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The effect of amygdaloid lesions on flight and defense behavior in cats
EXPERIMENTAL
The
NEUROLOGY
Effect
11,
of
61-79
(1965)
Amygdaloid
Defense
Lesions
Behavior HOLGER
on
Flight
and
in Cats
URSIN~
Neurophysiological Laboratory at the Anatomical Institute, University of Oslo, Norway, and Laboratory for Physiological Psychology, University of Chicago, Chicago, Illinois Received
July
13, 1964
The characteristics of flight and defense behavior in cats have been described in previous publications. Similar responses have been elicited by electrical stimulation of two separate zones within the amygdaloid complex. In the presented material, small bilateral lesions of the amygdala were produced electrolytically in six tame and nineteen wild stray cats. Postoperatively, previously wild cats showed loss or reduction of flight or defense behavior, or both. These two patterns of response could be reduced separately or in combination. Flight behavior was significantly reduced specifically by lesions of the flight zone, as defined by prior stimulation studies. No significant correlation was found between lesions of the similarly defined defense zone and a reduction of defense behavior. Neither type of behavioral change was seen postoperatively in the tame cats. Introduction
Bilateral lesions in the temporal lobes produce profound changes in behavior. Kliiver and Bucy (20) described a syndrome in monkeys consisting of psychic blindness (visual agnosia), strong oral tendencies, hypermetamorphosis (excessive tendency to attend and react to visual stimuli), hypersexuality and hyperphagia. Emotional behavior was also considerably changed in the direction of increased tameness; there was a dramatic decrease in aggressive behavior and a loss of fear reactions. Subsequent work has confirmed the fact that this whole syndrome of 1 Sponsored in part by the Norwegian Research Council for Science and the Humanities, and in part by the United States Public Health Service (NIH-FF-272). The author is indebted to Professor B. R. Kaada, University of Oslo, and Professor for generous help and encouragement. R. A. McCleary, University of Chicago, Valuable assistance at various stages of the work was provided by Caroline Jones, Else Melstr$m, Werner Pedersen, and Irving Zucker. 61
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behavioral changes, or parts of it, may be produced by bilateral temporal lobe lesions in a variety of species. The relevant literature has been reviewed by Gloor (10) and Ursin (35). What is still needed, however, is identification of structures in the temporal lobes that are involved in the various parts of the Kliiver-Bucy syndrome. A careful study which included the observation of the normal behavior patterns in question, by Green, Clemente and de Groot (ll), determined the anatomical substrate for two parts of the Kliiver-Bucy syndrome in the cat. They ascribed male hypersexuality to bilateral lesions restricted to the pyriform cortex, and hyperphagia to lesions of the basal and lateral parts of the amygdala. Which part of the temporal lobe resection is responsible for taming such operated animals, however, is still not clearly understood. Schreiner and Kling (30) reported increased tameness in cats following lesions restricted to the amygdaloid complex and the overlying pyriform cortex. Walker, Thomson and McQueen (39) found that postoperative tameness and fearlessness in monkeys correlated fairly well with the amount of damage to the amygdaloid complex, but there were exceptions to this. Rosvold, Mirsky and Pribram (29) found similar behavioral changes to correlate with the extent of damage to the basolateral nuclei. Ursin (35) suggested more specifically that, for an amygdaloid lesion to produce tameness, it must disrupt the fear (flight) and anger (defense) zones already demonstrated by stimulation of the amygdala Ursin and Kaada (3 7) elicited flight responses in an area extending from the rostra1 part of the lateral nucleus and the preamygdaloid area through the region of the central nucleus and into the internal capsule. Defense responses, on the other hand, resulted from stimulation of more ventromedial and caudal parts of the amygdala, i.e., from the posterior part of the lateral nucleus and from the lateral part of the basal nucleus (Fig. 1). The present experiments were designed to test further whether small lesions restricted to the amygdaloid complex would produce taming and, moreover, to see whether the same two separate zones could be confirmed by the type of emotional deficit resulting from localized lesions within the amygdala. Wild stray cats, used as the main experimental subjects, spontaneously show the entire range of emotional behavior that is observed following stimulation of the amygdala. It has been possible to identify objectively these various patterns of emotional behavior in such wild cats (36).
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p 101.
PYf.
n. 101. amyq.
OmYq.
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n 101. amyq.
omyq. p. mcd
II. bas. amyg.
FIG. 1. Schematic drawing indicating areas (vertical lines) from which flight (fear) and (horizontal lines) defense (anger) responses were elicited by electrical stimulation. Note the separation of the two zones and the overlapping medially in the region of the central nucleus (37).
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Anatomical
Considerations
The nuclear masses in the amygdaloid complex have been divided in two groups, the basolateral and the corticomedial. The basolateral group, phylogenetically younger (14, 15) and particularly well developed in the primate brain (4, 21), consists of the lateral and the basal nuclei. The basal nucleus itself is divided into a magnocellular lateral part, and a parvocellular medial part. The phylogeneticaly older corticomedial group comprises the medial, cortical and central nuclei and the nucleus of the lateral olfactory tract. In the cat, a medial part of the central nucleus can easily be identified; the cells are distinctly larger and deeper staining. The larger, lateral part is difficult to differentiate from the putamen. On the schematic drawings in this paper, only the medial part is outlined. It is relatively small in the cat, and lies immediately above the basal nucleus. The main afferent projection to the amygdala, demonstrated anatomically, is from the olfactory bulb (3). Electrophysiologically, however, afferent influences from all sensory modalities have been demonstrated (5, 22). The latencies found suggest mediation over long polysynaptic pathways. Wendt and Albe-Fessard (42) found more specifically that somatosensory influences are transmitted to the amygdala of the cat via the secondary somatosensory area (S II) of Rose and Woolsey (28). In recent years evidence has been accumulating to show that the stria terminalis contains afferent fibers. This has been shown anatomically by Ban and Omukai (1) in the rabbit, and such afferent fibers seem to be of importance for the defense response elicited by electrical stimulation in the cat (13). While the stria terminalis is the best known efferent projection from the amygdala, a more important efferent projection in mammalian brain now seems to be a group of medially directed fibers, passing ventral to the internal capsule, the ventral amygdalofugal pathway of Nauta (24). Both in human subjects (19) and monkeys (24) this fiber system is larger than the stria terminals. Gloor (9) has shown electrophysiologically in the cat that the basolateral group of nuclei discharges mainly through the ventral fibers while the corticomedial group projects mainly through the stria terminalis. Anatomically, Nauta points out that fibers of the stria terminalis arise mostly in the caudal part of the amygdaloid complex. In the cat, the basal nucleus sends fibers through both the stria terminalis and the ventral amygdaloid fibers, while the lateral nucleus projects only through ventral fibers (12).
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Nauta (24) has recently mapped in detail the projection areas of these two tiber systemsin the monkey. Just ventral to the central nucleus, the fibers from the two systems cross at right angles. Those from the ventral pathways then course through the central nucleus and form a direct connection to thalamic, sep.tal, lateral hypothalamic and lateral preoptic areas. The ventral fibers thus are connected with important sources of origin for both the stria medulearis and the medial forebrain bundle. These latter fiber bundles form links in what Nauta calls a reciprocal, multisynaptic “limbic system-midbrain circuit.” The stria terminalis, on the other hand, projects mainly to more medially placed areas in the hypothalamus and preoptic area and seems,therefore, less likely to participate in such a mechanism. Hall (12) describes fibers from the lateral nucleus in cats which project to the lateral preoptic and lateral hypothalamic areas. Fibers from the basal nucleus were found by Hall to have preterminals in preoptic regions, substantia innominata and around the anterior commissure. There is also evidence for a direct amygdalomesencephalicconnection, by-passing the hypothalamus, in both human beings and lower mammals. The fibers of this system probably run through the internal capsule and cerebral peduncle (9, 10, 19, 40). Earlier experiments by Ursin and Kaada (38) also point to the existence of such fibers. They found that, in order to abolish the “attention” response(behavioral and EEG arousal) which is elicited by electrical stimulation of the amygdala in cats, it was necessary to surgically circumscribe the amygdaloid complex not only anteromedially and medially, but posteromedially as well. Fiber connections with surrounding neocortical and rhinencephalic structures also have been demonstrated in human subjects and lower mammals (10, 19, 24). Method
The subjects consisted of a group of nineteen wild, stray cats and another group of six tame ,house cats. All were adults (both sexes) weighing 2.1 to 5.4 kg. The wildest and most difficult to handle of all the cats sent to the Anatomical Institute during the years 1958-61 were chosenfor the wild group in the present experiment. They were captured in traps on farms around Oslo and even experienced personnel could not handle them without nets and heavy gloves. Details of feeding and caging procedures have been described (36). After laboratory adaptation for 1 to more than 60 days, the animals
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were periodically observed for 10 to 90 days. The total preoperative period in the laboratory ranged from 3 weeks to 6 months. The first systematic postoperative observation took place 14 days after surgery and, over the following weeks, each cat was observed once or twice weekly. When behavioral changes were found postoperatively, the observation period was prolonged, usually for several months. During this period, the number of observations was kept to a minimum to avoid taming due to handling.The postoperative observation period for all animals ranged from 24 days to more than 6 months. The procedure used for the behavioral observations has been described (36). Briefly, the behavioral responsesto a seriesof graded provocations were systematically observed. There were four standard ways of increasing severity by which the animals were provoked: The investigator first stood in front of the cage, then opened its door and threatened, poked the subject with a stick, and finally trapped the animal with a net. Occurrence of standard responsesa (withdrawal, flight, hissing, growling, etc.) were noted at each stage of provocation. These responses correspond to those seen in the earlier stimulation study (37).? Numerical scoreswere available for only fifteen of the subjects. Accordingly, the evaluation of behavioral changes following the amygdaloid lesions had to be performed independent of this scoring system. A final set of criterions was achieved, and the protocols and scoring sheets,when available, were ranked several times and final conclusions reached before the behavioral data were compared with the histology. This set of criteria became somewhatcomplicated, taking into consideration the preoperative intensity level of the responsesand duration of postoperative changes. The various responsecategories were also given weight according to the experience with the scoring schedule (36). If someof the weaker response categories as “flattening of the ears” or LLwithdrawal” reoccurred postoperatively, this could still be compatible with change in flight or defense behavior. s The scoring sheet described in the previous paper actually was developed in its present form in 1961. For the ten animals in the present study which were observed during the years 1958-60, similar provocations were used, however, and the behavioral categories were identical since they are based on the responses seen in the earlier stimulation experiments. The care and observation of these wild cats for prolonged periods demand considerable effort both from the experimenter and the animal caretaker. Further, it is difficult to get hold of extremely wild cats; therefore, we included these earlier subjects in the present report.
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This detailed analysis was helpful in the primary evaluation of each subject, but did not yield any additional information, and became too complicated when the material was dealt with as a whole. The material was therefore treated as follows: Preoperatively, the cats were either tame, or showed consistent flight or defense behavior, or both. Postoperatively, flight and defense were either reduced, or not changed at all, each response type being considered separately. To be included in the flight group, the cat-at least when poked with a stick [stimulus condition 3 (36)]-had to show consistent opening of the eyes, pupillary dilatation, raising of ears, rapid searching movements, and withdrawal, as well as flight (at least occasionally). To be included in the defense group, the cat had to show preoperative presence of consistent crouching, flattening of ears, and hissing or growling or both, at least to poking with stick. Reduction of flight or defense was recognized when the cat showed loss of one or more of the preoperatively observed response categories, for a month or more postoperatively. Bilateral lesions were produced electrolytically by the usual stereotaxic method during Nembutal anesthesia. Postoperatively, the cats were given penicillin intramuscularly for a few days. In some instances of prolonged postoperative coma lasting for several days, physiological solutions of saline and glucose were given subcutaneously. The first two days after operation a few cats were given milk orally from a syringe with a rubber tubing. In so far as possible, however, the postoperative care was minimized to avoid interference with development of postoperative behavioral changes, even though this probably led to a higher postoperative mortality. The animal caretaker avoided handling of the cats during feeding and cleaning of cages. Other persons were not allowed to open the cage doors or disturb the cats in other ways. Following the completion of the preoperative behavioral testing, nine of the wild cats and all the tame ones were used for an endocrinological experiment. Polyethylene catheters were implanted in the external jugular vein, and two to four S-ml blood samples were taken over a period of 1-5 days. In most cases, the erythrocytes were suspended in a physiological saline solution and reinjected, No changes in behavior were observed following this procedure. The production of lesion of the amygdaloid complex took place no less than 1 week later. Similar blood samples were obtained 1 month after the operation, but the postoperative behavioral data on the 15 cats involved had been collected prior to this time. At the end of experiments, the brains were fixed in formalin, sectioned
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frontally at 20 or 40 ~1,and every tenth or twentieth section stained with thionin or cresyl violet. The sections were coded by a technician to avoid any bias in the experimenter’s evaluation of the lesions. Drawings were traced from a projected microscopic image of serial sections corresponding as close as possible to the levels shown in Fig. lA-F. Care was taken to choose sections representing both the various amygdaloid nuclei and the extent of lesions. If this could not be obtained from any single section, information was sampled from neighboring sections. The border areas of the lesions were examined microscopically with higher magnification. The extent of the bilaterally symmetrical lesion was that transferred to predrawn diagrams of the same type as were used in the stimulation experiment (Fig. 1). The levels A-F are very close together and we are confident that no topographic information of the extent of lesions was lost by this procedure. If a given nucleus was ablated on one side and the fibers from the same nucleus were interrupted on the other side, this was considered from a functional point of view to be essentially a bilateral lesion of that nucleus. The same is true for an area which is fiber-deprived bilaterally. Such lesions are considered to be “functional” lesions. The precise manner of defining a particular functional lesion depends, of course, on the distribution of pathways that one believes to be important for the phenomenon under study. Yet, as discussed above, there are alternative pathways for the amygdala. For the most part, the definition of functional lesions in the present study was based on anatomical considerations that follow from the localization hypothesis of Ursin and Kaada (37). In addition, special attention was paid to the stria terminalis. Retrograde degeneration in amygdaloid cells has never been observed in the cat, nor was it seen in the present material. Damage to pathways, therefore, had to be estimated directly, and yet the fibers involved did not stain heavily. The distribution of pathways was, therefore, inferred from the anatomical organization of the various amygdaloid nuclei, and all histological evaluation based on Nissl-stained material. Results
There seems to be a striking difference between the immediate postoperative behavior of cats with lesions in amygdala and cats with lesions in certain other brain structures (e.g., with septal, neocortical or thalamic lesions). Many of the subjects in the present study were drowsy or even comatose for several days postoperatively. Even when apparently awake,
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they were strikingly hypoactive (sluggish). The slang designation “amygdala hangover,” coined by Weiskrantz (41) for monkeys, is very descriptive also for cats. After this immediate postoperative period, little or no general change was seen, however, in the previously tame animals. Many of the cats that preoperatively had shown flight and defense responses, by contrast, were strikingly different also in later postoperative stages. All degrees of change in reactivity were seen. In some cats, preoperative levels of flight or defense returned rather quickly. For some, there was only a slight reduction in affective behavior which gradually returned to preoperative level; for others there was a very severe reduction, lasting throughout the whole observation period which, for cases of severe changes, extended to 6 months. Changes in defense behavior were less frequently produced than were changes in flight behavior. When produced, however, the reduction in defense responses was clear-cut and long-lasting. Lesion and Behavior Analysis. Figures 2 and 3 illustrate the extent of the lesions in the various subjects. Since all the sections in Fig. 1 could not be shown for each subject in this paper, sections C and E were chosen as the most critical. The localization of lesions at these two levels is most relevant to the localization hypothesis to be tested. From Fig. 1, it can be seen that lesions mainly localized to section C would be expected to reduce flight behavior, while lesions in section E would mainly reduce defense behavior. In general, the lesions were found to be small and localized mainly within the amygdaloid complex. Additional damage was found in putamen, pallidum, and internal capsule in a number of animals. The lesions also sometimes encroached upon the hippocampus, but only to a small extent. Before operation, thirteen cats showed consistent flight behavior during testing. This response was clearly reduced by the lesion in eight of these animals. The effective lesions for the reduction of flight behavior were most consistently localized in the rostra1 half of the lateral nucleus of amygdala. This corresponds to Fig. lB, C & D. The lesions in the five cats that did not show a decrement in flight behavior were small, diffusely scattered, and did not substantially involve the rostra1 half of the basolateral group of nuclei. Consistent defense responses were observed preoperatively in twelve cats. Significant reduction of defensive behavior following surgery was found in four. These four cats had lesions throughout the amygdaloid complex, but the area most consistently destroyed seemed to be the caudal Part
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of the basal nucleus. In two of the eight cats that did not show any reduction of defense behavior, no symmetrical lesion could be found at all. The lesions in the other six cats were extensive, however, and also were found in the caudal parts of the basal nucleus in three cats; however, the lesion in this area was very small in each of the three cats. At the level of Fig. lC, effective lesions tended to be more medially located than negative ones. In
Ft
#I4
Ft
x4
FtD
a
F-
FLIGHT
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x17
F-D-
\
FIG. 2. Extent of lesions. Each S is represented by two sections, corresponding to levels C and E on Fig. 1. F+ : reduction of flight; F-: no change in flight; D+ : reduction of defense; D-: no change in defense. Lightly shaded: Unilateral lesions (angle of lines indicates right or left side) ;. darkly shaded: bilaterally symmetrical lesions; dotted: bilaterally fiber-deprived area.
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Fig. ID, there was no difference between effective and ineffective lesions for this group. Stria terminalis was substantially damaged in two of the effective lesions (for defense behavior) but, in the other two affected cats, little or no encroachment of the stria terminalis and the corticomedial group of nuclei was found. Furthermore, extensive involvement of the stria terminalis fibers was found in two of the cats that showed no reduction of defense responses. This comparison of effective and ineffective lesions is admittedly far from conclusive, but it suggests a localization of flight and defense zones that is comparable to the findings in the stimulation experiments (Fig. 1). TO avoid a bias in the histological evaluation of this matter, coded drawings of the lesions at all levels (Fig. 1 A-F) for all cats in the experiment were rated by three independent observers. Each observer rated, on a seven-point scale, the degree to which the bilaterally symmetrical lesion involved the two zones which were defined in the earlier stimulation experiment. Interruption of medially passing fibers from each zone was taken into account, as exemplified by the functional lesions (dotted areas) shown in Figs. 2 and 3. Complete agreement in rating was found for half the lesions that led to reduction of flight behavior, and for two-thirds of the lesions that influenced defense behavior. Disagreement never exceeded two points between observers and no judge ever deviated from the median judgment by more than one point. Based on this rating, the material was divided into two: lesion, or no lesion of the respective zones. For this final judgment, there was disagreement between one observer and the two others for one subject in the flight material, and for two subjects in the defense material. When these ratings of the lesions were treated statistically (32), there was found to be a significant relationship between the decrement in flight behavior and the presence of a lesion in the flight zone (p = 0.005). With regard to animals showing a decrement in defense behavior, no significant correlation with lesion of the defense zone could be demonstrated (p = 0.42). In fact, there was a better, although not significant, relationship between the decrement in flight behavior and the location of lesions in the defense zone (p = 0.09). Reduction of defense responses also did not correlate with lesions of amygdaloid fiber projections postulated to be of importance for the defense response by other workers: stria terminalis efferent (7); or stria terminalis afferent, efferent via ventral amygdalofugal fibers (13).
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Since so few cats in the present study showed a decrement in defense behavior following amygdaloid damage, the present negative finding is interpreted only as a failure to demonstrate a statistically significant localization, rather than as the definite exclusion of this possibility. Six cats showed both flight and defense behavior preoperatively. Following the operation, ,one showed reduction of both affective patterns, four only decreased their display of flight behavior, and one showed no postoperative change at all. No subjects showed the postoperative combination of reduced defense behavior and unaltered flight. That such a dissociation of postoperative changes can occur, however, is suggested by observations on four moderately wild cats studied subsequently by the present author in a small supplemental study at another laboratory (University of Chicago). All four animals showed clearly reduced defense behavior postoperatively; in two of them, moreover, there was no associated loss of Cl
F-D
c2
b
F-D
+
P
FIG. 3. Extent of lesions in supplementary, Chicago material. Symbols as in Fig. 2.
flight behavior. The caudal parts of the basolateral complex were damaged in each of these animals and the lesion was confined to that area in the two that showed the dissociatedpostoperative deficit (Fig. 3). No other manifestations of the Kliiver-Bucy syndrome were systematically studied in the present material. No signs of male hypersexuality (mounting males, mounting outside territory) were observed in any of the present subjects. Discussion
The present results indicate that flight and defensebehavior may be reduced by lesionsrestricted to parts of the amygdaloid complex. The main
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results also indicate that an appropriate amygdaloid lesion can reduce flight behavior without influencing defense behavior. It is suggested by supplemental findings that it is also possible to reduce defense responses alone without influencing flight behavior. This is taken as further evidence to support the view that the two affective behavior patterns are distinguishable in the cat, and that separate neural mechanisms are involved. The data also show that the localization of the lesions seems to be crucial for the type of effects obtained. Flight behavior was reduced by damage to the flight zone demonstrated in previous stimulation experiments (37). Defense behavior may also be eliminated or reduced by small amygdaloid lesions, but the reduction of this response could not be predicted reliably from the localization of the lesion. This seems most reasonably attributed to the small number of cats showing postoperative reduction of defense behavior. In none of these subjects, however, was there any clear contradiction of the localization hypothesis. Neither was there any total lesion of the postulated defense zone in those subjects showing no changes in behavior. Finally, no other type of localization within the amygdala was suggested by the results. The failure to demonstrate any crucial localization for those lesions producing a loss of defense responses may also be due to differences between the defense responses of intact animals and the pattern of defensive behavior induced by stimulation. The localization hypothesis is based on the assumption that the two patterns of response are identical. However, it is true that growling was found to be more frequent than hissing in the stimulation studies, while the reverse was true for the response in intact cats (36). Fernandez de Molina and Hunsperger (6, 7) also found that amygdaloid stimulation produced growling more frequently than hissing, while the reverse was true for responses elicited from diencephalic structures. This suggests the possibility that defense behavior may be organized hierarchally in the central nervous system in a way which makes the effects of amygdaloid lesions ambiguous. When effective, on the other hand, the amygdaloid lesions did reduce the whole defense response, and not merely parts of it. Moreover, the observed decrement was always severe and long-lasting. Finally, even if the behavioral changes are evaluated without taking hissing into consideration, essentially the same results are obtained. The localization hypothesis which underlies the present work suffers from the lack of one important control; no lesions restricted to the pyri-
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form cortex have yet been obtained. Since fibers from this adjacent area travel through the amygdaloid nuclei, effects ascribed to amygdaloid lesion could be due to ablating fibers of passage from the pyriform cortex. Stimulation of this area, however, did not yield either flight, defense or attention responses (3 7). Among the many behavioral changes reported to follow temporal lobe lesions, increased tameness is certainly the best established one. Postoperative reduction of “fear,” escape behavior or agressive behavior or both, has been produced in all species investigated. This has been observed in human beings (34), monkeys (16, 20, 25-27, 29, 31, 39, 41), cats (18, 30, 31), dogs (8), rats (44) and in the lynx and agouti (31). The so-called “hyperemotionality,” produced by septal lesions in rats, is also known to be completely abolished by subsequent lesions in the amygdala ( 17). The relevance of these findings to the defects produced in avoidance behavior by the same lesions will be discussed in detail in a subsequent paper. Morgane and Kosman (23) suggested that taming, following amygdaloid lesions in cats, may be due only to adaptation to the laboratory environment. This explanation can not hold for other species like lynx and wild rats in which taming also has been described. For the present experiment, several objections may be raised against such an interpretation. For one thing, wild stray cats have been observed at Oslo for as long as 6 months without showing any significant changes in affective behavior (36). Moreover, small or misplaced lesions do not produce any significant taming effect. The ,frequently observed late postoperative recovery of affective behavior is also contrary to what would be expected if the increased tameness were only a function of adaptation. Increased rage behavior, somewhat paradoxically, also has been reported to follow temporal lobe lesions (2, 11, 33, 43). Such increased rage reactions have only been observed in cats. Since taming has been described also in this species by several authors, it is no longer possible results. to resort to “species differences” to explain these contradictory Whether lesions are produced by electrocoagulation or by aspiration seems to be of no importance. One reasonable possibility seems to be that the two types of behavioral change result from the differential involvement of at least two different temporal lobe structures, although this can not be documented at the present time. The data presented by Green, Clemente and de Groot (11) suggest an interesting possibility. Sixteen of their eighty-two cats with temporal lobe lesions showed aggressive be-
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havior postoperatively. All of these sixteen cats had epileptic seizures, and in all of them the lesions encroached upon the hippocampus. In the material of Bard and Mountcastle (2) and Spiegel, Miller and Oppenheimer (32), however, the lesions producing rage were reported to be restricted to the amygdala and the overlying pyriform cortex. Finally, Wood (43) did obtain “fear or anger” by stimulating the basal and central nucleus but, surprisingly, he reports that lesions of the central nucleus also produced a form of aggressive behavior, consisting of growling, biting and clawing. In the animals of the present study, no increment in any category of defense behavior was ever observed, neither in previously tame nor in previously wild cats. Many of the lesions, moreover, certainly did involve the central nucleus, and in some cases encroached upon the hippocampus as well. The hippocampal lesions were very small, however, and no epileptic seizures were ever observed. Fernandez de Molina and Hunsperger (6, 7) have described a subcortical system for types of flight and defense responses which are similar to those observed in the present work. Their proposed system extends from the dorsomedial parts of the amygdala, through stria terminalis, to the level of the anterior commissure; it then further extends to the preoptic area, through the hypothalamus, and caudally to the central gray matter of the midbrain. According to these investigators, defense and escape (flight) behavior can be elicited separately from separate zones in the brain stem. They describe two “inner” zones (perifornical regions of hypothalamus and central gray of mesencephalon) which are related to defense behavior and one LLouter” zone which is related to the flight pattern of response. Hilton and Zbroiyna (13) suggested that the fibers of the stria terminalis seem to be afferent rather than efferent with regard to amygdaloid control of affective behavior. These authors suggest, as an efferent pathway, a direct band to the hypothalamus which coincides with the ventral amygdalofugal fibers and with the medial extension of the flight and defense zone of Ursin and Kaada (37). Hilton and Zbroiyna, however, did not distinguish between the two responses they studied. Their defense response contained components of both flight and defense behavior. The suggested relationship between the stria terminalis (whether it be efferent or afferent) and the defense response is of interest, since Ursin and Kaada found their defense zone to be located caudomedially within the amygdala, mainly in the basal nucleus, a region having at least
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efferent connections through the stria terminalis. It is perhaps more likely, however, that the ventral amygdalofugal fibers, rather that the stria terminalis, handle the output from the medial structures, since the former fibers have more intimate connections with the limbic-midbrain circuit of Nauta, a circuit which, on general grounds, seems likely to be important for such affective behavior. References 1. BAN, T., and F. OMUKAI. 19.59. tions of the amygdaloid nuclei in 2. BARD, P., and V. B. MOUNTCASTLE. in expression of rage with special
Experimental studies on the fiber connecthe rabbit. J. Camp. Neurol. 113: 245-280. 1948. Some forebrain mechanisms involved reference to suppression of angry behavior. Res. Publ. Assoc. Res. Nervous Mental Disease 27: 362-404. 3. LE GROS CLARK, W. E., and M. MEYER. 1947. The terminal connections of the olfactory tract in the rabbit. Brain 70: 304-328. 4. CROSBY,E. C., and T. HUMPHREY. 1941. Studies of the vertebrate telencephalon. II. The nuclear pattern of the anterior olfactory nucleus, tuberculum olfactorium and the amygdaloid complex in adult man.J. Comp. Neurol. 74: 309-352. 5. DELL, P., and R. OLSON. 1951. Projections “secondaires” mCsencCphaliques, diencephaliques et amygdaliennes des afferences viscerales vagales. Compt. Rend. Sot. Biol. 146: 1088-1091. DE MOLINA, A., and R. W. HUNSPERGER. 1959. Central representa6. FERNANDEZ tion of affective reactions in forebrain and brain stem: Electrical stimulation of amygdala, stria terminalis, and adjacent structures. J. Physiol. London 146: 251-265. FERNANLIEZ DE MOLINA, A., and R. W. HUNSPERGER. 1962. Organization of 7. the subcortical system governing defense and flight reactions in the cat. J. Physiol. London 160: 200-213. 8. FULLER, J. L., H. E. ROSVOLD, and K. H. PRIBIWM. 1957. The effect on
9. 10. 11. 12. 13.
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affective and cognitive behavior in the dog of lesions of the pyriform-amygdalahippocampal complex. J. Camp. Physiol. Psychol. 50: 89-96. GLOOR, P. 195.5. Electrophysiological studies on the connections of the amygdaloid nucleus in the cat. Electroencephalog. Clin. Neurophysiol. 7: 223-264. GLOOR, P. 1960. Amygdala, pp. 1395-1420. In “Handbook of Physiology, Volume 1, Section I: Neurophysiology,” J. Field, H. W. Magoun, and V. E. Hall [eds.]. Williams and Wilkins, Baltimore, Maryland. GREEN, J. D., C. D. CLEMENTE, and J. DE GROOT. 1957. Rhinencephalic lesions and behavior in cats. J. Camp. Neural. 108: 505-536. HALL, E. 1963. Efferent connections of the basal and lateral nuclei of the amygdala in cat. Am. J. Anat. 113: 139-145. 1963. Amygdaloid region for defense HILTON, S. M., and A. W. ZBRO~YNA. reactions and its afferent pathway to the brain stem. J. Physiol. London 166: 160-173. HOLMGREN, N. 1925. Points of view concerning forebrain morphology in higher vertebrates. Acta Zool. Stockholm 6: 414-477.
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J. B. 1923. Further contributions to the study of the evolution forebrain. /. Camp. Neural. 38: 337-481. KENNARD, M. A. 1957. Effect of temporal pole ablations on epileptic tendencies of monkeys. Neurology 7: 404-414. KLING, F. A., and P. M. MEYER. 1958. Effects of amygdaloid lesions upon septal hyperemotionality in the rat. Science 128: 655-656. KLING, A., J. ORBACH, N. SCHWARZ, and J. TOWNE. 1960. Injury to the limbic system and associated structures in cats. Arch. Gen. Psychiat. 3: 391-420. KLINGER, J., and P. GLOOR. 1960. The connections of the amygdala and of the anterior temporal cortex in the human brain. J. Comp. Nezirol. 115: 333-369. KLUVER, H., and P. C. BUCY. 1939. Preliminary analysis of functions of the temporal lobes in monkeys. A.M.A. Arch. Neural. Psychiat. 42: 979-1000. LAUER, E. W. 1945. The nuclear pattern and fiber connections of certain basal telencephalic centers in the macaque. J. Comp. Neural. 82: 215-254. MACHNE, X., and J. P. SEGUNDO. 1956. Unitary responses to afferent volleys in amygdaloid complex. J. Neurophysiol. 19: 232-240. MORGANE, P. J., and A. J. KOSMAN. 1957. Alterations in feline behaviour following bilateral amygdalectomy. Nature 180: 598600. NAUTA, W. J. H. 1961. Fibre degeneration following lesions of the amygdaloid complex in the monkey. J. Anat. 95: 515-531. PINTO HAMLJY, T., G. SANTIBANEZ, C. GONZALES, and E. VICENCIO. 1957. Changes in behavior and visual discrimination performances after selective ablations of the temporal cortex. J. Camp. Physiol. Psychol. 50: 379.385. POIRER, L. J. 1952. Anatomical and experimental studies on the temporal lobe of the macaque. J. Comp. Nearol. 96: 209-248. PRIBRAM, K. H., and M. BAGSHAW. 1953. Further analysis of the temporal lobe syndrome utilizing frontotemporal ablations. J. Comp. Neural. 99: 347-375. ROSE, J. E., and C. N. WOOLSEY. 1949. Organization of the mammalian thalamus and its relationships to the cerebral cortex. Electroencephalog. Clin. Neurophysiol. 1: 390.403. ROSVOLD, H. E., A. F. MIRSXY, and K. H. PRIBRAM. 1954. Influence of amygdalectomy on social behavior in monkeys. J. Camp. Physiol. Psychol. 47: 173-178. SCHREIXER, L., and A. KLINC. 1953. Behavioral changes following rhinencephalic injury in cat. J. Neurophysiol. 16: 643-659. SCHREINER, L., and A. KLING. 1956. Rhinencephalon and behavior. Am. J. Physiol. 184: 486-490. SIEGEL, S. 1956. “Nonparametric Statistics.” McGraw-Hill, New York. SPIEGEL, E. A., H. R. MILLER, and M. J. OPPENHEIMER. 1940. Forebrain and rage reactions. J. Neurophysiol. 3: 538-548. TERZIAN, H., and G. DALLE ORE. 1955. Syndrome of Kliiver and Bucy. Reproduced in man by bilateral removal of the temporal lobes. Neurology 5: 373-380. URSIN, H. 1960. The temporal lobe substrate of fear and anger. Acta Psychiat. Neural. &and. 35: 378-396. JOHNSTON,
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43. 44.
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URSIN, H. 1964. Flight and defense behavior in cats. /. Camp. Physiol. Psychol. (in press). URSIN, H., and B. R. KAADA. 1960. Functional localization within the amygdaloid complex in the cat. Electroencephalog. Clin. Neurophysiol. 12: l-20. URSIN, H., and B. R. KAADA. 1960. Subcortical structures mediating the attention response induced by amygdala stimulation. Exptl. Neural. 2: 109-122. WALKER, A. E., A. F. THOMSON, and J. D. MCQUEEN. 1953. Behavior and the temporal rhinencephalon in the monkey. Bull. Johns Hopkins Hosp. 93: 65-93. WALL, P. D., and G. D. DAVIS. 1951. Three cerebral cortical systems affecting autonomic function. J. Neurophysiol. 14: 507-517. WEISKRANTZ, L. 1956. Behaviora changes associated with abIation of the amygdaloid complex in monkeys. J. Camp. Physiol. Psychol. 49: 381-391. WENDT, R., and D. ALBE-FESSARD. 1962. Sensory responses of the amygdala with special reference to somatic afferent pathways. pp. 171-198. In “Physiologie de I’hippocampe.” editions du centre national de la recherche scientifique, Paris. WOOD, C. D. 1958. Behavioral changes following discrete lesions of temporal lobe structures. Neurology 8: 215-220. WOODS, J. W. 1956. “Taming” of the wild Norway rat by rhinencephalic lesions. Nature 178: 869.
The
NEUROLOGY
Effect
11,
of
61-79
(1965)
Amygdaloid
Defense
Lesions
Behavior HOLGER
on
Flight
and
in Cats
URSIN~
Neurophysiological Laboratory at the Anatomical Institute, University of Oslo, Norway, and Laboratory for Physiological Psychology, University of Chicago, Chicago, Illinois Received
July
13, 1964
The characteristics of flight and defense behavior in cats have been described in previous publications. Similar responses have been elicited by electrical stimulation of two separate zones within the amygdaloid complex. In the presented material, small bilateral lesions of the amygdala were produced electrolytically in six tame and nineteen wild stray cats. Postoperatively, previously wild cats showed loss or reduction of flight or defense behavior, or both. These two patterns of response could be reduced separately or in combination. Flight behavior was significantly reduced specifically by lesions of the flight zone, as defined by prior stimulation studies. No significant correlation was found between lesions of the similarly defined defense zone and a reduction of defense behavior. Neither type of behavioral change was seen postoperatively in the tame cats. Introduction
Bilateral lesions in the temporal lobes produce profound changes in behavior. Kliiver and Bucy (20) described a syndrome in monkeys consisting of psychic blindness (visual agnosia), strong oral tendencies, hypermetamorphosis (excessive tendency to attend and react to visual stimuli), hypersexuality and hyperphagia. Emotional behavior was also considerably changed in the direction of increased tameness; there was a dramatic decrease in aggressive behavior and a loss of fear reactions. Subsequent work has confirmed the fact that this whole syndrome of 1 Sponsored in part by the Norwegian Research Council for Science and the Humanities, and in part by the United States Public Health Service (NIH-FF-272). The author is indebted to Professor B. R. Kaada, University of Oslo, and Professor for generous help and encouragement. R. A. McCleary, University of Chicago, Valuable assistance at various stages of the work was provided by Caroline Jones, Else Melstr$m, Werner Pedersen, and Irving Zucker. 61
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behavioral changes, or parts of it, may be produced by bilateral temporal lobe lesions in a variety of species. The relevant literature has been reviewed by Gloor (10) and Ursin (35). What is still needed, however, is identification of structures in the temporal lobes that are involved in the various parts of the Kliiver-Bucy syndrome. A careful study which included the observation of the normal behavior patterns in question, by Green, Clemente and de Groot (ll), determined the anatomical substrate for two parts of the Kliiver-Bucy syndrome in the cat. They ascribed male hypersexuality to bilateral lesions restricted to the pyriform cortex, and hyperphagia to lesions of the basal and lateral parts of the amygdala. Which part of the temporal lobe resection is responsible for taming such operated animals, however, is still not clearly understood. Schreiner and Kling (30) reported increased tameness in cats following lesions restricted to the amygdaloid complex and the overlying pyriform cortex. Walker, Thomson and McQueen (39) found that postoperative tameness and fearlessness in monkeys correlated fairly well with the amount of damage to the amygdaloid complex, but there were exceptions to this. Rosvold, Mirsky and Pribram (29) found similar behavioral changes to correlate with the extent of damage to the basolateral nuclei. Ursin (35) suggested more specifically that, for an amygdaloid lesion to produce tameness, it must disrupt the fear (flight) and anger (defense) zones already demonstrated by stimulation of the amygdala Ursin and Kaada (3 7) elicited flight responses in an area extending from the rostra1 part of the lateral nucleus and the preamygdaloid area through the region of the central nucleus and into the internal capsule. Defense responses, on the other hand, resulted from stimulation of more ventromedial and caudal parts of the amygdala, i.e., from the posterior part of the lateral nucleus and from the lateral part of the basal nucleus (Fig. 1). The present experiments were designed to test further whether small lesions restricted to the amygdaloid complex would produce taming and, moreover, to see whether the same two separate zones could be confirmed by the type of emotional deficit resulting from localized lesions within the amygdala. Wild stray cats, used as the main experimental subjects, spontaneously show the entire range of emotional behavior that is observed following stimulation of the amygdala. It has been possible to identify objectively these various patterns of emotional behavior in such wild cats (36).
FLIGHT
AND
DEFENSE
p 101.
PYf.
n. 101. amyq.
OmYq.
63
BEHAVIOR
n 101. amyq.
omyq. p. mcd
II. bas. amyg.
FIG. 1. Schematic drawing indicating areas (vertical lines) from which flight (fear) and (horizontal lines) defense (anger) responses were elicited by electrical stimulation. Note the separation of the two zones and the overlapping medially in the region of the central nucleus (37).
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Anatomical
Considerations
The nuclear masses in the amygdaloid complex have been divided in two groups, the basolateral and the corticomedial. The basolateral group, phylogenetically younger (14, 15) and particularly well developed in the primate brain (4, 21), consists of the lateral and the basal nuclei. The basal nucleus itself is divided into a magnocellular lateral part, and a parvocellular medial part. The phylogeneticaly older corticomedial group comprises the medial, cortical and central nuclei and the nucleus of the lateral olfactory tract. In the cat, a medial part of the central nucleus can easily be identified; the cells are distinctly larger and deeper staining. The larger, lateral part is difficult to differentiate from the putamen. On the schematic drawings in this paper, only the medial part is outlined. It is relatively small in the cat, and lies immediately above the basal nucleus. The main afferent projection to the amygdala, demonstrated anatomically, is from the olfactory bulb (3). Electrophysiologically, however, afferent influences from all sensory modalities have been demonstrated (5, 22). The latencies found suggest mediation over long polysynaptic pathways. Wendt and Albe-Fessard (42) found more specifically that somatosensory influences are transmitted to the amygdala of the cat via the secondary somatosensory area (S II) of Rose and Woolsey (28). In recent years evidence has been accumulating to show that the stria terminalis contains afferent fibers. This has been shown anatomically by Ban and Omukai (1) in the rabbit, and such afferent fibers seem to be of importance for the defense response elicited by electrical stimulation in the cat (13). While the stria terminalis is the best known efferent projection from the amygdala, a more important efferent projection in mammalian brain now seems to be a group of medially directed fibers, passing ventral to the internal capsule, the ventral amygdalofugal pathway of Nauta (24). Both in human subjects (19) and monkeys (24) this fiber system is larger than the stria terminals. Gloor (9) has shown electrophysiologically in the cat that the basolateral group of nuclei discharges mainly through the ventral fibers while the corticomedial group projects mainly through the stria terminalis. Anatomically, Nauta points out that fibers of the stria terminalis arise mostly in the caudal part of the amygdaloid complex. In the cat, the basal nucleus sends fibers through both the stria terminalis and the ventral amygdaloid fibers, while the lateral nucleus projects only through ventral fibers (12).
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Nauta (24) has recently mapped in detail the projection areas of these two tiber systemsin the monkey. Just ventral to the central nucleus, the fibers from the two systems cross at right angles. Those from the ventral pathways then course through the central nucleus and form a direct connection to thalamic, sep.tal, lateral hypothalamic and lateral preoptic areas. The ventral fibers thus are connected with important sources of origin for both the stria medulearis and the medial forebrain bundle. These latter fiber bundles form links in what Nauta calls a reciprocal, multisynaptic “limbic system-midbrain circuit.” The stria terminalis, on the other hand, projects mainly to more medially placed areas in the hypothalamus and preoptic area and seems,therefore, less likely to participate in such a mechanism. Hall (12) describes fibers from the lateral nucleus in cats which project to the lateral preoptic and lateral hypothalamic areas. Fibers from the basal nucleus were found by Hall to have preterminals in preoptic regions, substantia innominata and around the anterior commissure. There is also evidence for a direct amygdalomesencephalicconnection, by-passing the hypothalamus, in both human beings and lower mammals. The fibers of this system probably run through the internal capsule and cerebral peduncle (9, 10, 19, 40). Earlier experiments by Ursin and Kaada (38) also point to the existence of such fibers. They found that, in order to abolish the “attention” response(behavioral and EEG arousal) which is elicited by electrical stimulation of the amygdala in cats, it was necessary to surgically circumscribe the amygdaloid complex not only anteromedially and medially, but posteromedially as well. Fiber connections with surrounding neocortical and rhinencephalic structures also have been demonstrated in human subjects and lower mammals (10, 19, 24). Method
The subjects consisted of a group of nineteen wild, stray cats and another group of six tame ,house cats. All were adults (both sexes) weighing 2.1 to 5.4 kg. The wildest and most difficult to handle of all the cats sent to the Anatomical Institute during the years 1958-61 were chosenfor the wild group in the present experiment. They were captured in traps on farms around Oslo and even experienced personnel could not handle them without nets and heavy gloves. Details of feeding and caging procedures have been described (36). After laboratory adaptation for 1 to more than 60 days, the animals
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were periodically observed for 10 to 90 days. The total preoperative period in the laboratory ranged from 3 weeks to 6 months. The first systematic postoperative observation took place 14 days after surgery and, over the following weeks, each cat was observed once or twice weekly. When behavioral changes were found postoperatively, the observation period was prolonged, usually for several months. During this period, the number of observations was kept to a minimum to avoid taming due to handling.The postoperative observation period for all animals ranged from 24 days to more than 6 months. The procedure used for the behavioral observations has been described (36). Briefly, the behavioral responsesto a seriesof graded provocations were systematically observed. There were four standard ways of increasing severity by which the animals were provoked: The investigator first stood in front of the cage, then opened its door and threatened, poked the subject with a stick, and finally trapped the animal with a net. Occurrence of standard responsesa (withdrawal, flight, hissing, growling, etc.) were noted at each stage of provocation. These responses correspond to those seen in the earlier stimulation study (37).? Numerical scoreswere available for only fifteen of the subjects. Accordingly, the evaluation of behavioral changes following the amygdaloid lesions had to be performed independent of this scoring system. A final set of criterions was achieved, and the protocols and scoring sheets,when available, were ranked several times and final conclusions reached before the behavioral data were compared with the histology. This set of criteria became somewhatcomplicated, taking into consideration the preoperative intensity level of the responsesand duration of postoperative changes. The various responsecategories were also given weight according to the experience with the scoring schedule (36). If someof the weaker response categories as “flattening of the ears” or LLwithdrawal” reoccurred postoperatively, this could still be compatible with change in flight or defense behavior. s The scoring sheet described in the previous paper actually was developed in its present form in 1961. For the ten animals in the present study which were observed during the years 1958-60, similar provocations were used, however, and the behavioral categories were identical since they are based on the responses seen in the earlier stimulation experiments. The care and observation of these wild cats for prolonged periods demand considerable effort both from the experimenter and the animal caretaker. Further, it is difficult to get hold of extremely wild cats; therefore, we included these earlier subjects in the present report.
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This detailed analysis was helpful in the primary evaluation of each subject, but did not yield any additional information, and became too complicated when the material was dealt with as a whole. The material was therefore treated as follows: Preoperatively, the cats were either tame, or showed consistent flight or defense behavior, or both. Postoperatively, flight and defense were either reduced, or not changed at all, each response type being considered separately. To be included in the flight group, the cat-at least when poked with a stick [stimulus condition 3 (36)]-had to show consistent opening of the eyes, pupillary dilatation, raising of ears, rapid searching movements, and withdrawal, as well as flight (at least occasionally). To be included in the defense group, the cat had to show preoperative presence of consistent crouching, flattening of ears, and hissing or growling or both, at least to poking with stick. Reduction of flight or defense was recognized when the cat showed loss of one or more of the preoperatively observed response categories, for a month or more postoperatively. Bilateral lesions were produced electrolytically by the usual stereotaxic method during Nembutal anesthesia. Postoperatively, the cats were given penicillin intramuscularly for a few days. In some instances of prolonged postoperative coma lasting for several days, physiological solutions of saline and glucose were given subcutaneously. The first two days after operation a few cats were given milk orally from a syringe with a rubber tubing. In so far as possible, however, the postoperative care was minimized to avoid interference with development of postoperative behavioral changes, even though this probably led to a higher postoperative mortality. The animal caretaker avoided handling of the cats during feeding and cleaning of cages. Other persons were not allowed to open the cage doors or disturb the cats in other ways. Following the completion of the preoperative behavioral testing, nine of the wild cats and all the tame ones were used for an endocrinological experiment. Polyethylene catheters were implanted in the external jugular vein, and two to four S-ml blood samples were taken over a period of 1-5 days. In most cases, the erythrocytes were suspended in a physiological saline solution and reinjected, No changes in behavior were observed following this procedure. The production of lesion of the amygdaloid complex took place no less than 1 week later. Similar blood samples were obtained 1 month after the operation, but the postoperative behavioral data on the 15 cats involved had been collected prior to this time. At the end of experiments, the brains were fixed in formalin, sectioned
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frontally at 20 or 40 ~1,and every tenth or twentieth section stained with thionin or cresyl violet. The sections were coded by a technician to avoid any bias in the experimenter’s evaluation of the lesions. Drawings were traced from a projected microscopic image of serial sections corresponding as close as possible to the levels shown in Fig. lA-F. Care was taken to choose sections representing both the various amygdaloid nuclei and the extent of lesions. If this could not be obtained from any single section, information was sampled from neighboring sections. The border areas of the lesions were examined microscopically with higher magnification. The extent of the bilaterally symmetrical lesion was that transferred to predrawn diagrams of the same type as were used in the stimulation experiment (Fig. 1). The levels A-F are very close together and we are confident that no topographic information of the extent of lesions was lost by this procedure. If a given nucleus was ablated on one side and the fibers from the same nucleus were interrupted on the other side, this was considered from a functional point of view to be essentially a bilateral lesion of that nucleus. The same is true for an area which is fiber-deprived bilaterally. Such lesions are considered to be “functional” lesions. The precise manner of defining a particular functional lesion depends, of course, on the distribution of pathways that one believes to be important for the phenomenon under study. Yet, as discussed above, there are alternative pathways for the amygdala. For the most part, the definition of functional lesions in the present study was based on anatomical considerations that follow from the localization hypothesis of Ursin and Kaada (37). In addition, special attention was paid to the stria terminalis. Retrograde degeneration in amygdaloid cells has never been observed in the cat, nor was it seen in the present material. Damage to pathways, therefore, had to be estimated directly, and yet the fibers involved did not stain heavily. The distribution of pathways was, therefore, inferred from the anatomical organization of the various amygdaloid nuclei, and all histological evaluation based on Nissl-stained material. Results
There seems to be a striking difference between the immediate postoperative behavior of cats with lesions in amygdala and cats with lesions in certain other brain structures (e.g., with septal, neocortical or thalamic lesions). Many of the subjects in the present study were drowsy or even comatose for several days postoperatively. Even when apparently awake,
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they were strikingly hypoactive (sluggish). The slang designation “amygdala hangover,” coined by Weiskrantz (41) for monkeys, is very descriptive also for cats. After this immediate postoperative period, little or no general change was seen, however, in the previously tame animals. Many of the cats that preoperatively had shown flight and defense responses, by contrast, were strikingly different also in later postoperative stages. All degrees of change in reactivity were seen. In some cats, preoperative levels of flight or defense returned rather quickly. For some, there was only a slight reduction in affective behavior which gradually returned to preoperative level; for others there was a very severe reduction, lasting throughout the whole observation period which, for cases of severe changes, extended to 6 months. Changes in defense behavior were less frequently produced than were changes in flight behavior. When produced, however, the reduction in defense responses was clear-cut and long-lasting. Lesion and Behavior Analysis. Figures 2 and 3 illustrate the extent of the lesions in the various subjects. Since all the sections in Fig. 1 could not be shown for each subject in this paper, sections C and E were chosen as the most critical. The localization of lesions at these two levels is most relevant to the localization hypothesis to be tested. From Fig. 1, it can be seen that lesions mainly localized to section C would be expected to reduce flight behavior, while lesions in section E would mainly reduce defense behavior. In general, the lesions were found to be small and localized mainly within the amygdaloid complex. Additional damage was found in putamen, pallidum, and internal capsule in a number of animals. The lesions also sometimes encroached upon the hippocampus, but only to a small extent. Before operation, thirteen cats showed consistent flight behavior during testing. This response was clearly reduced by the lesion in eight of these animals. The effective lesions for the reduction of flight behavior were most consistently localized in the rostra1 half of the lateral nucleus of amygdala. This corresponds to Fig. lB, C & D. The lesions in the five cats that did not show a decrement in flight behavior were small, diffusely scattered, and did not substantially involve the rostra1 half of the basolateral group of nuclei. Consistent defense responses were observed preoperatively in twelve cats. Significant reduction of defensive behavior following surgery was found in four. These four cats had lesions throughout the amygdaloid complex, but the area most consistently destroyed seemed to be the caudal Part
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of the basal nucleus. In two of the eight cats that did not show any reduction of defense behavior, no symmetrical lesion could be found at all. The lesions in the other six cats were extensive, however, and also were found in the caudal parts of the basal nucleus in three cats; however, the lesion in this area was very small in each of the three cats. At the level of Fig. lC, effective lesions tended to be more medially located than negative ones. In
Ft
#I4
Ft
x4
FtD
a
F-
FLIGHT
AND
DEFENSE
BEHAVIOR
x17
F-D-
\
FIG. 2. Extent of lesions. Each S is represented by two sections, corresponding to levels C and E on Fig. 1. F+ : reduction of flight; F-: no change in flight; D+ : reduction of defense; D-: no change in defense. Lightly shaded: Unilateral lesions (angle of lines indicates right or left side) ;. darkly shaded: bilaterally symmetrical lesions; dotted: bilaterally fiber-deprived area.
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Fig. ID, there was no difference between effective and ineffective lesions for this group. Stria terminalis was substantially damaged in two of the effective lesions (for defense behavior) but, in the other two affected cats, little or no encroachment of the stria terminalis and the corticomedial group of nuclei was found. Furthermore, extensive involvement of the stria terminalis fibers was found in two of the cats that showed no reduction of defense responses. This comparison of effective and ineffective lesions is admittedly far from conclusive, but it suggests a localization of flight and defense zones that is comparable to the findings in the stimulation experiments (Fig. 1). TO avoid a bias in the histological evaluation of this matter, coded drawings of the lesions at all levels (Fig. 1 A-F) for all cats in the experiment were rated by three independent observers. Each observer rated, on a seven-point scale, the degree to which the bilaterally symmetrical lesion involved the two zones which were defined in the earlier stimulation experiment. Interruption of medially passing fibers from each zone was taken into account, as exemplified by the functional lesions (dotted areas) shown in Figs. 2 and 3. Complete agreement in rating was found for half the lesions that led to reduction of flight behavior, and for two-thirds of the lesions that influenced defense behavior. Disagreement never exceeded two points between observers and no judge ever deviated from the median judgment by more than one point. Based on this rating, the material was divided into two: lesion, or no lesion of the respective zones. For this final judgment, there was disagreement between one observer and the two others for one subject in the flight material, and for two subjects in the defense material. When these ratings of the lesions were treated statistically (32), there was found to be a significant relationship between the decrement in flight behavior and the presence of a lesion in the flight zone (p = 0.005). With regard to animals showing a decrement in defense behavior, no significant correlation with lesion of the defense zone could be demonstrated (p = 0.42). In fact, there was a better, although not significant, relationship between the decrement in flight behavior and the location of lesions in the defense zone (p = 0.09). Reduction of defense responses also did not correlate with lesions of amygdaloid fiber projections postulated to be of importance for the defense response by other workers: stria terminalis efferent (7); or stria terminalis afferent, efferent via ventral amygdalofugal fibers (13).
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Since so few cats in the present study showed a decrement in defense behavior following amygdaloid damage, the present negative finding is interpreted only as a failure to demonstrate a statistically significant localization, rather than as the definite exclusion of this possibility. Six cats showed both flight and defense behavior preoperatively. Following the operation, ,one showed reduction of both affective patterns, four only decreased their display of flight behavior, and one showed no postoperative change at all. No subjects showed the postoperative combination of reduced defense behavior and unaltered flight. That such a dissociation of postoperative changes can occur, however, is suggested by observations on four moderately wild cats studied subsequently by the present author in a small supplemental study at another laboratory (University of Chicago). All four animals showed clearly reduced defense behavior postoperatively; in two of them, moreover, there was no associated loss of Cl
F-D
c2
b
F-D
+
P
FIG. 3. Extent of lesions in supplementary, Chicago material. Symbols as in Fig. 2.
flight behavior. The caudal parts of the basolateral complex were damaged in each of these animals and the lesion was confined to that area in the two that showed the dissociatedpostoperative deficit (Fig. 3). No other manifestations of the Kliiver-Bucy syndrome were systematically studied in the present material. No signs of male hypersexuality (mounting males, mounting outside territory) were observed in any of the present subjects. Discussion
The present results indicate that flight and defensebehavior may be reduced by lesionsrestricted to parts of the amygdaloid complex. The main
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results also indicate that an appropriate amygdaloid lesion can reduce flight behavior without influencing defense behavior. It is suggested by supplemental findings that it is also possible to reduce defense responses alone without influencing flight behavior. This is taken as further evidence to support the view that the two affective behavior patterns are distinguishable in the cat, and that separate neural mechanisms are involved. The data also show that the localization of the lesions seems to be crucial for the type of effects obtained. Flight behavior was reduced by damage to the flight zone demonstrated in previous stimulation experiments (37). Defense behavior may also be eliminated or reduced by small amygdaloid lesions, but the reduction of this response could not be predicted reliably from the localization of the lesion. This seems most reasonably attributed to the small number of cats showing postoperative reduction of defense behavior. In none of these subjects, however, was there any clear contradiction of the localization hypothesis. Neither was there any total lesion of the postulated defense zone in those subjects showing no changes in behavior. Finally, no other type of localization within the amygdala was suggested by the results. The failure to demonstrate any crucial localization for those lesions producing a loss of defense responses may also be due to differences between the defense responses of intact animals and the pattern of defensive behavior induced by stimulation. The localization hypothesis is based on the assumption that the two patterns of response are identical. However, it is true that growling was found to be more frequent than hissing in the stimulation studies, while the reverse was true for the response in intact cats (36). Fernandez de Molina and Hunsperger (6, 7) also found that amygdaloid stimulation produced growling more frequently than hissing, while the reverse was true for responses elicited from diencephalic structures. This suggests the possibility that defense behavior may be organized hierarchally in the central nervous system in a way which makes the effects of amygdaloid lesions ambiguous. When effective, on the other hand, the amygdaloid lesions did reduce the whole defense response, and not merely parts of it. Moreover, the observed decrement was always severe and long-lasting. Finally, even if the behavioral changes are evaluated without taking hissing into consideration, essentially the same results are obtained. The localization hypothesis which underlies the present work suffers from the lack of one important control; no lesions restricted to the pyri-
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form cortex have yet been obtained. Since fibers from this adjacent area travel through the amygdaloid nuclei, effects ascribed to amygdaloid lesion could be due to ablating fibers of passage from the pyriform cortex. Stimulation of this area, however, did not yield either flight, defense or attention responses (3 7). Among the many behavioral changes reported to follow temporal lobe lesions, increased tameness is certainly the best established one. Postoperative reduction of “fear,” escape behavior or agressive behavior or both, has been produced in all species investigated. This has been observed in human beings (34), monkeys (16, 20, 25-27, 29, 31, 39, 41), cats (18, 30, 31), dogs (8), rats (44) and in the lynx and agouti (31). The so-called “hyperemotionality,” produced by septal lesions in rats, is also known to be completely abolished by subsequent lesions in the amygdala ( 17). The relevance of these findings to the defects produced in avoidance behavior by the same lesions will be discussed in detail in a subsequent paper. Morgane and Kosman (23) suggested that taming, following amygdaloid lesions in cats, may be due only to adaptation to the laboratory environment. This explanation can not hold for other species like lynx and wild rats in which taming also has been described. For the present experiment, several objections may be raised against such an interpretation. For one thing, wild stray cats have been observed at Oslo for as long as 6 months without showing any significant changes in affective behavior (36). Moreover, small or misplaced lesions do not produce any significant taming effect. The ,frequently observed late postoperative recovery of affective behavior is also contrary to what would be expected if the increased tameness were only a function of adaptation. Increased rage behavior, somewhat paradoxically, also has been reported to follow temporal lobe lesions (2, 11, 33, 43). Such increased rage reactions have only been observed in cats. Since taming has been described also in this species by several authors, it is no longer possible results. to resort to “species differences” to explain these contradictory Whether lesions are produced by electrocoagulation or by aspiration seems to be of no importance. One reasonable possibility seems to be that the two types of behavioral change result from the differential involvement of at least two different temporal lobe structures, although this can not be documented at the present time. The data presented by Green, Clemente and de Groot (11) suggest an interesting possibility. Sixteen of their eighty-two cats with temporal lobe lesions showed aggressive be-
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havior postoperatively. All of these sixteen cats had epileptic seizures, and in all of them the lesions encroached upon the hippocampus. In the material of Bard and Mountcastle (2) and Spiegel, Miller and Oppenheimer (32), however, the lesions producing rage were reported to be restricted to the amygdala and the overlying pyriform cortex. Finally, Wood (43) did obtain “fear or anger” by stimulating the basal and central nucleus but, surprisingly, he reports that lesions of the central nucleus also produced a form of aggressive behavior, consisting of growling, biting and clawing. In the animals of the present study, no increment in any category of defense behavior was ever observed, neither in previously tame nor in previously wild cats. Many of the lesions, moreover, certainly did involve the central nucleus, and in some cases encroached upon the hippocampus as well. The hippocampal lesions were very small, however, and no epileptic seizures were ever observed. Fernandez de Molina and Hunsperger (6, 7) have described a subcortical system for types of flight and defense responses which are similar to those observed in the present work. Their proposed system extends from the dorsomedial parts of the amygdala, through stria terminalis, to the level of the anterior commissure; it then further extends to the preoptic area, through the hypothalamus, and caudally to the central gray matter of the midbrain. According to these investigators, defense and escape (flight) behavior can be elicited separately from separate zones in the brain stem. They describe two “inner” zones (perifornical regions of hypothalamus and central gray of mesencephalon) which are related to defense behavior and one LLouter” zone which is related to the flight pattern of response. Hilton and Zbroiyna (13) suggested that the fibers of the stria terminalis seem to be afferent rather than efferent with regard to amygdaloid control of affective behavior. These authors suggest, as an efferent pathway, a direct band to the hypothalamus which coincides with the ventral amygdalofugal fibers and with the medial extension of the flight and defense zone of Ursin and Kaada (37). Hilton and Zbroiyna, however, did not distinguish between the two responses they studied. Their defense response contained components of both flight and defense behavior. The suggested relationship between the stria terminalis (whether it be efferent or afferent) and the defense response is of interest, since Ursin and Kaada found their defense zone to be located caudomedially within the amygdala, mainly in the basal nucleus, a region having at least
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efferent connections through the stria terminalis. It is perhaps more likely, however, that the ventral amygdalofugal fibers, rather that the stria terminalis, handle the output from the medial structures, since the former fibers have more intimate connections with the limbic-midbrain circuit of Nauta, a circuit which, on general grounds, seems likely to be important for such affective behavior. References 1. BAN, T., and F. OMUKAI. 19.59. tions of the amygdaloid nuclei in 2. BARD, P., and V. B. MOUNTCASTLE. in expression of rage with special
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