 309 adrenals, 200 adrenal weights, 246 adrenocortical responses, 270 albino, 264 androgen, 221 anestrus, 220 antibody formation, 278 blood level of TSH, 237 corticosterone, 236 Coxsackie infections, 256, 257 decline in birthrate, 291 during pregnancy, 196 effect of new environment, 265 effect of overcrowding, 269 effect of population density, 274 effect of social pressures, 268 eosinophil counts, 252 fighting social competition, 287 gonadotropins, 309 harderian glands, 240 hierarchy, 265 hypoglycemic shock, 321 hypophysectomized, 212 inanition, 222 inbred, 274 inbred albino, 273 laboratory, 196 lactation, 274 medullary hypertrophy, 227 method of inducing an inflammatory response, 277 nursing, 210 ovarian atrophy, 220 ovaries, 220 pituitary-adrenocortical activity, 273 pneumococcal infection, 256 pregnant, 210 preputial glands, 292 radiothyroidectomized, 239 release of iodine, 238 reproduction, 274 reproductive suppression, 275 resistance to infection, 277 shock death, 225 social hierarcy, 264 sociopsychologic interactions, 280 sjjlenic hypertrophy, 242, 273, 274 streptococcal infection, 256 susceptibility to trichinella, 277 testes, 238 thymus, 283 thj'roid activity, 235 trichinosis, 257 tuberculosis, 257, 279 tuberculosis infections, 256 Microsorex hiyi, 193, 246 Microtus (see also voles), 77, 301, 305, 323 hypoglycemic shock, 320 natural populations, 303 relationships between population den- sity and reproduction, 310 "shock disease", 225 Microtus agrestis, 196, 251, 273, 323 behavior, 222 estrous pattern, 222 inhibition of growth and i('])roduction, 316 number of births, 222 respons(>s to increased pf)pulation den- sity, 281 sociopsj-chologic factors, 264 splenic hypertrophy, 273 Microtus arvalis, 196, 218 confined populations, 272 crowding mortality, 280 sex accessories, 219 Microtus californicus, 323 reproduction, 317 Microtus montanus, 305, 316, 317, 320, 323 population density, 303, 314 population fluctuation, 303 Microtus ochrogaster reproduction, 317 Microtus oeconomus population cycles, 318 Microtus orcadensis nucleus pulposus enlargement, 261 sociopsychologic factors, 264 splenic hyjjertrophy, 273 Microtus pcnnsylvanicus, 323 adrenocortical-densitj' relationships, 304 adrenal weight, 285 body-adrenal relationships, 247 effect of increased population density, 284 J Subject Index 373 lice, 322 litter-size, SOS, 317 population fluctuations, 304 productive cycle, 319 responses to increased population den- sity, 281 Migrations lemming, 86 Milk let-down reflect, 2r)S Monkey (see also Rhesus monkey), 194 brucellosis, 256 colobus, 196 corticoids, 268 malaria, 256 Moose, 122 Mortality alterations, 94 effect of crowding on, 279 immediate cause, 323 increase, 323 in dense populations, 319 mass, 322 of young factors, 321 prenatal, 315 Motor activity, 16 Mt. Desert Island, 33, 53 Mouse (see also mice), 196, 170, 175 adrenalectomized laboratory, 201 adrenal gland, 196 adrenal weight, 197 albino, 280 copulation pressure, 289 crowding mortality, 280 development of, 196 dominant, 264 fertility, 288 fights, 296 male fertilit\-, 289 Xoninovolution of X-zone, 258 puberty, 197 Mouse (see also Clethrionomys) red-backed, 27, 52, 54 subordinate, 264 tundra, 318 velocity in a hierarchy, 149 Mule deer, 122 does, 24 fawns, 24 males, 24 Mus (see also mice and mouse) inhibition of growth and reproduction, 316 Muskrat (see also Ondatra), 323 endocrines, 305 relationships between population den- sity and reproduction, 310 reproduction, 317 reproductive organs, 305 Mus musculus {see also mice and mouse), 196, 217 medullar}^ hypertrophj^ 227 responses to increased population den- sity, 281 Myotis, 193 Myotis grisecens, 122 Myotis lucifugus, 122 Myotis yiunanensis, 122 Myotis velifer, 122 Natural populations, 323 Natural selection, 122 Neighbors contacting, 45, 46 distance between, 50 number of, 51 perception of, 51 signal field, 47 sign field, 47 Nerves postganglionic sympathetic, 22:] splanchnic sympathetic, 223 Nervous system sympathetic, 223 Neurohypophysis, 214, 241 Neutrophil count, 252 New York, 33, 54 New Zealand, 322 Niche characterization, 77 l)rimary component of, 77 specializations, 74 NIH Emotional Activit.y Alley, 17 Norepinephrine, 209 effects, 223, 224 secretion, 226, 227 source, 225 North American Census of Small Mam- mals, 26 374 Subject Index Norwa}^ Rat (see also rat, Rattus), 87, 180, 195, 320, 323 adrenalectomized, 202 adrenal weight, 266, 301 behavioral sink development by, 92 body-adrenal relationships, 247 domesticated, 163, 175 inhibition of reproduction, 307 intra-uterine mortality, 221 laboratory, 195 relationships between population den- sity and reproduction, 310 reproductive depression, 291 resorption of the embryos, 221 responses to sociopsychologic factors, 269 rural population, 302 social competition, 273 sociopsj'chologic interactions, 280 subordinate males, 265 wild, 179, 183, 195, 265 Number total of individuals, 110 Oak, 64 Ondatra (see also muskrat), 323 relationships between population den- sity and reproduction, 310 Ondatra zibethica reproduction, 317 Open-field emotional behavior, 89 Orders, 122 Organ isolated, 191 Ornithorhyn chics, 195 Oryciolagvs, 193, 323 Os penis stimulation, 212 Ovary, 194 Ovaries androgens, 220 Pan, 195 Pancreas, 260 Pancreatic islets, 240 Pantothenic acid deficient, 222 Parasitism, 322 Parotid. 260 Particle basic, 2 general classes, 3 Partner choosing of, 154 data regarding the choosing of, 156 Perception, 89, 139 Perodicus potto, 195 Peromyscus, 29, 30, 31, 32, 33, 34, 35, 36, 52, 53, 54, 55, 61, 64, 66, 67, 68, 69, 70, 75, 76, 77, 78, 79, 80, 88, 323 Peromyscus boylii inhibition of reproduction, 307 Peromyscus leucopus pituitary-adrenocortical, 273 population, 305 Peromyscus maniculatus inhibition of reproduction, 307 lice, 322 productive cycle, 319 Personality, 158 Phagocytosis inhibition, 210 Physiologic adaptation generalized effects, 254 Physiology classical, 184 evolution, 60 reproductive, 95 Pigs, 194 Pine, 64 Pineal, 204 Pipistrellus (see also bat), 193 Pitressin, 214, 232 Pituitary anterior, 197, 220 antidiuretic, 241 gonadotropins, 257 hormones, 218 lipid mobilizing factor, 241 posterior, 241 secretion of aldosterone, 203 Pituitary-adrenocortical exhaustion, 226 tumors, 218 Pitymys, 32, 52, 64, 66, 69, 70, 76, 196 Pitymys subterraneus, 196, 197 Population, 189 collapse, 314 densities, 190, 238 fertility, 290 Subject Index 375 fixed size, 263 food-limited, 298 freely growing, 281 individuals of, 103 limited size, 280 methods for estimating natural, 305 natural, 190, 262, 300, 306 physiologic adaptation, 261 reproductive function, 306 resident, 56 self-limited, 298 size, 240 uniforml}' distributed, 58 Population density, 226, 262, 287, 305 adrenocortical and reproductive re- sponses, 269 effect on adrenocortical function, 281 endocrine responses, 263 index of relative, 305 inflammation, 276 resistance to infection, 276 schematic summary, 326, 327 Potassium, 204 excretion, 201 levels, 204 level of body, 202 secretion of aldosterone, 204 Potto, 195 Preconstellation phase, 58 Pregneninolone, 210 Preputial development adrenal androgens, 292 stimulating, 292 stimulation, 212 Probability formulas, 144 Pi(A), 144 PiW, 144 tenninating trips, 12 vacillating at the termination of trips, 18 Proestrus, 239 Psychology classical, 184, 185 Rabbit, 193, 323 adrenalectomized, 236 corticosterone, 236 domestic, 236 embryo resorption, 239 parasitism, 322 release of radioiodine, 233 thyroid, 232 thyroid activity, 235 thyroidectomy, 239 thyrotoxicosis, 235 wild, 235, 236 Radial distance, 623 Radioiodine release in domestic rabbits, 236 release in wild rabbits, 236 uptake, 232 Rat (see also Norway rat, Rattus), 138, 159, 182, 194, 196, 212, 218, 309 ACTH and gonadotropin relationship, 260 adrenals, 201, 206 adrenal atrophy, 237 adrenal cortex, 200 adrenalectomized, 253 adrenalectomized laboratory, 201 adrenal hypertrophy, 237 adrenal weight, 302 adrenocortical secretion, 222 androgen, 221 anestrus, 220 albino Osborne-Mendel strain, 181 blood level of TSH, 237 chorionic gonadotropins, 220 corticosterone, 236 domesticated albino strain, 171 domesticated Norway, 8 effect of temperature changes on, 274 gonadectomized, 219 gonadotropins, 212, 309 growth, 210 harderian glands, 240 house, 212 hypertrophy of medulla, 227 hypophysectomized, 216, 233, 254 hypothalamic-hypophyseal-thyroidal re- lationships, 233 hypothyroid, 234, 239 inanition, 272 in a strong environment, 303 inbred, 274 infant, 210 length of estrous cycle, 238 method of inducing an inflammatory response, 277 376 Subject Index Rat — continued newborn, 210 Nonvay (see Norway rat) Osborne-Mendel, 17 ovarian atrophy, 220 pituitarj^ 236 pituitary-adrenocortical activity, 273 pneumococcal infection, 256 postparturitional loss, 221 pregnant, 210 release of iodine, 238 splenic hypertrophj^ 274 streptococcal infection, 256 submaxillary glands, 240 subordinate, 303 testes, 239 of immature, 238 thiouracil treatment, 239 thyroid, 232 thyroid activity, 235, 237 thyroidectomized, 228 tuberculosis infection, 256 uptake of radioiodine, 233 white, 237 wild, 195 Rat embryos action of estrogens, 259 Rat society, 161 velocity in high-density, 168 velocity-rank relationships in, 168, 169 Rattus (see rat, Norway rat) Rattus alexandrinus, 195 Rattus norvegicus, 195 adrenalectomized, 202 medullar}' hypertrophy, 227 relationships between population den- sity and reproduction, 310 Recapture radii, 5, 6 Receptor, 50 Refractory period, 49, 141, 153, 176 duration, 103, 112 frustrating, 110 frustrating type, 131 frustrating producion, 112 increasing, 130 satisfaction producing, 112 time spent in satisfying, 112 Refractory state maximal, 109 optimal, 109 Regression line, 81 Reichstein's compound S, 199, 205 Reithrodontomys, 6 Rejection psychological, 183 Relationships spatial, 64 summary of presumed, 137 Relative densitj', 78 Relative probability, 45 Removal study Chadwick Woods, Montgomery Count}', Maryland, 29 Rich Lake Island, New York, 27 Removal trapping observed data, 52 Renal nephron tubular cells, 201 Reproduction, 190, 286-291 evaluating the effects of densit}' on, 308 inhibition, 309 mice, female, 291 mice, male, 286 sexual, 133 suppression, 222, 257 Reproductive inhil)ition, 220 function, 292 evaluation, 306 inhibited by population density, 292 inhibition, 323 organs accessory weights, 287 Reserpine, 225 Response avoidance, 93 degree, 192 endocrine, 191 inflammatory, 210 intensity, 151 neural, 191 neuroendocrine, 191 nonspecific, 192 vascular, 191 Response-evoking capacities, 143, 146 Response-evoking capacity S behavioral origin, 140 circumplex depiction of behavior and personality superimposed upon, 157 ' Subject Index 377 circumplex, 155 formulae, 128, 1-13 S'-^\ 143 S^^\ 143 SjA, 128 Si^^', 128 S^'^), 143 S('), 143 Responsive state, 140 Rhesus monkey (see also monkey). 267 hj'drocortisone, 236 responses to sociopsychologic factors, 269 thyroid activity, 236 Rodents (see also specific categories), 212 Runaways underground, 76 Salivary glands, 260 Sanctions, 151, 163 Scent, 38 Schaefer's autonomy, 143 Schaefer's control, 143 Schaefer's hostility-rejection, 128, 143 Schaefer's love-acceptance, 128, 143 Serotonin, 216 Sex accessories, 238 involution, 218 Sex steroids, 206, 217 Sheep, 194 Shock, 192, 243, 244 "Shock disease," 226, 280, 320 Shrews (see also Sorex and Blarina), 26, 27, 75, 193, 197 long-tailed, 246 population, 305 short-tailed, 305 Sight, 38 Sigmodon {see also Cotton rat), 323 litter size, 317 relationships Ix^twecn })o})ulation den- sity and reproduction, 310 Sign, 47 Sign field, 49 Signal, 53, 57, 167 detection, 41 inhibitory, 68 intensity, 48, 49 learning of, 39, 50 neural, 78 noxious, 78 simultaneous, 48 sound, 41 Signal field, 47, 49 Sika deer, 323 mass mortality, 320 population density, 306 Size basic group, 86 effect on response-evoking capacity, 130 Slow loris, 196 Snowshoe hare (see also hare), 253 Social behavior, 128 more effective, 136 Social dominance, 74 adrenal activity, 267 changing, 89 Social factors adrenocortical functions, 236 interspecific, 77 reproductive functions, 263 Social groups budding off, 121 Social hierarchy evolution, 70 Social interaction, 133 basic processes, 116 consequences and examples, 148 frequency of satisfactory, 117 frustration from, 110 as a function of density, 117 heightened frequency, 95 intensity, 152 model, 101 optimum satisfaction, 118 and refractory period, 117 satisfaction from, 110 withdrawal from, 173 Social phenomena, 3 Social pressure endocrine responses, 263 Social rank, 64 Social relations instability, 67 Social response blocking, 104 mechanism, 104 Social subordination interspecific, 67 378 Subject Index Social system, 3, 4 semiclosed, 100 Social withdrawal, 145 Society human, 184 rat, 161 Sodium: potassium ratio serum, 204 Sodium retention, 201 Sorex, {see also shrew), 27, 29, 31, 32, 36, ' - 38, 52, 61, 68, 69, 70, 72, 75, 77, 78 /Sorex araneus, 196, 197 Sorex cinereus, 193, 246 Sorex dispar, 193, 246 Sorex fumeus, 193, 246 (Sorex palustris, 193, 246 Soricidae {see also shrew, Sorex, and Blarina) adrenal, 246 Space general theorj- of use, 34 interspecific and intraspecific use, 34 social use, 2 theoretical conceptualization of use, 70 Spatial equilibrium, 57 Species, 3 alpha, 36, 37 l)eta, 36, 37 distance between neighbors, 42 dominant, 36, 52, 67, 68, 78 incipient, 74 rf^lationship between two dominant, 52 removal captures, 55 socially dominant, 55, 57 subordinate, 36, 38, 52, 61, 67, 68, 78 survival, 122 Spermatogenesis, decrease, 258 Spleen house mice, 251 h^'pertrophy, 251 Microtus agrestis, 251 volves, 251 weights, 249, 251 Splenic hypertrophy, 271 Standard area, 5 State nonresponsive P, 140 Stations feeding, 95 Status subordinate, 68 Steady state evolutionary, 108 Steroid hormones, 218 Steroids, 248 sex, 258 site of action, 216 urinary, 249 Stimuli alarming, 212, 215 Stimuli auditor}^ 70 emotional, 243 conditioned, 75 Strange object reaction, 89 Strange-object response, 179 Stress, 88, 193, 196, 213, 235 generalized state, 182 resulting from group size change, 118 Stressful state amount of time spent, 112 Stressors nonspecific, 119 Stretch receptors secretion of aldosterone, 204 Strife intraspecific, 262 Sudanophilia, 248 Supraopticohypophyseal tract, 214 Survival threshold of, 132 Sylvilag^is {see also rabbit), 193 SjTnpathetic nervous system ganglia, 198 System Iwpothesized communication, 58 two-species, 36 Tachyglossus, 195 Target diameter determined by variabihty of l^diavioral traits, 140 genotype, 140 hj'pothesized divergence, 132 of individual, 110 variability, 127 Territory, 263 of male mice, 287 Subject Index 379 Testis interstitial cells, 194 Testosterone, 208 Thetas satisfaction and frustration, 131 Thiouracil, 237 Thymicolymphatic system, 249 Thymus, 283 cortex, 249 involution, 208, 211, 249, 250 medulla, 249 weights, 249 Thja-ocarotid artery, 204 Thyroglobulin, 230 Thyroid activity factors regulating, 231 index, 231 mice, 235, 236 NaCl intake, 238 rabbit, 236 rat, 235, 236 gland, 191, 228 honnone actions, 229 formation, 230 inhibition, 236 responses to external stimuli, 234 Thyroidal-gonadal interrelationships, 238 Thyroidectomy, 228, 234 Thyrotropin, 231 inhibition, 236 Thyroxine, 228, 229, 231 effects, 230 Tonus vascular, 224 Trap, 20, 37 "Havahart," 184 probability of encountering, 52 Trapline, 53, 82 standard, 26 Trapped-out area invasion, 82 Trapping, 76 comparison of results between short- term and long-term removal, 28 continuous removal, 26, 37 removal, 76 short-term removal, 26 Tribe as a social entity, 98 Trichinella increased invasiveness, 278 Trichinella spiralis, 277, 278 Trichinosis effects of crowding, 278 Triiodothyronine, 228, 229, 231 TSH mice, 237 rabbits, 237 rats, 237 rate of release, 231 release, 232, 236 secretion, 237, 258 Tuberculosis crowding, effect on, 279 murine, 279 Two-dimensional field use, 19 Tyrosine, 230 Ungulates captive, 198 domesticated, 196 Urine metabolites, 207 Vaginal orifice closure, 291 Vagus nerve, 204 Vasopressin, 214 Velocity, 164 biological, 111 effect of interval between ^'s on, LSI effect of tranquilizer on, 172 effect on fat, 174 effect on weights of adrenals, kidney; and heart, 174 formulae, 111, 112, 113 a, 112 aaa, 112 aap, 112 afaa, 112 af'ap, 112 «mfaa^"\ 113 d, no faa, 112 f'ap, 112 i, 112 380 Subject Index 12, 112 /i', 112 N, 110 Nb, 113 N^""', 113 No, 113 0a, 112 ^a^""), 113 0a^»', 113 6>(''), 112 0f, 112 0"), 112 ^a'""*, 113 V, 111 minimal, 173 rank, 171 reduction in hierarchj^ of mice, 148 Visitation frequency, 165 Vitamin A effects on behavior, 170 Vitamin B insufficiency, 222 Vocalization, 38, 48, 75 loss of, 77 Voles, (see also Microius, Clethrionomys, and Pitymys), 193, 196, 253, 261, 293, 317, 318, 322, 323 adrenalectomized, 218 adrenal weight, 285, 286, 301 adrenocortical-densit}' relationships, 304 anestrus, 220 birth rates, 292 competition for food, 297 confined populations, 272 copulatory pressure, 290 crowding mortality, 280 decline in birthrate, 291 decrease in reproduction, 286 depression of fertility, 221 effects of high density, 276 effect of increased population density, 284 effect of overcrowding, 269 effect of population densities, 275 eosinophil counts, 252 female, 286 fights, 296 hypoglycemic shock, 320, 321 inhibition of growth and reproduction, 316 intraspecific strife, 323 laboratory, 274 litter survival, 294 meadow, 196, 218, 272, 323 northern montana, 304 mortality, 322 natural populations, 303 nests, 294 ovarian atrophy, 220 pine, 196 population fluctuation, 312 red-backed, 196, 311, 312, 314, 318, 323 relationships between population den- sity and reproduction, 310 reproductive function, 314 responses to increased population den- sity, 281 responses to sociopsychologic factors, 269 self-limited populations, 299 social pressure, 288 sociopsychologic factors, 264 sociopsychologic interactions, 280 splenic hypertrophy, 242, 272, 273, 274 X-zone, 283 White-footed mice (see also Peromyscris), 273, 323 White-footed mice population, 305 Withdrawal, 162 Withdrawal state, 180 Woodchuck (see also Marmota), 193 relationships between population den- sity and reproduction, 310 Wound healing delay, 210 X-zone acidophilic cells, 197 androgens, 197 basophilic nuclei, 197 Crocidura russula, 197 experimental treatments, 196 function, 217 hormones, 196 pituitary luteinizing hormone, 197 Pitymys subterraneus, 196, 197 reactions to, 196 shrews, 197 Subject Index 381 Sorex araneiis, 197 voles, 196 Zona fasciculata, 217 carbohydrate-active corticoid.s, 2C0 hormones, 205 hyperplasia, 246 hypertrophy, 246 regulation of hormones, 213 Zona glomerulosa aldosterone, 213 beef cattle, 200 hypertrophy, 246 rats, 200 Zona reticularis carbohydrate-active corticoids, 200 function, 217 sex steroids, 217