Elsevier

Psychoneuroendocrinology

Volume 29, Issue 7, August 2004, Pages 883-890
Psychoneuroendocrinology

High levels of estrogen enhance associative memory formation in ovariectomized females

https://doi.org/10.1016/j.psyneuen.2003.08.001Get rights and content

Abstract

The ovarian hormone estrogen is presumed to modulate processes of learning and memory in adulthood. In this study, we examined the effects of short-term estrogen replacement on associative memory formation. Adult ovariectomized female rats received two injections of estradiol (10, 20 or 40 μg) 24 h apart and were trained 4 h following each injection on the hippocampal-dependent task of trace eyeblink conditioning. Only the highest dose of estrogen, which produced plasma estradiol levels >250 pg/ml, enhanced conditioned responding. One day after the last injection, estrogen treated rats continued to exhibit elevated levels of conditioning and extinguished responding when the conditioned stimulus was no longer presented. Exposure to estrogen did not alter pain sensitivity or activity levels, but did greatly increase uterine weight. These results provide additional support to the view that that ovarian steroids are beneficial to the performance of certain forms of learning and memory tasks, albeit at supraphysiological doses. They are discussed with reference to hormone replacement and its effects on cognitive processes.

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).

References (52)

  • H.N Fugger et al.

    Novel effects of estradiol and estrogen receptor alpha and beta on cognitive function

    Brain Res.

    (2000)
  • L.A.M Galea et al.

    High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory

    Behav. Brain Res.

    (2001)
  • R.B Gibbs

    Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition

    Horm. Behav.

    (1999)
  • R.R Gupta et al.

    Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats

    Brain Res.

    (2001)
  • A Klintsova et al.

    Astrocytic volume fluctuates in the hippocampal CA1 region across the estrous cycle

    Brain Res.

    (1995)
  • V.N Luine et al.

    Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters

    Horm. Behav.

    (1998)
  • M.F O’Neal et al.

    Estrogen affects performance of ovariectomized rats in a two-choice water escape working memory task

    Psychoneuroendocrinology

    (1996)
  • M.G Packard

    Posttraining estrogen and memory modulation

    Horm. Behav.

    (1998)
  • S.M Phillips et al.

    Effects of estrogen on memory function in surgically menopausal women

    Psychoneuroendocrinology

    (1992)
  • L.A Schleifer et al.

    Lack of effects of acute estradiol on mood in postmenopausal women

    Pharmacol. Biochem. Behav.

    (2002)
  • S.S Smith

    Female sex steroid hormones: from receptors to networks to performance—actions on the sensorimotor system

    Prog. Neurobiol.

    (1994)
  • R.W Stackman et al.

    Stability of spatial working memory across the estrous cycle of Long-Evans rats

    Neurobiol. Learn. Mem.

    (1997)
  • S.G Warren et al.

    LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats

    Brain Res.

    (1995)
  • D.S Woodruff-Pak et al.

    Trace conditioning: abolished by cerebellar lesions but not lateral cerebellar cortex aspirations

    Brain Res.

    (1985)
  • S Asthana et al.

    High-dose estradiol improves cognition for women with AD: results of a randomized study

    Neurology

    (2001)
  • B Berry et al.

    Spatial learning and memory at defined points of the estrous cycle: effects on performance of a hippocampal-dependent task

    Behav. Neurosci.

    (1997)
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      Although results can vary based on sex, gonadal status, age, species, timing of treatment, and the task being used to measure memory, the balance of studies report that E2 facilitates the acquisition and/or consolidation of episodic memories in both female and male rodents (Frick, 2009; Bimonte-Nelson et al., 2010; Daniel, 2013; Luine, 2014; Tuscher et al., 2015; Hamson et al., 2016; Koss and Frick, 2017; Sheppard et al., 2018). For example, considerable research has shown that acute or chronic systemic E2 administration improves spatial memory among ovariectomized female rats and mice in traditional hippocampus-dependent tasks like the Morris water maze, radial arm maze, and T-maze, as well as in tests of object or social recognition, object location, inhibitory avoidance, and trace eyeblink conditioning (e.g., O’Neal et al., 1996; Daniel et al., 1997; Fader et al., 1998, 1999; Luine et al., 1998; Bimonte and Denenberg, 1999; Gibbs, 1999; Daniel and Dohanich, 2001; Sandstrom and Williams, 2001, 2004; Bowman et al., 2002; Heikkinen et al., 2002; Holmes et al., 2002; Garza-Meilandt et al., 2006; Bohacek and Daniel, 2007; Hammond et al., 2009; Singh et al., 1994; Frye and Rhodes, 2002; Leuner et al., 2004). Furthermore, acute systemic E2 given immediately post-training to ovariectomized rats and mice enhances memory consolidation in the Morris water maze and object recognition tasks (e.g., Luine et al., 2003; Gresack and Frick, 2006; Walf et al., 2006; Frye et al., 2007; Fernandez et al., 2008; Inagaki et al., 2010).

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