Limbic System Modulation of Stress Ulcer Development PETER G . HENKE Department of Psychology St. Francis Xavier University Antigonish. Nova Scotia, Canada B2G ICO
INTRODUCTION The limbic system has been linked to so-called psychosomatic disorders for decades. In fact, MacLean’ coined the term “visceral brain” to describe a system of structures that included the amygdala, the hippocampal formation, the septa1 region, and the cingulate gyrus, as well as their connections with diencephalic regions. Recent data suggest that many of these structures modulate the organism’s reaction to aversive conditions. In general, these data suggest that the amygdala connects stress-related sensory experiences and affective responses, based on the recognition that the situation may be threatening. For example, it is assumed that in the amygdala somatic sensory inputs conveying touch, pressure, and kinesthetic feedback become a threatening restraint experience to the animal. The hippocampal formation and midline cortical areas, on the other hand, may be part of a coping system, where experiential factors make the animal resistant or, conversely, vulnerable to stress inputs.
AMYGDALA The amygdala has well-developed anatomical connections with the hypothalamus, via the ventral amygdalofugal (and-petal) pathway and the stria terminalis, and also direct projections to the lower brain stem-that is, the solitary tract nucleus and the dorsal vagal complex. These latter fibers come from the central nucleus of the amygdala.*Studies have found that bilateral lesions of the centromedial amygdala attenuated restraint- and shock-induced ulcer^.^' Similar lesions also attenuated the stomach pathology produced as a consequence of lateral hypothalamic lesions! Electrical stimulation of the centromedial amygdala, in awake and anesthetized rats, initiated ulcer formation.’.’ One may interpret the lesion effect as a kind of disconnection symptom-similar to the effects described by Kluver and Bucyg in 1937. These investigators described monkeys with temporal lobectomies that showed virtually no fear of stimuli that previously had elicited strong fear reactions. These animals also explored and reexplored, frequently by mouth, stimuli they had encountered before; and they showed indiscriminate dietary and sexual behaviors. The authors labeled these bizarre behaviors as examples of “psychic blindness”-that is, sensory stimuli 201
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ANNALS NEW YORK ACADEMY OF SCIENCES
had lost their previous significance or meaning to the animal. Expressed in a different way, sensory information was disconnected by the lesion from the appropriate, adaptive behaviors. Latter studies showed that most of these symptoms, described in the socalled Kluver-Bucy syndrome, could be traced to the amygdala. These latter studies also showed that animals with amygdalar lesions have difficulties in associating sensory stimuli with rewards or punishments. The lesion produced a kind of “flattening of affect” or “calming effect” in response to almost any kind of situation.” Studies investigating the responses of multiple units during restraint stress also agreed with this assessment. Units were found that responded in the medial, central, and lateral nuclei of the amygdala as well as in the bed nucleus of the stria terminalis. Some of these units also responded when a tone was presented that had been paired with the restraint experience-in other words, these units reflected a kind of ‘‘sensitization” or “conditioning” process. But low-level electrical stimulation of amygdalar areas produced stomach ulcers only when electrodes were placed in the central nu~leus.”-’~ This nucleus, as pointed out, has direct projections to the lower brain stem, via the ventral amygdalofugal pathway. When these ventral projection fibers were cut, the ulcerogenic effects of amygdalar stimulations were also eliminated.’ On the other hand, when a hyperfunctional state was produced by “kindling” this region-that is, when brief, daily stimulations were presented until after-discharges were recorded, the animal became significantly more susceptible to subsequent restraint-induced ulcers.” There are also other data on cats, reported by Adamec,” that show that partial kindling in the basomedial amygdalar nucleus produced long-lasting “personality ” changes. It appears that these cats became more defensive, in other words, more fearful of threatening stimuli. When the behaviors of neurons in the central nucleus were examined more closely, it was found that some multiple units responded differently in ulcer-susceptible as compared to ulcer-resistant rats. Following an initial increase in activity during the restraint period, some multiple units were suppressed during the later stages of the stressful experience (Type I), but other units returned to near baseline levels (Type 2 ) . The subsequent inspection of the stomachs showed that Type 1 units were mostly seen in ulcer-susceptible rats, Type 2 units generally in stress-resistant animals. In other words, distinct neural “signatures” seemed to exist.16 An investigation of emotionality characteristics and stress vulnerability also showed that when rats were divided into high and low emotional categories (based on the criterion of defecation in an open-field apparatus before five rearing responses had occurred), Type 1 units were predominantly found in the more emotional animals. Type 2 activity was associated with reduced levels of emotional reactivity. But at the same time, low-level electrical stimulation of the areas of either types of units did produce gastric erosions.16One interpretation of the findings might be that similar neurons in the central nucleus of the amygdala generate distinct patterns of activity-that is, that these neurons behave differently under stressful conditions. The fact that genetic differences might be important in producing these different unit profiles was suggested by additional data. Two lines of rats, selectively bred on the basis of extreme performance differences in shuttle-box conditioning- the so-called Roman high-avoidance (RHA) and low-avoidance (RLA) rats’’-also could be distinguished by the type of unit activity seen in the central amygdala during restraint. RLA rats showed mostly Type 1 patterns; the opposite was the case for the RHA rats; they showed mostly Type 2 activity. It was found that the RLA animals also had more stress ulceration induced by physical restraint.I6 It is known that RLA rats also “freeze” more, defecate more, and also show less ambulation in the open-field situation than do the RHA animals.” In a general way, the data agree with previous studies suggesting a connection between open-field behavior and stress-ulcer susceptibility.”
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A number of investigations on the putative transmitters and modulators in the central amygdalar nucleus indicate that dopamine (DA) transmission, probably originating from cells located in the ventral tegmental area (AlO), might be modulated by several neuropeptide transmitters. Data show that DA by itself is protective when applied to the central nucleus, and in addition, DA also eliminates the ulcerogenic effects of thyrotropin-releasing-hormoneinjections into this area. In a similar fashion, the protective effects of neurotensin or metenkephalin can be eliminated by blocking DA transmission in the central n~cleus.”~‘The results may be interpreted to indicate that these neuropeptides modulate DA transmission in this nucleus under stressful conditions,*’DA activity being protective, as suggested by several other reports?6*2’
HIPPOCAMPUS AND MIDLINE CORTEX The idea that the hippocampal formation might be part of a coping system was largely based on data showing that large bilateral lesions in this structure aggravated restraint u l ~ e r s . In ~ ~other . ~ ~ words, the lesions produced a kind of deficiency phenomenon. There are also behavioral studies that indicate that severe stress conditions produce similar deficits to those found after hippocampal lesions-for instance, extinction impairments, reversal learning deficits, or memory impairments.”‘ It may be that hippocampal damage or, possibly, a functional suppression of neuronal activity there mimics the effects of severe stress conditions. Two major input-output pathways of the hippocampus are the fimbria-fornix system to hypothalamic areas and the perforant path projections from the entorhinal cortex in the temporal lobe. The results of lesions in these two pathways show that the entorhinal connection is the crucial one during stress ulcer development. The cutting of the fibers in the fimbria-fornix had no significant effect on restraint ulceration.” As a result of these studies, measurements of the evoked potentials of the granule cells in the dentate region were performed. Stimulation of the perforant path fibers from the entorhinal area showed that physical restraint suppressed the granule cell population spikes in ulcer-susceptible rats. Rats with little stress ulceration, on the other hand, showed increased population spikes after restraint. In other words, electrophysiological activity in the dentate g y m of the hippocampus seemed to be correlated with stress ulcer severity.” Previous studies had also shown that bilateral hippocampal lesions aggravated the so-called learned helplessness effect.” In general terms, this phenomenon refers to impaired coping performance after the animal has experienced uncontrollable aversive events, usually electric shock stimulation.u Psychological explanations have emphasized the cognitive and emotional consequences of uncontrollable stress conditions; biochemical accounts have usually pointed to impaired catecholamine transmission following this experience.’c36 When recordings of evoked potentials of the granule cells in the dentate gyrus of rats after such a helplessness-inducing experience were examined, it was found that this experience suppressed the population spikes. The data were interpreted to indicate that suppressed hippocampal activity seemed to correlate with impaired coping ability. It was also speculated that two ways that could produce this suppression in the dentate gyrus might involve (a) catecholamine depletion or (b) increased corticosterone secretion.” Both manipulations are known to inhibit population potentials in the hippocampus.”-” It is known that there are pronounced norepinephrine projections into
204
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the hippocampus, and the hippocampus also contains the highest density of corticosterone receptors in the brain?'"'' On the other hand, increasing the synaptic efficacy in the entorhinal-dentate pathway, by using high-frequency electrical stimulation, produced animals that were significantly more resistant to stress ulcer formation." How the hippocampus might influence ulcer development is unclear. As pointed out, the fimbria-fornix pathway to the hypothalamus is not crucial.'1 However, there are direct connections from the ventral subiculum of the hippocampal formation to the central nucleus of the amygdala,'2 and other researchers have reported that some hippocampal influences on hypothalamic neurons are relayed through the amygdala." This projection system, therefore, may be the important link. If the amygdala is important in recognizing a threatening situation, as is suggested by the data, then presumably whether or not the situation is controllable or escapable becomes an important aspect of this perception. This information could be provided by hippocampal mechanisms. Multiple-unit recordings in the anterior cingulate cortex of rats indicated that neurons there also respond during restraint stress. Injections of the antianxiety agent chlordiazepoxide suppressed the activity of some of the units. On the other hand, electrical stimulation near these identified neurons produced stomach ulcers." Pretreatment with atropine eliminated these effects of stimulation, whereas cimetidine was ineffective." Bilateral lesions of this area attenuated stress ulcers after a single restraint session,&but then also prevented the animal from adapting to repeated stress sessions. In other words, the animals with brain lesions showed greater amounts of gastric ulcers after repetitive stress, whereas the controls no longer showed the initial degree of stomach pathology." A similar effect was found with intraperitoneal injections of chlordiazepoxide. At higher doses, chlordiazepoxide attenuated ulcers after single restraint but also prevented adaptation to repeated stress experiences." If it is assumed that habituation to repeated stress experiences represents a form of learning, then the animal with either cingulate lesions or under benzodiazepine therapy seemingly has difficulty in developing tolerance to stress conditions. In other words, these animals may be buffered against acute stress, but they may also be impaired in learning to cope with chronic stress conditions.
CONCLUSIONS The present proposal that limbic system structures modulate stress ulcer development by increasing or decreasing the demands placed on the organism is generally supported by the data. The amygdala has been linked to emotional experiences, the behavioral responses they may produce, and also the visceral reactions seen under such circum~tances.~'~~ Threatening stimuli, either learned or unlearned, trigger immediate responses in the amygdala, producing fast changes in behavior and visceral physiology. The latter effects are controlled predominantly by the central nucleus of the am~gdala.~' The system seems to be designed to allow quick reactions to threatening events, increasing the survival chances of the organism. However, when the adjustments made by the animal are ineffective, the threat is not removed. In times of such extreme demands, stress ulcer development is aggravated by neural events that trigger emotional reactions. Normally, adjustments to threatening circumstances involve the execution of behaviors, learned and unlearned, designed to eliminate the threat. The hippocampal
HENKE LIMBIC SYSTEM MODULATION
205
formation and midline cortical areas are assumed to be essential parts of such a socalled coping system. It may be speculated that through these areas environmental experiences contribute programs or strategies useful for survival. Successes or failures in coping attempts presumably feed back to the amygdala, modifying the original threat perceptions. These coping strategies are assumed to require memory-that is, storage and retrieval of information. The hippocampus has a long history of being associated with such cognitive activities.”*’*
REFERENCES 1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
MACLEAN,P. A. 1949. Psychosom. Med. 11: 338-353. PRICE,J. L. 1981. In The Amygdaloid Complex. Y. Ben-An, Ed.: 121-132. Elsevier/ North-Holland Biomedical Press. Amsterdam. HENKE,P. G. 1980. J. Comp. Physiol. Psychol. 94:313-323. HENKE,P. G. 1980. Physiol. Behav. 2 5 575-579. HENKE,P. G. 1981. Physiol. Behav. 27: 143-146. GRIJALVA, C. V.,Y. TACHB,M. W. GUNION,J. H. WALSH& P. J. GEISELMAN. 1986. Brain Res. Bull. 16 55-61. HENKE,P. G. 1980. Physiol. Behav. 2 5 107-1 12. INNES,D. L. & M. F. TANSY.1980. Brain Res. Bull. S(Supp1. 1): 33-36. KLUVER,H. & P. C. BUCY.1937. Am. J. Physiol. 119 352-353. GODDARD,G. V. 1964. Psychol. Bull. 62: 89-109. HENKE,P. G. 1983. Brain Res. Bull. 1 0 833-837. HENKE,P. G. 1984. Behav. Brain Res. 11: 35-45. HENKE,P. G. 1985. Behav. Brain Res. 1 6 19-24. HENKE,P. G. & R. M. SULLIVAN. 1985. Brain Res. Bull. 14 5-8. ADAMEC,R. 1978. In Limbic Mechanisms. K. E. Livingston & 0. Hornykiewicz, Eds.: 405-455. Plenum Press. New York, NY. HENKE,P. G. 1988. Behav. Neurosci. 102 77-83. DRISCOLL,P. & K. BAITIG. 1982. In Genetics of the Brain. I. Lieblich, Ed.: 95-123. Elsevier Biomedical Press. Amsterdam. GLAVIN,G. B. 1980. Brain Res. Bull. S(Supp1. 1): 51-58. HENKE,P. G., R. M. SULLIVAN & A. RAY. 1988. Neurosci. Lett. 91: 95-100. RAY,A. & P. G. HENKE.1989. Indian J. Med. Res. 90:224-228. RAY,A., P. G. HENKE& R. SULLIVAN. 1987. Brain Res. 409: 398-402. RAY,A., P. G. HENKE& R. M. SULLIVAN. 1988. Neurosci. Lett. 84: 302-306. RAY,A., P. G. HENKE& R. M. SULLIVAN.1988. Brain Res. 442 195-198. RAY, A., P. G. HENKE& R. M. SULLIVAN. 1988. Physiol. Behav. 42: 359-364. HENKE,P. G. 1988. Neurosci. Biobehav. Rev. 1 2 143-150. GLAVIN,G. V.,A. M. DUGANI& C. PINSKY.1986. Neurosci. Lett. 7 0 379-381. HERNANDEZ, D. E., J. W. ADCOCK,R. C. ORLANDO,K. S. PATRICK,C. B. NEMEROFF & A. J. PRANCE.1984. Life Sci. 35: 2453-2458. KIM,C., H. CHOI,J. K. KIM, M. S. KIM, H. J. PARK,B. T. AHN & S. H. KANG.1976. Brain Res. 109: 245-254. MURPHY, H. M., C. H. WIDEMAN & T. S. BROWN.1979. Neuroendocrinology. UI: 123- 130. DOUGLAS,R. J. 1975. In The Hippocampus, Vol. 2. R. L. Isaacson & K. H. PRIBRAM, Em.: 327-362. PLENUMPRESS. NEW YORK,NY. 1981. Brain Res. Bull. 7: 395-398. HENKE,P. G., R. J. SAVOIE& B. M.CALLAHAN. HENKE,P. G. 1990. Behav. Brain Res. 36.97-103. ELMES, D. G., L. E. JARRARD & P. D. SWART.1975. Physiol. Psychol. 3 51-55. SELIGMAN, M. E. P. 1975. Helplessness. W. H.Freeman. San Francisco, CA. ABRAMSON, L. Y., M. E. SELIGMAN & J. D. TEASDALE. 1978. J. Abnorm. Psychol. 87: 49-74.
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40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.
ANNALS NEW YORK ACADEMY OF SCIENCES WEISS,J. M. & L. A. POHORECKY. 1976. In Animal Models of Human Psychopathology. A. Serban & A. Kling, Eds.: 141- 173. Plenum Press. New York, NY. BLISS,T. V. P., G. V. GODDARD& M. RIIVES.1983. J. Physiol. (Lond.) 334: 475-491. DIAMOND, D. M., M. C. BENNETT, D. A. ENGSTROM,M. FLESHNER & G. M. ROSE. 1989. Brain Res. 492 356-360. PICKEL,V. M., M. SEGAL,& F. E. BLOOM.1974. J. Comp. Neurol. 155: 15-42. MCEWAN,B., H. CHAO, R. SPENCER,R. BRINTON,L. MACISAAC& A. HARRELSON. 1987. Ann. N. Y. Acad. Sci. 512 394-401. HENKE,P. G. 1989. Neurosci. Lett. 107: 110-113. LOHMAN,A. H. M. & F. T. RUSSHEN.1981. In The Amygdaloid Complex. Y. Ben-Ari, Ed: 63-76. Elsevier/North-Holland Biomedical Press. Amsterdam. POLETTI,C. E., M. KLIOT& G. BOYTIN.1984. Neurosci. Lett. 4 5 211-216. HENKE,P. G. 1984. Int. J. Psychophysiol. :23-32. HENKE,P. G. 1983. Pharmacol. Biochem. Behav. 19 483-486. HENKE,P. G. & R. J. SAVOIE.1982. Brain Res. Bull. 8: 489-492. SULLIVAN, R. M. & P. G. HENKE.1986. Brain Res. Bull. 17: 493-496. HENKE,P. G. 1987. Pharmacol. Biochem. Behav. 26 561-563. HENKE,P. G. 1979. Neurosci. Biobehav. Rev. 3 75-82. HENKE,P. G. 1982. Neurosci. Biobehav. Rev. 6 381-390. MILNER,B., S. CORKIN& H.-L. TEUBER.1968. Neuropsychologia 6 215-234. MISHKIN,M., B. MALAMUT & J. BACHEVALIER. 1984. In Neurobiology of Learning and Memory. G. Lynch, J. L. McGaugh & N. W.Weinberger, Eds.: 65-77. Guilford Press. New York, NY.
INTRODUCTION The limbic system has been linked to so-called psychosomatic disorders for decades. In fact, MacLean’ coined the term “visceral brain” to describe a system of structures that included the amygdala, the hippocampal formation, the septa1 region, and the cingulate gyrus, as well as their connections with diencephalic regions. Recent data suggest that many of these structures modulate the organism’s reaction to aversive conditions. In general, these data suggest that the amygdala connects stress-related sensory experiences and affective responses, based on the recognition that the situation may be threatening. For example, it is assumed that in the amygdala somatic sensory inputs conveying touch, pressure, and kinesthetic feedback become a threatening restraint experience to the animal. The hippocampal formation and midline cortical areas, on the other hand, may be part of a coping system, where experiential factors make the animal resistant or, conversely, vulnerable to stress inputs.
AMYGDALA The amygdala has well-developed anatomical connections with the hypothalamus, via the ventral amygdalofugal (and-petal) pathway and the stria terminalis, and also direct projections to the lower brain stem-that is, the solitary tract nucleus and the dorsal vagal complex. These latter fibers come from the central nucleus of the amygdala.*Studies have found that bilateral lesions of the centromedial amygdala attenuated restraint- and shock-induced ulcer^.^' Similar lesions also attenuated the stomach pathology produced as a consequence of lateral hypothalamic lesions! Electrical stimulation of the centromedial amygdala, in awake and anesthetized rats, initiated ulcer formation.’.’ One may interpret the lesion effect as a kind of disconnection symptom-similar to the effects described by Kluver and Bucyg in 1937. These investigators described monkeys with temporal lobectomies that showed virtually no fear of stimuli that previously had elicited strong fear reactions. These animals also explored and reexplored, frequently by mouth, stimuli they had encountered before; and they showed indiscriminate dietary and sexual behaviors. The authors labeled these bizarre behaviors as examples of “psychic blindness”-that is, sensory stimuli 201
202
ANNALS NEW YORK ACADEMY OF SCIENCES
had lost their previous significance or meaning to the animal. Expressed in a different way, sensory information was disconnected by the lesion from the appropriate, adaptive behaviors. Latter studies showed that most of these symptoms, described in the socalled Kluver-Bucy syndrome, could be traced to the amygdala. These latter studies also showed that animals with amygdalar lesions have difficulties in associating sensory stimuli with rewards or punishments. The lesion produced a kind of “flattening of affect” or “calming effect” in response to almost any kind of situation.” Studies investigating the responses of multiple units during restraint stress also agreed with this assessment. Units were found that responded in the medial, central, and lateral nuclei of the amygdala as well as in the bed nucleus of the stria terminalis. Some of these units also responded when a tone was presented that had been paired with the restraint experience-in other words, these units reflected a kind of ‘‘sensitization” or “conditioning” process. But low-level electrical stimulation of amygdalar areas produced stomach ulcers only when electrodes were placed in the central nu~leus.”-’~ This nucleus, as pointed out, has direct projections to the lower brain stem, via the ventral amygdalofugal pathway. When these ventral projection fibers were cut, the ulcerogenic effects of amygdalar stimulations were also eliminated.’ On the other hand, when a hyperfunctional state was produced by “kindling” this region-that is, when brief, daily stimulations were presented until after-discharges were recorded, the animal became significantly more susceptible to subsequent restraint-induced ulcers.” There are also other data on cats, reported by Adamec,” that show that partial kindling in the basomedial amygdalar nucleus produced long-lasting “personality ” changes. It appears that these cats became more defensive, in other words, more fearful of threatening stimuli. When the behaviors of neurons in the central nucleus were examined more closely, it was found that some multiple units responded differently in ulcer-susceptible as compared to ulcer-resistant rats. Following an initial increase in activity during the restraint period, some multiple units were suppressed during the later stages of the stressful experience (Type I), but other units returned to near baseline levels (Type 2 ) . The subsequent inspection of the stomachs showed that Type 1 units were mostly seen in ulcer-susceptible rats, Type 2 units generally in stress-resistant animals. In other words, distinct neural “signatures” seemed to exist.16 An investigation of emotionality characteristics and stress vulnerability also showed that when rats were divided into high and low emotional categories (based on the criterion of defecation in an open-field apparatus before five rearing responses had occurred), Type 1 units were predominantly found in the more emotional animals. Type 2 activity was associated with reduced levels of emotional reactivity. But at the same time, low-level electrical stimulation of the areas of either types of units did produce gastric erosions.16One interpretation of the findings might be that similar neurons in the central nucleus of the amygdala generate distinct patterns of activity-that is, that these neurons behave differently under stressful conditions. The fact that genetic differences might be important in producing these different unit profiles was suggested by additional data. Two lines of rats, selectively bred on the basis of extreme performance differences in shuttle-box conditioning- the so-called Roman high-avoidance (RHA) and low-avoidance (RLA) rats’’-also could be distinguished by the type of unit activity seen in the central amygdala during restraint. RLA rats showed mostly Type 1 patterns; the opposite was the case for the RHA rats; they showed mostly Type 2 activity. It was found that the RLA animals also had more stress ulceration induced by physical restraint.I6 It is known that RLA rats also “freeze” more, defecate more, and also show less ambulation in the open-field situation than do the RHA animals.” In a general way, the data agree with previous studies suggesting a connection between open-field behavior and stress-ulcer susceptibility.”
HENKE LIMBIC SYSTEM MODULATION
203
A number of investigations on the putative transmitters and modulators in the central amygdalar nucleus indicate that dopamine (DA) transmission, probably originating from cells located in the ventral tegmental area (AlO), might be modulated by several neuropeptide transmitters. Data show that DA by itself is protective when applied to the central nucleus, and in addition, DA also eliminates the ulcerogenic effects of thyrotropin-releasing-hormoneinjections into this area. In a similar fashion, the protective effects of neurotensin or metenkephalin can be eliminated by blocking DA transmission in the central n~cleus.”~‘The results may be interpreted to indicate that these neuropeptides modulate DA transmission in this nucleus under stressful conditions,*’DA activity being protective, as suggested by several other reports?6*2’
HIPPOCAMPUS AND MIDLINE CORTEX The idea that the hippocampal formation might be part of a coping system was largely based on data showing that large bilateral lesions in this structure aggravated restraint u l ~ e r s . In ~ ~other . ~ ~ words, the lesions produced a kind of deficiency phenomenon. There are also behavioral studies that indicate that severe stress conditions produce similar deficits to those found after hippocampal lesions-for instance, extinction impairments, reversal learning deficits, or memory impairments.”‘ It may be that hippocampal damage or, possibly, a functional suppression of neuronal activity there mimics the effects of severe stress conditions. Two major input-output pathways of the hippocampus are the fimbria-fornix system to hypothalamic areas and the perforant path projections from the entorhinal cortex in the temporal lobe. The results of lesions in these two pathways show that the entorhinal connection is the crucial one during stress ulcer development. The cutting of the fibers in the fimbria-fornix had no significant effect on restraint ulceration.” As a result of these studies, measurements of the evoked potentials of the granule cells in the dentate region were performed. Stimulation of the perforant path fibers from the entorhinal area showed that physical restraint suppressed the granule cell population spikes in ulcer-susceptible rats. Rats with little stress ulceration, on the other hand, showed increased population spikes after restraint. In other words, electrophysiological activity in the dentate g y m of the hippocampus seemed to be correlated with stress ulcer severity.” Previous studies had also shown that bilateral hippocampal lesions aggravated the so-called learned helplessness effect.” In general terms, this phenomenon refers to impaired coping performance after the animal has experienced uncontrollable aversive events, usually electric shock stimulation.u Psychological explanations have emphasized the cognitive and emotional consequences of uncontrollable stress conditions; biochemical accounts have usually pointed to impaired catecholamine transmission following this experience.’c36 When recordings of evoked potentials of the granule cells in the dentate gyrus of rats after such a helplessness-inducing experience were examined, it was found that this experience suppressed the population spikes. The data were interpreted to indicate that suppressed hippocampal activity seemed to correlate with impaired coping ability. It was also speculated that two ways that could produce this suppression in the dentate gyrus might involve (a) catecholamine depletion or (b) increased corticosterone secretion.” Both manipulations are known to inhibit population potentials in the hippocampus.”-” It is known that there are pronounced norepinephrine projections into
204
ANNALS NEW YORK ACADEMY OF SCIENCES
the hippocampus, and the hippocampus also contains the highest density of corticosterone receptors in the brain?'"'' On the other hand, increasing the synaptic efficacy in the entorhinal-dentate pathway, by using high-frequency electrical stimulation, produced animals that were significantly more resistant to stress ulcer formation." How the hippocampus might influence ulcer development is unclear. As pointed out, the fimbria-fornix pathway to the hypothalamus is not crucial.'1 However, there are direct connections from the ventral subiculum of the hippocampal formation to the central nucleus of the amygdala,'2 and other researchers have reported that some hippocampal influences on hypothalamic neurons are relayed through the amygdala." This projection system, therefore, may be the important link. If the amygdala is important in recognizing a threatening situation, as is suggested by the data, then presumably whether or not the situation is controllable or escapable becomes an important aspect of this perception. This information could be provided by hippocampal mechanisms. Multiple-unit recordings in the anterior cingulate cortex of rats indicated that neurons there also respond during restraint stress. Injections of the antianxiety agent chlordiazepoxide suppressed the activity of some of the units. On the other hand, electrical stimulation near these identified neurons produced stomach ulcers." Pretreatment with atropine eliminated these effects of stimulation, whereas cimetidine was ineffective." Bilateral lesions of this area attenuated stress ulcers after a single restraint session,&but then also prevented the animal from adapting to repeated stress sessions. In other words, the animals with brain lesions showed greater amounts of gastric ulcers after repetitive stress, whereas the controls no longer showed the initial degree of stomach pathology." A similar effect was found with intraperitoneal injections of chlordiazepoxide. At higher doses, chlordiazepoxide attenuated ulcers after single restraint but also prevented adaptation to repeated stress experiences." If it is assumed that habituation to repeated stress experiences represents a form of learning, then the animal with either cingulate lesions or under benzodiazepine therapy seemingly has difficulty in developing tolerance to stress conditions. In other words, these animals may be buffered against acute stress, but they may also be impaired in learning to cope with chronic stress conditions.
CONCLUSIONS The present proposal that limbic system structures modulate stress ulcer development by increasing or decreasing the demands placed on the organism is generally supported by the data. The amygdala has been linked to emotional experiences, the behavioral responses they may produce, and also the visceral reactions seen under such circum~tances.~'~~ Threatening stimuli, either learned or unlearned, trigger immediate responses in the amygdala, producing fast changes in behavior and visceral physiology. The latter effects are controlled predominantly by the central nucleus of the am~gdala.~' The system seems to be designed to allow quick reactions to threatening events, increasing the survival chances of the organism. However, when the adjustments made by the animal are ineffective, the threat is not removed. In times of such extreme demands, stress ulcer development is aggravated by neural events that trigger emotional reactions. Normally, adjustments to threatening circumstances involve the execution of behaviors, learned and unlearned, designed to eliminate the threat. The hippocampal
HENKE LIMBIC SYSTEM MODULATION
205
formation and midline cortical areas are assumed to be essential parts of such a socalled coping system. It may be speculated that through these areas environmental experiences contribute programs or strategies useful for survival. Successes or failures in coping attempts presumably feed back to the amygdala, modifying the original threat perceptions. These coping strategies are assumed to require memory-that is, storage and retrieval of information. The hippocampus has a long history of being associated with such cognitive activities.”*’*
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