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Journal of Neuroscience, Vol 15, 709-720, Copyright © 1995 by Society for Neuroscience
Conditioned fear-induced changes in behavior and in the expression of the immediate early gene c-fos: with and without diazepam pretreatment
CH Beck and HC Fibiger
Department of Psychology, University of Alberta, Edmonton, Canada.
The synthesis of Fos, the protein product of the immediate early gene c-
fos, was used to map metabolically some of the neural substrates of
conditioned fear in the rat. Analysis of the behaviors emitted by the rats
during the test session provided strong evidence that the conditioning
procedure was effective. Exposure to the environment in which they had
previously received footshock significantly increased the number of
Fos-like immunoreactive neurons in nearly 50 brain regions, both cortical
and subcortical. Among the structures showing the most dramatic increases
in fear-induced c-fos expression were the cingulate, piriform, infralimbic,
and retrosplenial cortices, the anterior olfactory nucleus, claustrum,
endopiriform nucleus, nucleus accumbens shell, lateral septal nucleus,
various amygdalar nuclei, paraventricular thalamic nucleus, ventral lateral
geniculate nucleus, the ventromedial, lateral, and dorsal hypothalamic
nuclei, the ventral tegmental area, and the supramammillary area. These
data demonstrate that a relatively simple classical conditioning procedure
activates a large number of widely dispersed cortical and subcortical
structures. Some of the structures showing increased c-fos expression have
important autonomic functions and may therefore have reflected centrally
mediated changes in blood pressure and respiration produced by the
anxiogenic stimuli. In a second experiment, the effects of pretreatment
with the anxiolytic drug diazepam (2.5, 5.0, or 10 mg/kg) were evaluated.
The benzodiazepine produced dose-related decreases in the frequency of
crouching (freezing) elicited by the aversively conditioned contextual
cues. Diazepam also produced dose-related decreases in conditioned
stress-induced c-fos expression in all but one structure, the effects being
statistically significant in 38 of 60 sampled structures. Diazepam dose
dependently increased fear-induced c- fos expression in the central nucleus
of the amygdala. There was considerable regional variability with respect
to sensitivity to diazepam, the retrosplenial cortex and the
supramammillary area being the only two structures to show decreases after
the lowest dose of diazepam. In contrast, the entorhinal cortex, nucleus
accumbens core, ventromedial and posterior hypothalamic nuclei, median
raphe, and locus coeruleus were particularly resistant to diazepam, all
failing to show statistically significant decreases in conditioned
fear-induced c-fos expression even at the highest dose. The extent to which
diazepam decreased conditioned stress-induced c-fos expression was
unrelated to previous estimates of benzodiazepine receptor density in the
sampled structures.
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