tlru~n
Rewarc~h
Rullrrin.
Vol.
3.
pp. 691495.
c Pergamon
Press
plc.
1990. Printed
Oihl-9230190
in the U.S.A.
$3.00
i
.Ml
Hippocampal Pathway to the Amygdala and Stress Ulcer Development PETER G. HENKE Department
of Psychology,
St. Francis
Xavier
University,
Received
Antigonish,
Nova Scotia.
Canudu
B2G ICO
2 1 June 1990
HENKt, P. Cl. Hippocampn/ parh~voy to the amygdalrt and stress ulcer development. BRAIN RES BULL 25f5) 691-695. 1990.The objective of the first study was to localize the reported aggravation of stress ulcers found after large bilateral hippocampal lesions in rats. Lesions in the ventral hippocampus produced a similar increase in the severity of gastric erosions after cold-restraint. as was seen after large bilateral lesions. Dorsal hippocampal damage produced no differential effects. In the second experiment. high-frequency electrical stimulation of the ventral CA1 region of the hippocampus, a procedure known to induce long-term potentiation. increased the evoked potentials in the lateral central nucleus of the amygdala, and in adjacent parts of the lateral and basolateral nuclei. The increase in the efficacy of synaptic transmission in this pathway attenuated stress ulcer development. It was concluded that the ventral hippocampus is part of a coping system, and a strengthening of synaptic connections with the central amygdala increases the coping ability of rats under stress conditions. Hippocampus
Amygdala
Stress ulcer
Cold-restraint
LARGE hippocampus lesions in rats have been reported to aggravate stress ulcers ( 17.2 1). Conversely, electrophysiological potentiation of input pathways from the entorhinal cortex to the dentate gyrua of the hippocampal formation reduced the severity of stress ulcers (I I). Recording studies have also found that evoked dentate granule cell potentials were increased in stress-resistant rats. but decreased in rats which showed a high degree of stress ulceration (12). These data may be interpreted to indicate that the hippocampal formation may be part of a circuit which mediates some aspects of resistance to stressful situations (13.14). Based on functional considerations (1, 20. 24, 27) a division may be presumed to exist between dorsal and ventral regions of the hippocampus. Therefore, the initial study investigated the effects of selective lesions in dorsal or ventral hippocampus on stress ulcer development. EXPERIMENT
Long-term
potentiation
combined these two approaches. The control group consisted of animals which sustained comparable cortical and callosal damage. After hemostasis had been assured. the wound was packed with sterile gelfoam and the scalp was closed. Apparatus and Procedure After a ten-day recovery period. the animals were food-deprived for 24 h, and then immobilized in Plexiglas restrainers (Fisher Scientific Co.), for 3 h at 4°C. Immediately after the immobilization period, the animals were deeply anaesthetized with sodium pentobarbital and the brains and stomachs were removed. The stomachs were inspected under a microscope I x IO) and gastric erosions were measured to the nearest 0. I mm. The brains were dehydrated, fixed, sectioned at I5 )L. and every 5th section was stained with thionin.
1 RESULTS
METHOD
Forty male Wistar rats, 90-120 days old, were randomly assigned to four groups (n = 10): bilateral total hippocampal lesions (TH), dorsal lesions (DH). ventral lesions (VH), and control operations (C). After the rats had been anaesthetized with sodium pentobarbital (SO mg/kg, IP). the lesions were made by aspiration, under visual guidance through a dissecting microscope, using a 22-gauge blunt-tipped syringe needle. In the DH-group, mediodorsal neocortex, the underlying corpus callosum, and the anterodorsal hippocampus were removed. In the VH-animals, lateral and more caudal neocortical tissue was removed before the ventral portions of the hippocampus were aspirated. TH-lesions
AND
DISCUSSIOK
After examination of the brains, two rats were discarded from further analysis due to extensive damage to thalamic areas, reducing groups TH and VH to nine subjects. Figure 1 shows the maximum and minimum damage seen in the hippocampus of the DHand VH-groups. The amount of cortical damage was comparable to the brain damage seen in the corresponding control animals. In animals of group TH, extensive lesions were seen in both dorsal and ventral regions. The damage to hippocampus in group TH ranged from approximately 70-90%. with the most dorsal and ventral tips being spared. In group DH, the greatest extent of damage was generally seen between - 3.5 mm and - 5.5 mm, whereas in group VH the maximum damage was seen between - 4.3 and - 6.0. re bregma. In DH-animals, dorsal hippocampal fields CAl4. as well as dorsal dentate gyrus. were consistently
FIG. 1. Maximum and minimum damage in dorsal (top) and ventral (bottom) regions of the hippocampus.
In VH-rats, ventral CAl-3 areas, ventral dentate gyrus and ventral subiculum sustained the greatest amount of damage (Fig. 1). The gastric pathology data are summarized in Table 1. Both groups TH and VH showed significantly more and larger stress ulcers than the control group (Mann-Whitney, U-test, pcO.05, two-tailed). The gastric erosions were restricted to the acid secreting part of the stomachs. In the freshly excised stomachs, bleeding was usually associated with the ulcers. The present data implicate the ventral hippocampus in the inhibition of the effects of stressful conditions on gastric functions. Bilateral lesions of the major input/output pathways of the hippocampus, i.e., fimbria-fomix and perforant pathway, showed that the connections with the entorhinal cortex, but not with those through the fimbria-fomix, were important during stress ulcer development (15). The entorhinal cortex contains fibers which connect the hippocampus with the amygdala, which in turn, apparently, is an important relay station for hippocampal influences on hypothalamic responses (20,24). A number of studies have shown that the amygdala is important in the modulation of stress ulcer severity (8-10). Consequently, the hypothesis that hippocampal influences on stress ulcer development might be mediated via amygdalar areas was tested in the next study.
nical hippocampal connections indicate the existence of caudally directed fibers from hippocampal field CA1 to subiculum. rntorhinal cortex and amygdala (3, 5, 22, 24, 25). In the rat and monkey, significant projections from the ventral hippocampus to the central amygdala are seen. These fibers originate in CA1 and project to the lateral portion of the central nucleus of the amygdala (5,22), A number of studies have shown that the central amygdala is important during stress ulcer development. In fact, the results of lesion and stimulation experiments, pharmacological manipulations, as well as recording data, clearly indicate that this area of the amygdala, through its ventrally directed projections to hypothalamic and lower brainstem regions, modulates stress ulcer severity in rats (8-10). The hypothesis tested in the present study was that an increased synaptic efficacy of inputs from CA1 to the central amygdala might reduce the gastric pathology induced by restraint. Highfrequency electrical stimulation of the ventral CA1 region was performed in order to increase the magnitude of evoked potentials in the amygdala prior to restraining the animal. This electrophysiological procedure is known to induce long-term potentiation (LTP) in this pathway (2), and it has been shown to attenuate stress ulcers when applied to the entorhinal-dentate pathway in rats (II).
damaged.
EXPERIMENT 2 Anatomical and electrophysiological investigations of nonforTABLE 1 HIPPOCAMPAL LESIONS AND STRESS ULCERS Mean Cumulative
Lesions
(mm) ( ‘-
Dorsal Ventral Total Control
2.4 6.7 6.3 2.6
*p