THE SEPTAL SYNDROME AND THE DIENCEPHALIC “AFFECTIVE DEFENSE” PATHWAYS By JOHN EDWARD SWISHER A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA August, 1965 ACKNOWLEDGMENTS The author wishes to express his deep appreciation to Dr. Bradford N. Bunnell, Chairman of his Supervisory Committee, for his guidance and personal interest in this project. Dr. Fred A. King was also very help- ful, and through his kind office technical assistance in the preparation of histological specimens was made available. The services of Drs. Wilse B. Webb, Donald Goodman, Robert L. King, and James D. Winefordner, members of his Supervisory Committee, are gratefully acknowledged. Very special thanks are due Mrs. Jerre L. Basch for her encouragement and assistance with the surgery and behavioral testing. Miss Hope Razzano prepared a number of the histological slides. ii TABLE OF CONTENTS ACKNOWLEDGMENTS ii LIST OF TABLES iv LIST OF FIGURES v INTRODUCTION 1 METHOD 6 RESULTS 10 DISCUSSION SUMMARY BIBLIOGRAPHY 37 APPENDIX A 42 APPENDIX 44 BIOGRAPHICAL SKETCH iii LIST OF TABLES Table 1. Stereotaxic Coordinates for Septal and Perifornical Lesions 8 Table 2. Mean King Scale Ratings of Rats Receiving No Lesions (G), Septal Lesions (S), Perifornical Lesions (PF), and Combined Septal-Perifornical Lesions (SPF) 10 Table 3. Postoperative Day 1 Differences and Significance of Differences between Groups 11 Table 4. Postoperative Day 1 Comparisons on Items of the Rating Scale 13 Table 5. Effects of Single and Combined Lesions on King Scale Ratings 17 iv LIST OF FIGURES Fig. 1. Postoperative changes in irritability rating 11 Fig. 2. Representative septal and perifornical lesions 15 Fig. 3. Rat D55A, showing septal and anterior thalamic lesions Fig. 4. Brain sections from rat D57A, which received combined lesions in the septum and dorsomedial thalamic nuclei . . 18 Fig. 5. Example of a radical amygdala-pyriform lesion produced by stereotaxically guided cutting, followed by aspira- tion of the severed structures 19 Fig. 6. Amygdalectomy produced by RF coagulation by means of five electrode placements per side !9 INTRODUCTION The early work of Bard (1928) demonstrated that cats deprived of telencephalon and diencephalon rostral to the mid-hypothalamus would exhibit a relatively well- organized rage pattern at low threshold. Fur- ther elimination of tissue in the vicinity of the posterior hypothalamus results in animals which can still respond defensively, although at high threshold and in a fragmentary manner (Bard and Macht, 1958)* Thus it appears that parts of the caudal diencephalon facilitate and coordin- ate mechanisms of defensive behavior situated lower in the brain stem. In turn, higher regions of the brain evidently exert a net inhibitory influence upon the hypothalamic-mesencephalic defense centers, since their removal tends to release defensive behavior from normal restraint. A great amount of research has been devoted to understanding the iden- tity and interplay of these excitatory and inhibitory systems. One such release phenomenon may be obtained when the septal region of the forebrain is destroyed (Spiegel, Miller, and Oppenheimer, 19^0). In the rat, this septal syndrome is characterized by an exaggerated reactivity to stimulation of the dorsum; a tendency to attack and bite intruding objects; a curious rabbit-like gait when fleeing; vigorous biting, struggling, and squealing while being handled; and increased susceptibility to "animal hypnosis" or cataplexy (Brady and Nauta, 1953 and 1955). With daily handling these symptoms usually subside within two weeks, often much sooner. 1 2 Other effects of septal lesions, which may or may not be related to the symptoms of irritability, are difficult to analyze. Following early reports of septal "emotionality," King (1958) found that septal rats learn active avoidance in a shuttle box more rapidly than controls, supporting the interpretation that the enhanced acquisition results from the greater fear of the operated rats. Later it was shown that septal animals exhibit severe deficits of passive avoidance (McCleary , 1961; Kaada, Rasmussen, and Kveim, 1962; Fox, Kimble, and Lickey, 1964). This finding was taken to indicate that the effects of septal ablation are a form of motor release essentially unrelated to emotionality. The septal syndrome, according to this view, consists of exaggerated skeletal and autonomic components of fear-anger reactions without the cognitive aspects and goal-directedness of true emotion. Consistent with this hypo- thesis are reports that septal rats perform poorly on a DRL reinforcement schedule (Ellen, Wilson, and Powell, 1964) and that they are more resistant to extinction (Schwartzbaum, Kellicutt, Spieth, and Thompson, 1964), both effects suggesting a loss of ability to suppress approach tendencies. Quite recently this motor release interpretation has also been questioned. It has been found that septal lesions augment thirst and perhaps hunger (Harvey and Hunt, 1965) , which could well account for poor performance on tasks involving approach-avoidance conflict. A- "deficit in passive avoidance can result not only from a loss of restraint but aiso from an increased approach tendency as seen in water-deprived septal rats (Harvey, Lints, Jacobson, and Hunt, 1965) . Indeed, the willingness of an animal to accept shock to obtain a goal has long been used as the 3 obstruction method for measuring the strength of drives (Munn, 1950)* Moreover, in contrast to the impaired DRL performance reported by Ellen et al. (1964), Harvey and Hunt (1965) found that septal rats responded more efficiently than controls on several types of schedule including DRL. The methodological or other cause of this discrepancy has not yet been determined. Changes in avoidance performance are also somewhat problematical. Although the finding of enhanced acquisition of active avoidance by King (1958) has been well substantiated (Krieckhaus, Simmons, Thomas, and Kenyon, 1964; Fox et al., 1964), it appears that preoperatively established avoidance is abolished by septal lesions (Moore, 1964; Rich and Thompson, 1965) and, further, these animals may be unable to reacquire avoidance conditioning postoperatively (Rich and Thompson, 1965) . Whether the difference between these results and those of earlier workers who found improvement are due to pseudoconditioning, as Rich and Thompson (1965) suggest, or to other factors is presently uncertain. Whatever the status of these various septal effects may be, it is widely reported that the septal irritability syndrome is independent of them (Schwartzbaum, et al. , 1964; Thomas, Moore, Harvey, and Hunt, 1959; Krieckhaus et al. , 1964; Moore, 1964), and might well involve separate anatomical mechanisms. It has been proposed that the septal syndrome is mediated by the hypothalamus; more specifically, that hypothalamic rage or defense centers are released from tonic inhibition when the septum is destroyed (King and Meyer, 1958; Gellhorn and Loofbourrow, 1963). Such "affective defense" centers have been mapped by Hess (195*0 and his coworkers by means of 4 chronically implanted electrodes. In particular, stimulation of the rostral hypothalamus surrounding the fornix columns elicits well- directed escape or attack apparently indistinguishable from the responses of cats confronted with a barking dog. Hunsperger (1956) has shown that this perifornical defense system extends continuously from the amygdala, along the stria terminalis, perifprnical region, intermediate hypo- thalamus, and into the periaqueductal gray. A number of components of agonistic behavior (aggressiveness, threat, or fear) may be obtained from this system, including such septal-like items as vocalization, urination and defecation, biting, and escape (Brown and Hunsperger, 1963). Typical feline responses, such as folding the ears down or back, protrusion of claws, arching of the back, hissing, and striking with the forepaws are also observed, the specific pattern depending upon external stimuli, location of the electrode, and stimulation intensity. Moore (i960), who has studied the septal syndrome in cats, explicitly notes the similarity between the effects of destroying the septal area and stimulating the perifornical region in these animals. Both structural and functional considerations, then, seem to favor the possibility that septal efferents traveling with the fornix normally inhibit the hypothalamic mechanisms of defensive behavior. Nonetheless, the septal nuclei possess rich interconnections with the hippocampus, amygdala, and basal regions of the telencephalon (Valverde, 1963> Powell, 1963)> any of which may be involved -in the transmission of septal inhi- bition. 5 The present experiment was specifically designed to determine whether or not the known hypothalamic mechanisms of emotional expression are responsible for the excitatory phase of the septal syndrome. An experimental group (SPF) was given combined septal and perifornical hypothalamic lesions. For control purposes three additional groups were included: operated control (C), septal (S), and perifornical (PF). All animals were rated before and after the operation on a scale known to be sensitive to the septal syndrome (King, 1959)* Should the septal syndrome result from a release of perifornical excitation, removal of the perifornical region may be expected to block its development. On the other hand, if under such circumstances the septal syndrome still appears, pathways other than the perifornical "affective defense" mechanisms must be involved. It was reasoned, therefore, that if the perifornical region is a crucial link in the septal syndrome, then the SPF rats should exhibit a low level of irritability comparable to that of C and PF animals; if not, then the SPFs should closely resemble the S rats. METHOD Subjects. Data were obtained from 46 naive male Long-Evans rats, ranging in preoperative weight from 210 to 397 grams. During the experi- mental period they were housed individually, with food and water constant- ly available. Procedure. Each subject was rated on successive afternoons, util- izing a scale slightly modified from that devised by King (1959) to quantify the septal syndrome. The ratings were made simultaneously but independently by two experimenters, one of whom handled the rats while the other recorded the data. Beginning with the rat in his home cage, the following items were scored: l) Object presentation (OP). Animal is presented with a pencil-shaped probe in front of the snout and ob- served for escape or attack; 2) Response to tap on the back (TR) . Scored according to the magnitude of startle response; 3) Resistance to capture (RC). Rat is gently picked up and observed for biting and attempts to escape; 4) Resistance to handling (RH). Rat is shifted from hand to hand, noting tendency to bite and struggle; 5) Vocalization (VOC). Amount of squealing during the rating sequence; 6) Urination-defecation (UD). Amount and kind of excretion during rating; 7) An additional measure for cataplexy was added to the scale, since it had been observed that septal rats appear to be unusually susceptible to this symptom. This item (CAT) was rated by holding the posterior end of the rat in the left hand and pinning the animal in a supine position with the right 6 7 hand for 5-10 seconds. Delays in righting after removal of the right hand were taken to indicate cataplexy. The entire rating scale is included in Appendix A. Ratings were taken on five preoperative and one or more postoperative days, until the animal died or the score dropped to a low level. Prior to the first postoperative rating, the rats and their cages were scrambled by one rater (JLB) to minimize experimenter bias on the part of the other (JES). In addition, it had been planned to obtain a measure of performance on a passive avoidance task; however, the rapid deterioration of the animals receiving hypothalamic lesions precluded this testing. Surgery. Upon completing the fifth preoperative rating, the subjects were divided randomly into four groups: operated control (C) , septal (S), perifornical (PF), and combined septal-perifornical (SPF), according to the lesions they were to receive. Anesthesia was induced by a standard intraperitoneal injection of .2 cc of 5° mg/cc Nembutal and .2 cc of 300 mg/cc chloral hydrate. Further injections of chloral hydrate main- tained, as necessary, the proper depth of anesthesia. Also, .3 cc of .4 mg/cc atropine and 100,000 units of penicillin were administered to each rat at the time of operation. Following standard surgical procedures, the appropriate bilateral lesions were produced stereotaxically through a stainless steel electrode made from a #0 insect pin, insulated except at the tip with GE formvar enamel. The coagulating current was generated by a Grass LM-3 radio frequency lesion maker, and the circuit was completed through a stainless steel anal electrode. 8 The electrode was inserted six times in each animal, including the controls. However, the control punctures were performed to make an electrode track similar to that in the true lesions, but without encroach- ing upon the area which would have been occupied by a lesion. Orientation of the electrode was in accordance with the coordinate system of de Groot (1959), referring the anterior plane to the interaural line, depth to the surface of the brain, and lateral to the midsagittal sinus. The specific coordinates are given in Table 1. It should be noted that both sets of septal coordinates were applied to each rat, so that the lesions would conform better with the shape and extent of the septum. Table 1 Stereotaxic Coordinates for Septal and Perifornical Lesions Type Lesion Anterior Lateral Deep . Lesion Control Septal #1 8.0 .4 5.4 3.3 #2 7.7 .4 5.1 3.3 Perifornical 6.0 1.2 7.4 6.4 For all lesions the current was passed for ten seconds. Initially, an intensity of 63 was used for septal lesions and 58 or 57 for pen- fornicals. As early histological results indicated that these intensi- ties were too great, smaller lesions were made in subsequent operations with lower values of 62 and 55, respectively. These adjustments dxd not 9 seem to have any noticeable behavioral effect, and therefore data from rats receiving larger and smaller lesions were combined. RESULTS Behavioral. Mean irritability ratings for the days immediately before and after surgery are given in Table 2 and depicted graphically in Fig. 1. After the operation Group C exhibited no change in score, while S and SPF animals underwent a sharp increase. Likewise the PF group showed a rise, although somewhat less than the S and SPF rats. Table 2 Mean King Scale Ratings of Rats Receiving No Lesions (C) , Septal Lesions (S), Perifornical Lesions (PF), and Combined Septal-Perifomical Lesions (SPF) Group N Rater Preop 4 Preop 5 Postop 1 C 6 JES 4.6 3.8 3.8 JLB 4.8 3.5 3.8 PF 11 JES 3.4 3.9 8.9 JLB 3.1 3.7 9.4 SPF 15 JES 3.1 3.0 13.2 JLB 3.2 2.8 13.8 s 14 JES 3.8 3.2 14.2 JLB 3.8 3.3 14.6 10 11 Fig. 1. Postoperative changes in irritability rating. Table 3 Postoperative Day 1 Differences and Significance of Differences between Groups Comparison Difference Significance S vs C 10.4 .002 SPF vs C 9.^ *002 PF vs C 5.1 *002 S vs SPF SPF vs PF 1.0 4.3 n. s .02 12 As can be noted in Table 3, all three lesioned groups differed significantly from the controls (Mann-Whitney U, 2-tailed). It is also apparent that perifornical destruction does not preclude the rise in irritability which typically follows septal lesions, since the SPFs are significantly higher in rating than the PFs (p < .01, 1-tailed) . On the other hand, the difference between groups S and SPF is small and not significant. Usually before the second postoperative day, both groups of rats with PF lesions began to exhibit a progressive deterioration symptom- ized by somnolence, poor grooming, nasal discharge, and ultimately death. In most instances this debility did not seriously affect the first postoperative rating; however, the small difference between the S and SPF groups seems in part attributable to a slight somnolence in the latter animals. Although ratings beyond the first postoperative day were recorded, meaningful comparisons between groups which received PF lesions and those that did not are impossible, since the debility of the former animals caused the ratings to drop sharply. Also, PF and SPF groups began to be depleted by death of the animals soon after the operation. Therefore, data beyond postoperative day 1 are excluded from the text of this report (see Appendix B) . Scores for the Ss dropped quite rapidly after the first day, as did those for the albino septals of King (1959) and the Long-Evans hooded rats of Yutzey , Meyer, and Meyer (1964). 13 Analysis of individual items of the rating scale (Table 4) reveals some interesting effects. To facilitate presentation of these data, statistical results will be given in parentheses. The score treated will be indicated first, followed by the groups compared, and finally by the highest level of significance. The Mann-Whitney U-test, 2-tailed, is used throughout. Table 4 Postoperative Day 1 Comparisons on Items of the Rating Scale Group OP TR RC RH voc UD CAT c ■ .1 .4 .8 1.2 .6 .7 .0 PF 2.5 1.6 1.0 .9 .6 .4 1.8 SPF 3.1 1.6 1.8 1.9 1.5 .6 2.6 S 2.2 1.8 2.1 2.9 1.6 1.1 2.4 In confirmation of the overall results, the SPFs scored higher than the Ss on all items except response to a tap on the back (TR) , on which these two groups were equal. It is also noteworthy that virtually all of the increase of the PFs was on three items: OP, TR, and CAT. On object presentation the PFs exhibited a marked tendency to attack the probe, often with considerable vigor (OP: PF vs C, .02). SPFs attacked even more vigorously, significantly more so than Ss (OP: SPF vs S, .05) but not the PFs. 14 All three lesioned groups increased in responsiveness to the tap on the back (TR: PF vs C, .002; SPF vs C, ,02; S vs C, . 05), but dif- ferences between these groups were insignificant. Resistance to capture was enhanced in both groups receiving septal lesions, but not by peri- fornical ablation (RC: S vs C, .05; SPF vs PF, .05). The results on resistance to handling would indicate that PF lesions diminish the struggling and biting associated with this score. However, the PF and SPF rats were observed to cease their struggles soon after being picked up, and become quite limp. The somewhat lowered scores on RH reflect this general fatigue effect as much as a specific reduction in struggling and biting. Vocalization, like resistance to capture, was increased by septal lesions and not by perifornical damage (VOC: S vs C, .05; SPF vs PF, .02). Scores on urination-defecation were slightly, but not significantly, depressed by PF lesions. Interpretation of the cataplexy ratings is complicated by the somno- lence and fatigability of the rats that received PF lesions. This item was very satisfactory when applied to septal rats, and the Ss manifested a strong and characteristic tendency to bob up and down as they breathed. Limp, somnolent PFs, on the other hand, did not make these movements. It was often impossible to determine how much of the immobility in PFs and SPFs was due to cataplexy and how much was due to other factors. For this reason no specific meaning can be attached to the numerical increase in this case. Nonetheless it did appear to the raters that the PFs and SPFs exhibited a genuine increase in proneness to cataplexy. 15 Neuroanatomical. Histological sections of the brains were stained for Nissl substance (cresyl violet or neutral red), and in a number of cases for Myelin as well (Weil or luxol fast blue). In general, the lesions were appropriate in size and extent, although some of the earlier PF lesions were rather large. The septal lesions destroyed nearly all of the septum above and rostral to the anterior commissure, often extending far enough caudally to interrupt the fornix (Fig. 2). Damage to the perifornical region was observed lateral to the upper part of the third ventricle, and immediately rostrodorsal to the ventromedial Fig. 2. Representative septal and perifornical lesions. Sections correspond approximately with anterior planes 7*8 and 6,8, respectively, of de Groot (1959)* hypothalamic nucleus. Anteriorly the PF lesions terminated close to the boundary between the preoptic region and the rostral hypothalamus. In every case the fornix and surrounding gray matter was severely damaged. However, the lesions in one PF rat (D60B) were exceptionally 16 far posterior, occupying a position immediately dorsal to the ventro- medial nucleus. This animal failed to exhibit the debility and irrita- bility that typically occurred in PFs. When this animal was perfused it was noted that its stomach was much distended with air or water, a condition which did not appear in other members of this group. Additional data. Prior to undertaking the main experiment, a number of exploratory operations were performed with the object of examining various regions of the brain that for one reason or another might participate in the septal syndrome. Essentially the same procedure was followed as above, except that the rats had been handled during previous behavioral experiments, and control procedures were minimal. Hence these data (Table 5) can be no more than suggestive. Some of the histological results are shown in Figs. 3-6. These observations, however tentatively, are consistent with the view that the septal syndrome is not dependent on the dorsomedial or anterior thalamic nuclei, periaqueductal gray, amygdala, or frontal polar region. Damage to the rostral hypothalamus seemed to produce irritability and to augment the septal syndrome. Amygdaloid lesions also tended to produce irritability, but only after a lapse of three ‘ weeks or more. In the absence of septal destruction, irritability was not produced in the few rats that received lesions in the ventral midline metencephalic tegmentum or caudal medial forebrain bundle. 17 Table 5 Effects of Single and Combined Lesions on King Scale Ratings Lesion N Effecta Histologyb Comments Anterior thalamic nuclei plus septal (Fig. 3) Dorsomedial thalamic nuclei plus septal (Fig. 4) Periaqueductal gray plus septal Anterior polar region plus septal Amygdala-pyriform (Fig. 5) plus septal Amygdala (Fig. 6) plus septal Anterior hypothalamus plus septal Amygdala-pyriform (Fig. 5) Amygdala (Fig. 6) Medial forebrain bundle (caudal hypothalamus) 2 1 2 ■2 1 2 2 1 1 and 2 2 1 3 2 2 3 2 2 2 2 3 0 2 2 3 2 0 2 10 0 Well-developed hop Somnolent and aphagic Irritable after three weeks Irritable after several months Very slight irrita- bility after three weeks, increased by addition of septal lesions Aphagia, ataxia, ptosis Destroyed fibers direct from septum to this region Anterior hypothalamus 1 3 Ventromedial pontine tegmentum 1 0 Note: For Effect, 0 means no syndrome; 1, syndrome apparently normal; 2, slowly developing syndrome; 3> long lasting, well- developed irrita- bility. a0 denotes no irritability; 1, syndrome apparently normal; 2, slowly de- veloping syndrome; 3> long lasting, well- developed irritability. b0 denotes no histological data; 1, RF lesions properly placed, but some- what small; 2, large RF lesion destroying whole structure; 3, radical lesion produced by stereotaxic cuting and suction (septal by coagulation; 18 Fig. 3. Rat D55A, showing septal and anterior thalamic lesions. Anterior planes 7.3 and 5*6. This rat increased 6.5 points on the rating scale. Fig. 4. Brain sections from rat D57A, which received combined lesions in the septum and dorsomedial thalamic nuclei. Anterior planes 7.5 and 4.2 (de Groot, 1959). King scale rating increased 8.5 points postopera tively. 19 Fig. 5* Example of a radical amygdala-pyriform lesion produced by stereotaxically guided cutting, followed by aspiration of the severed structures. Fig. 6. Amygdalectomy produced by RF coagulation by means of five electrode placements per side. DISCUSSION Since the perifornical region of the hypothalamus is associated with the facilitation of defensive behavior (Hess, 195^), it would seem plausible to expect that its destruction would raise the threshold for such responses. Paradoxically, the rats with perifornical lesions became irritable. They showed a strong tendency to attack intruding objects and to overreact to a tap on the back; they did not, however, demonstrate an increased tendency to bite, struggle, or squeal during handling. Quite probably these behavioral changes resulted from damage near the medial preoptic area, since it has been reported that lesions in this vicinity result in a “septal- like" syndrome (Larsson and Heimer, 1964). Maire and Patton (1956) similarly obtained, ^rom raoS with anterior hypothalamic-preoptic lesions, states in which "gentle blowing on the hair of the back often provoked wild jumping and squealing. When prodded lightly with a metal bar, operated animals attacked it viciously with teeth and claws." The likeness between this syndrome and the behavior of the present series of PFs is unmistakable, although exaggerated squealing was not observed in the latter rats. Also, Maire and Patton (1956) found that their rats became quite hyper- active, a characteristic that was not clearly present in the PF group. No doubt differences in the method of production, size, and shape of the lesions account for these discrepancies. 20 21 The more or less rapid deterioration of the PF and SPF rats, at times accompanied by copious nasal discharge, closely resembles other effects obtained by Maire and Patton (1956) following rostral hypothalamic-preoptic lesions. These experimenters found that lesions immediately above the. optic chiasm, close to the midline, cause rapidly fatal pulmonary edema. Other rats, with lesions in the same general area, died without developing lung congestion, presumably because of hyperthermia. Although the PF lesions were somewhat dorsal and lateral to the ones placed by Maire and Patton, closely related anatomical systems were evidently disturbed in the two studies. Despite the fact that perifornical lesions alone served to produce a definite change in behavior mimicking the septal syndrome, xt is clear that additional septal lesions caused irritability significantly greater than that attributable to hypothalamic damage. On two items that were not appreciably affected by perifornical lesions - resistance to capture and vocalization - the added septal lesions of the SPFs yielded increases quite comparable to those of septal lesions alone. These comparisons are especially valid because SPFs and PFs were equally somnolent, and differences between these groups cannot be ascribed to this factor. All indications, then, are that the septal syndrome is not dependent upon the perifornical "affective defense" centers of the hypothalamus. The septal syndrome must therefore be expressed via a descending pathway other than that destroyed in the present experiment, and apart from the septohabenular connections previously eliminated by Brady and Nauta (1955) It is also clear that the neocortex is not involved crucially in this 22 relay (Yutzey et al., 1964). Before attempting to interpret these results more fully, it is well to take cognizance of some of the difficulties involved in any attempt to unify the general mass of experimental evidence regarding defensive behavior into a reasonably parsimonious, internally consistent theory. Accordingly, several of the major factors will be touched upon before proceeding with a discussion of the various possible anatomical mechanisms whereby the septal syndrome may be mediated. Behavioral nomenclature. This problem has been noted by Green, Clemente, and de Groot (1957), who observe that "rage is readily con- fused with fear, aggressiveness or, perhaps, frustration and even types of playfulness, while placidity might be confused with indifference, catalepsy, catatonia, stupor, and idiocy." Compounding this difficulty is the plethora of terms applied to essentially the same phenomenon, or the use of the same term for several distinct emotional-behavioral states. Thus, a marked tendency of an animal to defend himself is variously referred to as "rage," "savageness," "affective defense," "irritability," "anger," "emotionality," "pseudoaffective behavior," "wildness," and, perhaps most inappropriately, "aggressiveness." It is felt that the last designation should be restricted to those forms of behavior in which the subject actively seeks out another animal to attack. Another word which presents some difficulty here is "emotional- ity" which, owing to its broad connotations in the sphere of human discourse in addition to its narrow ones in the study of rat behavior (Hall, 1934), should perhaps be avoided. Of the remaining expressions, 23 "rage," "affective defense," and "irritability" have appeared frequently and have been rather consistently applied to behavior which resembles the septal syndrome. These three terms or the abbreviation DR (defense reaction) will be used more or less interchangeably. In general, the word preferred by the author of a paper will be applied when discussing his work. Type of lesion. In studies in which lesions are produced in the central nervous system it is sometimes difficult to determine whether the results are due to a primary loss of tissue or to irritation of the surrounding, more or less intact regions. The finding of clearly in- compatible, opposite results from lesions of the amygdala by Bard and Mountcastle (1947) and Schreiner and Kling (1953) may exemplify this source of confusion. Green, Clemente, and de Groot (1957) suggest that the slowly developing rage of Bard and Mountcastle' s (1947) cats resulted from incidental damage to the hippocampus and the resulting seizure discharge. A more carefully documented nuance of lesion production was reported by Reynolds (1963) , who compared the effects of anodal DC and radio fre- quency (RF) methods of coagulating brain tissue. Rats receiving DC lesions in the ventromedial hypothalamic nucleus, and in which the electrolytic deposition of iron was demonstrated, manifested the usuai symptoms of irritability and hyperphagia (Wheatley, 1944). On the other hand, RF lesions otherwise comparable did not yield the behavioral effects nor was iron deposited from the electrode. Reynolds proposes that the metal causes discharging foci and that this activity, not release, is 24 the source of hyperphagia and irritability. In assessing the literature on brain lesions and emotional behavior, it may be noted that Hunsperger (1956) is one of the few investigators who used RF current to coagulate brain tissue. As far as the septal syndrome is concerned, the method of lesion production is not critical. Brady and Nauta (1953) made septal lesions with a cutting device; Moore (1964) with a suction pipette; Zeman and King (1958) with implanted tumors; and in the present experiment RF was used. All of these techniques were effective in causing the septal syndrome. Another point that bears mention is the possibility that studies in which lesions are produced serially (e.g. Bard and Mountcastle, 1947; Rothfield and Harman, 1954) may involve readjustments of the "spontaneous reorganization" type (Stewart and Ades, 1951) which could mask certain effects of tissue destruction. Such an effect might explain why total neocortical and paleocortical ablation reportedly produces rage (Bard and Mountcastle, 1947), while bilateral spreading depression evidently does not, at least not without subcortical lesions (Teitelbaum and Cytawa, 1965). Some work critically comparing the effects of spreadxng depression and decortication, and of simultaneous and serial lesions, seems indicated. M iacent or overlapping reoiprocal networks. Finally, a complexity that may contribute heavily to the problem of septal inhibitory outlet is the fact that in the immediate vicinity of the septal nuclei - indeed, within the septum itself - lie points which produce irritability when 25 stimulated. Fernandez de Molina and Hunsperger (1959) have evoked DRs from points in the stria terminalis throughout its course, part of which abuts the ventrolateral septum near the anterior commissure. Similarly, Hernandez-Peon et al. (1963) elicited rage from the ventrolateral septum, medial preoptic area, and points along the borders separating septal, caudate, and accumbens .nuclei. This was done by means of precise cholinergic stimulation. Incidental observations of Forman and Ward (1957) and Galeano et al. (1964) confirm the presence of defense facili- tatory sites in the septum, especially the lateral portion. Before leaving the topic of septal stimulation, a remarkable observation of Olds (1955) should be mentioned. In conducting his studies on self- stimulation he noted that septal stimulation causes an immediate arrest of all ongoing activity. Most interestingly, when the stimulation ceased these rats exhibited "rebound" behavior strongly reminiscent of the syndrome resulting from septal lesions. Unfortunately, Olds did not report the exact location of the electrodes which produced this effect. In addition to these sources of excitation, other structures lying beneath the septum and intimately interconnected with it appear to be inhibitory. Damage in the vicinity of the olfactory tubercle (Fulton and Ingraham, 1929; Spiegel, Miller, and Oppenheimer, 1940) and preoptic region (Nauta, 1946; Maire and Patton, 1956; Larsson and Heimer, 1964) will produce a long lasting septal-like syndrome. It may be that these struc- tures comprise, with the septum, a more or less unitary rage inhibitory 26 region, having a common discharge pathway. Such a system could corres- pond with the motor inhibitory area described by Kaada (1962) in certain aspects. However tempting a scheme of this type may be, there are indica- tions that throughout the brain separate or even opposing functions can occupy the same general location. It is especially relevant that Hernandez-Peon et al. (1963) have shown that cholinergic stimulation of the upper medial preoptic area produces sleep, while noradrenalin applied through the same cannula yields alertness or rage. No doubt more extensive pharmacological investigations will continue to reveal effects of this type. A completely satisfactory integration of these facts is not possible at the present time; however, it does seem that the septum and surround- ing structures consist of opposing, juxtaposed, and perhaps partly over- lapping circuits with respect to defensive behavior. At least part of the failure to identify the precise anatomical locus responsible for the septal syndrome (Harrison and Lyon, 1957) may be explainable in terms of such intertwining neural systems. With these suggestions, pre- cautions, and hazards in mind, the remaining septal efferents may be considered. These will be categorized, for purposes of discussion, into hypothalamic, thalamic, and telencephalic. Hypothalamic. Since the hypothalamic connections of the septal nuclei which travel with the fornix columns have already been eliminated from further consideration, this section will be confined to the other major septohypo thalamic tract, the medial forebrain bundle. Anatomically 27 the medial forebrain bundle is well situated to conduct from the septum, olfactory tubercle, and preoptic area to modify activity in the DR centers of the hypothalamus and periaqueductal gray (Powell, 1963). It would be expected that if DR inhibition occurred by this means, inter- ruption of the medial forebrain bundle between the basal telencephalon and hypothalamus would mimic the effect of septal lesions. While damage to the medial preoptic area above the chiasm does produce a septal type syndrome, similar lesions in the lateral preoptic which would sever the medial forebrain bundle do not affect the DR threshold (Larsson and Heimer, 1964). Teitelbaum and Cytawa (1965) have destroyed the lateral hypothalamic hunger center, which also lies along the course of the medial forebrain bundle, but obtain irritability only if spreading de- pression is applied. These workers used anodal current to produce the lesions, however, and in view of Reynolds' data (1963) it may be sus- pected that discharging foci rather than simple release are responsible for the behavioral change. In neither case did the effect of inter- rupting the medial forebrain bundle alone resemble the septal syndrome, and it would seem, therefore, that most or all DR inhibition from the septum must be exerted by way of other connections. Thalamic. The septum is strongly connected with the anterior, dorsomedial, and reticular nuclei of the thalamus (Powell, 1963) • ?or various reasons these nuclei, particularly the first two, have been held to participate in emotion. The anterior nuclei are part of the classical Papez (1937) circuit, although their absence does not produce obvious behavioral changes (Brierly and Beck, 1958). A somewhat 28 stronger case can be made for the involvement of the dorsomedial nucleus in emotion. Ablation of this part of the thalamus has been performed in man as a substitute for prefrontal lobotomy, and in addition to reliev- ing anxiety dorsomedial thalamotomy is said to calm "aggressive, assault- ive, screaming patients" (Spiegel and Wycis, 1962). Stimulation of the dorsomedial nucleus yields responses indicative of fear or pain and cats will learn to avoid such stimulation. Roberts (1962), for these reasons, concludes that this structure is part of the neural mechanism of fear. Lesions of the dorsomedial nucleus, as might be expected from this theory, virtually abolish fear-motivated active avoidance responses (Vanderwolf, 1963). Thus it is anatomically and behaviorally feasible that the septal syndrome results from a release of thalamus-mediated fear. Evidence from a small number of rats with combined septal-anterior or septal-dorsomedial thalamic lesions is inconsistent with this hypothesis, however, since the septal syndrome appeared unabated by the thalamic destruction (Table 5) • Telencephalic. In addition to the diencephalic connections, the septal nuclei distribute efferents to the hippocampus, amygdala, and basal telencephalon (Valverde, 1963; Powell, 1963). These three struc- tures will now be considered in turn. The hippocampus, like the anterior thalamic nuclei, was assigned by Papez (1937) to a prominent place in his theory of emotion. Bard and Mountcastle (19^7) extirpated the hippo- campus in two cats, which were reported to display enhanced pleasure reactions. Hippocampal stimulation, in some instances at least, lowers the rage threshold (MacLean, 1952; Kaada et al. , 1962 ) , and Green, Clemente, 29 and de Groot (1957) attribute the rage that developed in some of their amygdalectomized cats to irritative damage to the hippocampus. There is some indication, then, that the hippocampus facilitates DRs, and that its absence results in a sort of taming. Rothfield and Harman (1954) report that while fornicectomy or neodecortication alone do not lower the rage threshold, together they do. The fornix was divided between the septum and the hippocampus, and since slight damage to the anterior hippocampus was produced the possibility of irritation cannot be ruled out. In any case, Rothfield and Harman conclude that in the absence of neocortex inhibitory influences pass from the rhinen- cephalon to the hypothalamus via the fornix. Taking their data at face value, however, it seems equally possible that the septum might inhibit the hippocampus. Bearing directly on this point 'is the incidental finding of Moore (1964) that while several of his septal lesioned cats developed the syndrome, prior hippocampal ablation appeared to block the development of irritability. To date this is the most positive evidence that a structure is of crucial importance in the transmission oj. septal release, and systematic testing should be undertaken to demonstrate conclusively the role of the hippocampus in the septal syndrome and other forms of emotional expression. Results obtained by stimulating and ablating the amygdala are among the most difficult to interpret (Goddard, 1964). With respect to DRs, it seems that the amygdala sends excitation to the hypothalamus by way of the stria terminalis, since destruction of the perifornucax 30 region abolished responsiveness to amygdaloid stimulation (Hunsperger, 1956). However, the evidence of Zbrozyna (I960), who severed the stria terminalis and then stimulated both ends, indicates transmission in the opposite direction. Whatever means are involved in conducting DR facili- tation from the amygdala, this activity could be suppressed by the septum. These two structures are connected by multisynaptic relays through the diagonal band and anterior amygdaloid area (Valverde, 1963). Behaviorally , it has been reported that lesions of the amygdala markedly attenuate the septal syndrome. In their interpretation of this finding, King and Meyer (1958) consider the possibility that both septal and amygdaloid efferents, although having opposite effects, impose them directly on the hypothalamus. Alternatively, the two could be connected in series so that the septal nuclei normally restrain the amygdala, but this seems unlikely. King and Meyer (1958) observed that the effect of amygdalectomy diminished with time, possibly indicating that the taming is not sufficiently permanent to warrant any conclusion that the amygdala is a necessary link in the expression of the septal syndrome, nowever, their lesions were subtotal and some degree of recovery might be attribu- table to the remaining intact portions of the amygdala. It would appear from the exploratory studies reported above (Table 5), in which rats with radical amygdaloid lesions were allowed to recover before placing the septal lesions, that the amygdala is in fact nonessential. ihe dispensability of the amygdala for- other forms of rage is shown by the fact that its removal does not seriously or permanently reduce DRs obtained by making DC lesions in the ventromedial hypothalamus (Kling 31 and Hutt, 1958) or by stimulating the perifornical region (Hunsperger, 1956). Finally, attention passes to the excitatory networks in and around the septum itself (Hernandez-Peon et al. , 1963). It has been noted above that both excitatory and inhibitory effects on DRs have been obtained in the septum and basal telencephalon. Unfortunately, the precise distribution and especially the modes and degrees of inter- action between these systems have not been determined physiologically, and it is therefore quite difficult to assess the possibility that lesions in the more inhibitory regions release excitation in nearby DR centers. Contributing further to this problem is the fact that the descending pathways whereby the telencephalon communicates with the lower rage facilitatory effectors are not known. It might be expected that a simple course is followed by the perifornical system through the intermediate hypothalamus into the mesencephalon. On the contrary, Hunsperger (1956) found that interruption of this system in the caudal hypothalamus resulted in an isolated rostral component which continued to yield DRs at low threshold. Until these uncertainties are resolved, an experimental analysis of the possibility that septal release is achieved locally will be problematical. In sum, it is evident that septal inhibition of defensive behavior is not mediated by the fornix columns and surrounding gray matter, by the habenula, or by the neocortex. There is, furthermore, some reason to doubt that any of the direct septal efferents to the diencephalon are involved. The amygdala, while it may exert a general facilitatory effect on defensive behavior and the mechanisms responsible for the 32 septal syndrome, does not seem crucial. On the other hand, preliminary evidence is available which indicates that the hippocampus might be the site of septal inhibition. It also seems possible that septal inhibition of defensive behavior may be achieved locally within the septum itself and in subjacent regions. Cataplexy. The marked cataplexy associated with septal damage has been little studied, and no attempt seems to have been made to determine what relationship may obtain between this phenomenon and others such as "animal hypnosis," "playing 'possum," human catatonia, and bulbocapnine catalepsy. One interesting lead is the finding that in "hypnotized" rabbits the hippocampal theta rhythm is reduced (Silva et al., 1959). It has been reported that this rhythm is paced by cells in the septum, and that it is abolished by septal destruction (Green and Arduini, 195^5 Brugge, 1965). Perhaps reduction of the theta activity by septal ablation lowers the threshold for "hypnosis." Recordings from opossums in their characteristic death feint are not significantly different from typical waking activity (Norton et al. , 1964). Unfortunately, no electrodes were placed in the hippocampus and theta rhythms were apparently absent from the neocortex. It re- mains uncertain whether the electrical manifestations of "animal hypnosis" and "playing 'possum" are similar. Other -problems . Although the present experiment was not specific- ally planned to deal with them, it may be profitable to consider two major issues concerning the septal syndrome. The first of these is the question of "septalness": whether it is destruction of the septal nuclei 33 proper, or incidental damage to surrounding structures that is respon- sible for the irritable behavior. Brady and Nauta (1955) weighed the possibility that interruption of the fornix was critical, but Harrison ano Lyon (1957) showed tnat this is not the case. The latter experi- menters went on to report that there is no consistent relationship between lesion size and position, and the magnitude of the septal syndrome. Their conclusion was that some unspecified structure outside the septum must be held responsible for the syndrome. The poor relation- ship between lesions and irritability has also been noted by Thomas et al. (1959) • The presence of widespread and probably overlapping facilitatory and inhibitory regions in the telencephalon suggests the slightly differ- ent interpretation that for reasons of congenital individual or species differences, and possibly "functional" determinants, parts of the inhibi- tory system are differentially relied upon in the intact animal. One rat, for example, might develop strong septal inhibition, to the expense of medial preoptic area or olfactory tubercle; conversely, those animals which normally depend on the medial preoptic would exhibit a relatively slight degree of septal irritability. Any formulation of this type must be highly tentative at the present time, but might provide an explanation of how identical appearing lesions produce in some instances quite differ- ent degrees of the septal syndrome. The fact that the syndrome can be produced by restricted lesions rather far apart is consistent with the hypothesis of a single, fairly large inhibitory system. Recovery of the syndrome would then be a matter of the remaining parts of the system assuming, partly through a type of learning, the function of the lost 34 parts. If this is true, then it is predictable that destruction of a large portion of the inhibitory region should result in a septal syndrome which is refractory to habituation. Another factor which may help to account for the results of Harrison and Lyon (1957) is that since the septum includes both excitatory and inhibitory points , both are usually destroyed simultaneously and some degree of balance may be retained by the remaining parts of the septum and basal telencephalon. The other major question to be discussed is whether the septal syndrome is a manifestation of true emotion, in the full motivational sense, or whether, instead, it is simply a matter of motor release. The latter interpretation is based primarily on the findings of McCleary (1961) and Kaada et al. (1962) concerning passive avoidance deficits. It has already been mentioned that these results may be due to increased approach tendencies (Harvey et al. , 1965) , and this negative evidence therefore loses much of its force. Several attempts have been made to demonstrate fear enhancement by means of active avoidance training. King (1958), for example, reported that septal rats learn to perform in a shuttle box more rapidly than controls, and concludes that they did so because of greater fear motivation. Krieckhaus et al. (1964) confirmed this finding, but feel that an adequate explanation can be found in the reduction of competing unconditioned responses. Also, animals trained preopera tively to avoid shock lose the response following septal lesions; furthermore, they reacquire active avoidance only with difficulty (Rich and Thompson, 1965). Roberts (1962) , in support of his theory that the dorsomedial nucleus of the thalamus is part of the fear mechanism, also 35 employed active avoidance. In this case, it was stimulation of the dorsomedial nucleus that the animals learned to avoid. However, this demonstration fails to distinguish between the aversive properties of fear and simple pain, and is thus inconclusive. A straightforward alternative 'to active avoidance as a measure of increased fear is suggested by the observation that septal rats, if they escape during rating, show a notable tendency to seek a place to hide. Septal rats, if indeed more fearful, might be expected to learn and run a maze with a dark hole as the incentive. While irritable and nonirri table septal rats both learn avoidance more quickly than controls, the latency is significantly less in the animals exhibiting the septal syndrome (Krieckhaus et al. , 1964). This difference could be related to the enhanced tendency of the irritable rats to flee. It is somewhat difficult to reconcile observations of this kind with the increased "boldness" of irritable septal rats in leaving their cage to enter an open field, however (Thomas et al. , 1959). At the present time it seems impossible to produce firm answers to questions relating to the nature of the septal syndrome. It is begin- ning to appear that septal function cannot be so easily characterized in terms of one or a few simple behavioral categories such as thirst, fear, or motor inhibition. With the complex interconnections of the septal region and other structures implicated in the interpretation and responsiveness to threatening situations, allowing for almost unlimited degrees and kinds of interaction, this is perhaps not so surprising. SUMMARY Rats with septal, perifornical hypothalamic, and combined septal - perifornical lesions were compared with control animals on a rating scale designed to quantify the septal syndrome. Destruction of the perifornical "affective defense" zone failed to block development ox the septal syndrome. Analysis of scores reveals that either septal or perifornical lesions enhanced the rat's tendency to attack an intruding object and to jump when struck on the back. 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Vn -fr Va> t-O \ O P’ W Vji -T~ VJ N H O M Vji -fr V,) j\> APPENDIX A SEVEN RATING SCALES EMOTIONALITY REACTION TO OBJECT PRESENTATION: Pencil is presented close to animal's snout. - Rat ignores pencil - Rat alert and attentive, some body tenseness - Legs and body tense and immobile, vibrissae point forward - Scurries away or makes an occasional mild biting attack on pencil - Intermediate - Very aggressive attack, disorganized panic, or violent flight SSPONSE TO TAP ON BACK - No reaction - Twitching or restlessness - Twitching or scurrying away - Jumps or hops up a bit, but then settles down - Leaps in air and runs about in fright. Big hop and movement afuer - Leaps violently, dashes off in panic, frantic rebounding from side to side of cage SSISTANCE TO CAPTURE: Glove id rat is grasped firmly but - Remains calm, does not move when approached, does not struggle when- grasped - Remains calm when approached, but scurries away and tugs a bit when grasped - Retreat and moderate struggle - Retreats when approached, struggles vigorously when grasped - Strong attempt to escape when approached, struggles strongly and is disorganized. Some biting - Leaps violently when grasped, bites, frantically, exceedingly cb-j.fi cult to catch is extended forward to animal slowly not roughly. L2 43 APPENDIX A (CONTINUED) IV. RESISTANCE TO HANDLING: Animal passed from hand to hand for about 30 seconds. 0 - Relaxes in hand, does not attempt to escape 1- Restless with some feeble squirming 2 - Sporadic attempts to pull out of hand 3 - Struggles pretty continuously and quite vigorous in attempt to escape 4 - Bites also 5 - Frantic biting, powerful tugging and disorganized twisting V. VOCALIZATION TO CAPTURE AND HANDLING 0 - None 1 - Few squeaks 2 - Frequent squeaking 3 - Frequent squealing- squawking 4 - Squealing continuous 5 - Frantic and loud screeching continued VI. URINATION AND DEFECATION IN REACTION TO HANDLING 0 - None 1 - Slight urination 2 - Few stools VII. CATAPLEXY: Animal is held in the left hand by the hindquarters. With the right hand the rat is restrained in a supine position for about 5-10 seconds, then released. 0 - Animal sits up or struggles as soon as released 1 - Rights or struggles after release, but with a brief latency 2 - Longer latency 3 - Remains supine indefinitely (at least 30 seconds) and exhibits a marked tendency to bob up and down with respiratory movements. APPENDIX B Total Scores for individual Rats throughout Period of Testing Rat Preop 5 Postop 1 2 3 Day 4 5 Control D383 5k 3k 2k 31 4 rp 1 D39B 3k 5k 2k 1 ll T B423 2 1 2 1 0 T Do23 8 k 8 5 .4 4l T D683 42 2 5k ll T D75B 3k 3 6 4 T Perifornical D24B 5k 5k 9b r^ah ,ab ±2 X D28B 2 9 17 61 P D32B ll ll 7b 6ab X D33B 5 41 7l X D43B 3 61 12l 16 X D53B 4 k 5 81 6 X D59B 3k 42" 7a 2ab X D603 4 3 41 2k 3! P D6?B n 1 J-2 2 lla 9e 7 8* 81 D71B 22 2l 8 6 P D783 2 k 6 13l 13kf 5k X 10 11 111 8 44 45 APPENDIX B ( CONTINUED) Rax. Day Preop Postop 4 51234 56 789 10 11 Ssotal-oerifornical D233 2 2k 10 9 6 p D34B 4 0 21 9 -1 o-L -02 6k P D34B 22 1 i 13 X D443 ik 2 52 X D45B 4 5 182 8a D493 1 1 8 X D52B 6 5 19k 17 D563 22 4 1 — 1 11 D57B 4 2 14 l62a p D58B 2 3 19ac l6iac 142' ae ^ac -^tac iq! DolB 42 1 52 162 12 13 13 14 11 D65B 2 2 4 ka D693 2 5S 12k T _L 12k 8k X D723 32 22 11 X D73S 5 3^ 10 X Septal Do23 4 4 l6g- 3 1 D313 cl >2 3s 13 % 12 D37B 3 3 10 1 12 D40B 3 1 21 k 15 92 46 APPENDIX B (CONTINUED) Rat Preop Postop 4 5 1 2 3 Seotal (Continued) D47B 0 1 19k 10 D48B 3 5 l8i 1 5k D50B 6 5 /i 62 7 D51B 4i li 10 8 D55B 3 3k 8i 3k D63B 3i 3i 4 li 1 D64B 8 / O r 4 3 2k d66b 42 ik 21 1 5k II2 D70B 2k 2 18 15 15 D74B ■ 2 4i 20 l6i I4i' Day 4 5 6 7 8 9 10 II 1? 122 7 4i 1 1 Hi 13i 9 ^ 5 P Note: X signifies death of rat; T, termination of rating; * , rat perfused; I, rat immobile, could not be rated. aSomnolent Weakness and respiratory infection "^Nasal discharge More alert f cAtaxic No somnolence BIOGRAPHICAL SKETCH John Edward Swisher was born January 8, 1932, at Jacksonville, Florida. In June, 1949, he was graduated from Landon High School. From September, 1949, to October, 1952, he attended Vanderbilt and Stetson Universities. He served as an aviator with the United States Navy from 1953 through 1956. In the spring of 1957 he reentered Stetson University and there received the degree Bachelor of Science in June, 1958. From September of that year through 1962 he was en- rolled in the Graduate School of the University of Florida, where he received the degree Master of Science in June, 19 6l. Mr. Swisher was employed as an Assistant Professor of Psychology at the University of Miami from February, 1963, to June, 1965. 47 This dissertation was prepared under the direction of the chairman of the candidate's supervisory committee and has been approved by all members of that committee. It was submitted to the Dean of the College of Arts and Sciences' and to the Graduate Council, and was approved as partial fulfillment of the requirements for the degree of Doctor of Philosophy. August 14, 1965 M c*. Dean , College of Arts and Sciences Dean, Graduate School Supervisory Committee: