High levels of estrogen enhance associative memory formation in ovariectomized females
Introduction
The ovarian hormone estrogen has a profound influence on the morphological and electrophysiological properties of the hippocampus, a brain region implicated in certain forms of learning and memory. It has been shown that exposure to estrogen either exogenously or endogenously during proestrus greatly enhances the density of dendritic spines in area CA1 of the hippocampus (Gould et al., 1990, Woolley and McEwen, 1993, Shors et al., 2001). Over the 5-day estrous cycle of the rat, spine density can fluctuate as much as 30% (Woolley et al., 1990). Moreover, these changes in the dendritic spines have been shown to reflect changes in synapse density and to be accompanied by changes in astrocytic volume (Woolley and McEwen, 1992, Klintsova et al., 1995). In addition to these structural alterations, hippocampal electrophysiology is also sensitive to estrogen (Wong and Moss, 1992). For example, both in vivo and in vitro studies have shown that estrogen affects hippocampal excitability, as well as the induction of LTP (Warren et al., 1995, Cordoba Montoya and Carrer, 1997) and LTD (Desmond et al., 2000).
Such hormonally regulated changes in hippocampal synaptic plasticity may have important behavioral implications. Indeed, there are numerous studies that have examined the effects of estradiol on hippocampal-dependent learning. However, the results have been equivocal, with estrogen reported to impair, enhance or have no effect on performance. Studies examining performance in the spatial water maze task during the estrous cycle have reported small deficits (Frye, 1995, Warren and Juraska, 1997) or no difference (Berry et al., 1997) in females during exposure to proestrous levels of estrogen. In the radial arm maze, a test of spatial working memory, stable performance across the estrous cycle was demonstrated (Stackman et al., 1997). In contrast, our laboratory has observed that performance of both hippocampal-dependent and -independent types of classical eyeblink conditioning are enhanced during proestrus relative to other stages of estrus and to performance in males (Shors et al., 1998, Wood et al., 2001).
In hormone replacement studies, estrogen administration in ovariectomized rats enhances performance on some types of tasks but impairs performance on others. For example, estrogen improves spatial working memory aspects of the radial arm maze (Fader et al., 1999, Daniel et al., 1997, Luine et al., 1998, Bimonte and Denenberg, 1999, Gibbs, 1999, Korol and Kolo, 2002). Beneficial effects of estrogen replacement have been observed in spatial water maze tasks (O’Neal et al., 1996, Packard and Teather, 1997, Sandstrom and Williams, 2001). Estrogen has also been shown to adversely affect learning of conditioned place preference (Galea et al., 2001) and contextual fear memories (Markus and Zecevic, 1997, Gupta et al., 2001).
Although these studies differ with respect to route and duration of hormone administration, age of the animals and type of task used, circulating estradiol levels were within the physiological range, typically less than 100 pg/ml. However, there are several reports demonstrating that supraphysiological doses of estrogen have positive effects on cognition. For example, inhibitory avoidance performance is improved in rats treated with both physiological and supraphysiological doses of estradiol (Fugger et al., 2000, Frye and Rhodes, 2002). In humans, administration of estradiol after surgical menopause enhanced short-term memory when subjects were tested at a time when estradiol levels were supraphysiological (more than 4× that of their preoperative baseline) (Phillips and Sherwin, 1992). More recently, it was reported that postmenopausal women with Alzheimer’s disease treated with a high dose of estrogen exhibited enhanced attention and memory as compared to placebo treated controls (Asthana et al., 2001). High levels of plasma estrogen have also been shown to have a positive effect on mood in postmenopausal women (Klaiber et al., 1979, Sherwin, 1991; but see Schleifer et al., 2002).
Given the various reports that exogenous estrogen can affect learning processes, we evaluated the effects of both physiological and supraphysiological acute doses of estrogen on associative learning. Following ovariectomy, females were injected with differing doses of estradiol and trained on the hippocampal-dependent task of trace eyeblink conditioning. This task was chosen because it is affected by sex differences and stages of estrus (Solomon et al., 1986, Moyer et al., 1990, Shors, 1998, Beylin et al., 2001).
Section snippets
Subjects and surgical procedures
Adult virgin female Sprague–Dawley rats (250–300 g) were obtained from Zivic Laboratories and housed individually prior to and following surgery in the Department of Psychology animal facility, Rutgers University. Rats had unlimited access to water and Purina Lab Chow (Ralston-Purina, St. Louis, MO) and were maintained on a 12:12 h light–dark cycle with light onset at 07:00 h. After at least a 1-week acclimation period, animals were anesthetized with 30 mg/kg pentobarbital injected
Discussion
In two experiments, we show that acute exposure to exogenous estrogen can enhance performance in ovariectomized female rats that are trained on the hippocampal-dependent learning task of trace eyeblink conditioning. In the first experiment, different levels of plasma estradiol were associated with different degrees of conditioning. Only those females with very high levels of estradiol (>250 pg/ml) emitted more learned responses than their respective oil-treated controls. The enhanced
Acknowledgements
We thank M. Slomovits for assistance with data collection. This work was supported by the National Institute of Mental Health (59970) and the National Alliance for Research on Schizophrenia and Depression (to T.J.S.). B.L. was supported by a predoctoral NRSA fellowship (MH63568).
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