Interactive reportEstrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats1
Introduction
Fear is a psychological construct used to describe the various behavioral and physiological changes that take place when an organism is faced with a threatening situation [16], [23], [35]. As with many behavioral systems [10], [12], [51], fear-related behavior exhibits a prominent sexual dimorphism in both rodents [7] and humans [31]. Recently, we reported a reliable sex difference in contextual fear conditioning [43], a form of Pavlovian conditioning in which an unconditional stimulus (US, a footshock) elicits freezing behavior (immobility except for breathing) in the context of US delivery. In this study, male rats exhibited significantly higher levels of contextual freezing than female rats. Interestingly, we also discovered a sex difference in perforant path-dentate granule cell long-term potentiation (LTP) [37]. LTP is an enduring form of synaptic plasticity that has been posited to mediate various forms of learning [41], [45], including contextual fear conditioning [25], [39]. The positive correlation between hippocampal synaptic plasticity and contextual fear conditioning is consistent with the proposed role of the hippocampus in contextual fear conditioning [5], [40].
An interesting question concerns the hormonal factors that regulate sexually dimorphic fear conditioning. Although the influence of gonadal steroids on several behavioral systems has been characterized [61], the involvement of these hormones in fear conditioning is poorly understood. Recently, Anagnostaras et al. found that castration in adult male rats did not affect the sex difference in either fear conditioning or hippocampal LTP [6]. In contrast, a role for ovarian steroids in fear conditioning has been suggested by a study indicating that contextual fear conditioning in female rats varies across the estrous cycle [44]. Specifically, female rats in proestrus (when plasma levels of estrogen are high) exhibit reliably lower levels of conditional freezing compared to females in estrus (when plasma levels of estrogen are low). Consistent with these results, it has been reported that cycling female rats perform more poorly than ovariectomized female rats in an aversively motivated avoidance learning task [19], [24]. Moreover, a preliminary report indicates that exogenous estradiol administration in ovariectomized female rats reduces contextual fear conditioning [4]. These data suggest that ovarian steroids and estrogen, in particular, may be important in regulating fear conditioning in adult female rats.
The possible role for ovarian steroids in contextual fear conditioning is interesting in the light of other work implicating estrogen in the regulation of hippocampal neuronal morphology [63], [64], [65], [66] and synaptic plasticity [14], [17], [26] in female rats. In the present experiments we examined the relationship between ovarian steroids and contextual fear conditioning. We conducted three experiments to examine the hypothesis that estrogen exerts an inhibitory influence on both contextual fear conditioning and perforant path-granule cell LTP in adult female rats. Our results reveal an important role for estrogen in modulating contextual fear conditioning and hippocampal synaptic plasticity in adult female rats.
Section snippets
Experimental strategy
Three experiments were conducted. In experiment 1, the effect of ovariectomy on contextual fear conditioning in adult female rats was examined to test the hypothesis that ovarian steroids in female rats play a role in sexually dimorphic fear conditioning. We compared three groups of adult rats: (1) ovariectomized females, (2) sham-operated females, and (3) sham-operated males. The latter two groups were included to replicate our previous report of sex differences in contextual fear conditioning
Experiment 1: ovariectomy eliminates the sexual dimorphism in contextual fear conditioning
One rat died during surgery and five rats were excluded due to incomplete ovariectomy, leaving the following group memberships: sham-males (n=12), sham-females (n=11), and ovariectomized females (n=8). Freezing on the conditioning day was averaged across the three postshock periods and is shown in Fig. 1A. All groups exhibited immediate postshock freezing and the level of postshock freezing was not different between the groups. This observation was confirmed in an ANOVA by a non-significant
Discussion
The present study examined the role of ovarian steroids in modulating sex differences in fear conditioning and hippocampal LTP. Ovariectomized (OVX) female rats exhibited levels of freezing that were similar to male rats and significantly higher than that in intact female rats. Estrogen treatment in ovariectomized female rats reduced both contextual fear conditioning and hippocampal LTP. Collectively, these data reveal a positive correlation between contextual fear conditioning and hippocampal
Acknowledgements
The research reported here was supported by a National Institutes of Health grant (R29MH57865) to SM. We would like to thank Dr. Jill Becker for helpful advice concerning the design of these experiments and comments on an earlier version of this manuscript.
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Published on the World Wide Web on 1 December 2000.
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Present address: Northwestern University, Department of Neurobiology and Physiology, 2153 N Campus Dr., Evanston, IL 60208-0877, USA.