Brain Research 888 2001 356–365 www.elsevier.com locate bres
Interactive report
Estrogen modulates sexually dimorphic contextual fear conditioning
1
and hippocampal long-term potentiation LTP in rats
a b
a a ,2
Rishi R. Gupta , Srijan Sen , Lisa L. Diepenhorst , Charles N. Rudick ,
a,b ,
Stephen Maren
a
Department of Psychology , University of Michigan, 525 E. University Ave., Ann Arbor, MI 48109-1109, USA
b
Neuroscience Program , University of Michigan, 525 E. University Ave., Ann Arbor, MI 48109-1109, USA
Accepted 30 October 2000
Abstract
The present study examined the role of ovarian steroids in contextual fear conditioning and hippocampal synaptic plasticity in female rats. In experiment 1, adult female rats were ovariectomized and submitted to contextual fear conditioning, a procedure in which rats
received unsignaled footshock in a novel observation chamber; freezing behavior served as the measure of conditional fear. Ovariectomized female rats froze at levels comparable to male rats, both of which froze significantly more than sham-operated female
rats. In experiment 2, estrogen replacement in ovariectomized female rats reduced fear conditioning to a level comparable to that of sham-operated females in experiment 1. In experiment 3, the influence of estrogen on the induction of long-term potentiation LTP at
perforant path-dentate granule cell synapses in ovariectomized female rats was examined. Estrogen decreased both population spike LTP and EPSP-spike potentiation at perforant path synapses. Taken together, these experiments indicate that ovarian steroids regulate both
sexually dimorphic behavior and hippocampal plasticity in a fear-conditioning paradigm.
2001 Elsevier Science B.V. All rights
reserved.
Theme : Neural basis of behavior
Topic : Learning and memory: systems and functions
Keywords : Estrogen; Fear conditioning; Hippocampus; Long-term potentiation; Rat
1. Introduction ditioning in which an unconditional stimulus US, a
footshock elicits freezing behavior immobility except for Fear is a psychological construct used to describe the
breathing in the context of US delivery. In this study, various behavioral and physiological changes that take
male rats exhibited significantly higher levels of contextual place when an organism is faced with a threatening
freezing than female rats. Interestingly, we also discovered situation [16,23,35]. As with many behavioral systems
a sex difference in perforant path-dentate granule cell [10,12,51], fear-related behavior exhibits a prominent
long-term potentiation LTP [37]. LTP is an enduring sexual dimorphism in both rodents [7] and humans [31].
form of synaptic plasticity that has been posited to mediate Recently, we reported a reliable sex difference in con-
various forms of learning [41,45], including contextual fear textual fear conditioning [43], a form of Pavlovian con-
conditioning [25,39]. The positive correlation between hippocampal synaptic plasticity and contextual fear con-
ditioning is consistent with the proposed role of the
1
Published on the World Wide Web on 1 December 2000.
hippocampus in contextual fear conditioning [5,40].
Corresponding author. Tel.: 11-734-936-6532; fax: 11-734-763-
An interesting question concerns the hormonal factors
7480.
that regulate sexually dimorphic fear conditioning. Al-
E-mail address : marenumich.edu S. Maren.
2
though the influence of gonadal steroids on several be-
Present address: Northwestern University, Department of Neurobiol-
havioral systems has been characterized [61], the in-
ogy and Physiology, 2153 N Campus Dr., Evanston, IL 60208-0877, USA.
volvement of these hormones in fear conditioning is poorly
0006-8993 01 – see front matter
2001 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 3 1 1 6 - 4
R .R. Gupta et al. Brain Research 888 2001 356 –365
357
understood. Recently, Anagnostaras et al. found that effects of ovariectomy on fear conditioning. Specifically,
castration in adult male rats did not affect the sex we predicted that estrogen administration prior to fear
difference in either fear conditioning or hippocampal LTP conditioning would attenuate the acquisition of contextual
[6]. In contrast, a role for ovarian steroids in fear con- fear.
ditioning has been suggested by a study indicating that In experiment 3, we used electrophysiological tech-
contextual fear conditioning in female rats varies across niques to characterize the influence of estrogen administra-
the estrous cycle [44]. Specifically, female rats in proestrus tion on the induction of perforant path-dentate gyrus long-
when plasma levels of estrogen are high exhibit reliably term potentiation LTP in ovariectomized female rats.
lower levels of conditional freezing compared to females Perforant path LTP has been reported to be sexually
in estrus when plasma levels of estrogen are low. dimorphic [37,43] and it was therefore of interest to
Consistent with these results, it has been reported that examine the modulation of this form of synaptic plasticity
cycling female rats perform more poorly than ovariectom- by ovarian steroids.
ized female rats in an aversively motivated avoidance learning task [19,24]. Moreover, a preliminary report
2.2. Subjects and surgery indicates
that exogenous
estradiol administration
in ovariectomized female rats reduces contextual fear con-
Long–Evans rats were obtained from a commercial ditioning [4]. These data suggest that ovarian steroids and
supplier Harlan Sprague–Dawley, Indianapolis, IN. They estrogen, in particular, may be important in regulating fear
were individually housed in metal cages located in the conditioning in adult female rats.
vivarium and maintained on a 14:10 h light dark cycle. The possible role for ovarian steroids in contextual fear
Rats had unrestricted access to food and water and were conditioning is interesting in the light of other work
handled daily for 4 days prior to surgery to acclimate the implicating estrogen in the regulation of hippocampal
rats to the experimenter. Twenty-five female 150–174 g neuronal morphology [63–66] and synaptic plasticity
and 12 male 175–199 g were used in experiment 1, 29 [14,17,26] in female rats. In the present experiments we
female 150–174 g rats in experiment 2, and 33 female examined the relationship between ovarian steroids and
rats 150–174 g in experiment 3. contextual fear conditioning. We conducted three experi-
In experiments 1–3, rats were anesthetized with methox- ments to examine the hypothesis that estrogen exerts an
yfluorane and were bilaterally ovariectomized; sham-oper- inhibitory influence on both contextual fear conditioning
ated males in experiment 1 underwent the same procedure, and perforant path-granule cell LTP in adult female rats.
except that no tissue was removed. Three days after Our results reveal an important role for estrogen in
ovariectomy, vaginal lavages were performed on the modulating contextual fear conditioning and hippocampal
operated females for 10 days to screen for improperly synaptic plasticity in adult female rats.
ovariectomized rats. The presence of cornified epithelial cells in the vaginal smears was evaluated, and a conserva-
tive criterion was used for inclusion of animals in the
2. Materials and methods
