The beneficial effects of estradiol on attentional processes are dependent on timing of treatment initiation following ovariectomy in middle-aged rats

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Summary

The goal of the present study was to explore the effects of long-term hormone deprivation on the ability of subsequent estrogen treatment to affect attention performance on the 5-choice serial reaction time task (5-CSRTT). In an initial experiment to assess estradiol effects in young adults, 2-month-old rats were trained on the 5-CSRTT, then ovariectomized and immediately implanted with capsules containing cholesterol (n = 10) or estradiol (n = 10). Then rats were tested on the 5-CSRTT under baseline task parameters, under increased task difficulty (behavior challenge condition), and finally in muscarinic and nicotinic drug challenge conditions. In a second experiment, 10-month-old rats were trained on the 5-CSRTT and at 12 or 17 months of age rats were ovariectomized and treated with estradiol or cholesterol, so that one group received continuous cholesterol control treatment, two groups received estradiol treatment immediately following ovariectomy (either at 12 or 17 months), and one group received delayed estradiol treatment initiated 5 months following ovariectomies. At 17 months of age, rats were tested on the 5-CSRTT. Baseline performance was comparable between estradiol- and cholesterol-treated rats of both age groups. However, young estradiol-treated rats outperformed controls when behavior was challenged by shortening the intertrial interval (Short ITI). In the same Short ITI condition, middle-aged rats receiving immediate estradiol treatment beginning at the age of 17 months, but not 12 months, outperformed controls as well as animals receiving delayed estradiol treatment. No differences between groups were found in the cholinergic drug challenge conditions. These data indicate that chronic estradiol treatment for approximately 1 month but not 6 months is able to enhance attention performance, and that prolonged ovarian hormone deprivation attenuates these beneficial effects of subsequent estradiol treatment. These findings have implications for informing clinical research about the importance of timing and duration of hormone treatment.

Introduction

The steroid hormone estrogen has been purported to promote healthy cognitive aging in postmenopausal women (Sherwin, 2002). However, in a large clinical trial conducted by the National Institutes of Health, the Women's Health Initiative Memory Study, estrogen failed to benefit cognitive aging if administered to postmenopausal women on average about 20 years after menopause (Espeland et al., 2004, Shumaker et al., 2004). Following this unexpected outcome, the critical period hypothesis has been put forward, proposing the existence of a critical time period following loss of ovarian function during which estrogen treatment must be initiated in order to exert positive effects on cognitive function (Maki, 2006, Resnick and Henderson, 2002, Sherwin, 2007). Preliminary evidence in support of the critical period hypothesis in humans has been accumulated (Dumas et al., 2008, Henderson et al., 2005, MacLennan et al., 2006, Zandi et al., 2002). Studies using rodent models provide more experimental control over treatment regimens and have so far also provided support for the critical period hypothesis on a behavioral (Daniel et al., 2006, Gibbs, 2000) and molecular level (Bohacek et al., 2008, Bohacek and Daniel, 2009, McLaughlin et al., 2008), suggesting that enhancing effects of estrogen for cognitive function depend on early treatment initiation. To date, however, the behavior studies have focused exclusively on hippocampus-sensitive tasks, because a large body of work has identified mechanisms of estrogen action specifically in the hippocampus (for review, see Spencer et al., 2008). However, the effects of estrogen in other brain areas associated with cognition remain poorly understood. One prominent structure that is sensitive to the effects of estrogen is the prefrontal cortex, where estrogen can increase spine density (Luine et al., 2006, Morrison et al., 2006) and cholinergic activity (Gibbs and Gabor, 2003, Luine, 1985), similar to the effects of estrogen observed in the hippocampus (Spencer et al., 2008, Woolley, 1998). Because of the central role of the prefrontal cortex in higher order cognitive function, and given that this structure is sensitive to the effects of estrogen treatment, the goal of the present study was to test the validity of the critical period hypothesis as it applies to prefrontal cortex sensitive cognitive performance.

Attentional processes are an important cognitive domain mediated by the prefrontal cortex (Dalley et al., 2004). Therefore, in the present study we tested the effects of estrogen and the timing of treatment initiation using the 5-choice serial reaction time task (5-CSRTT), a well-established prefrontal cortex sensitive task (Dalley et al., 2004, Muir et al., 1996) that assesses a broad array of attention-related performance measures (Robbins, 2002). Although it has been shown that high-dose estradiol injections improve certain aspects of 5-CSRTT performance of ovariectomized young and aged rats (Barnes et al., 2006), constant supraphysiological levels of estrogen treatment have impairing effects on rats trained post-surgically on attention-related operant working memory and response timing tasks (Wang et al., 2008). Additionally, previous findings suggest that ovariectomized rats trained post-surgically outperform gonadally intact animals on a sustained attention task (McGaughy and Sarter, 1999). In order to establish the effects of our chronic estrogen treatment regimen using physiological levels of estradiol delivery, we first assessed 5-CSRTT performance in young adult ovariectomized rats trained before and tested after ovariectomy. Then, in a separate experiment, we tested the critical period hypothesis by training middle-aged rats on the task before ovariectomies, and then initiating chronic estradiol treatment either immediately or 5 months following ovariectomy. We hypothesized that the effects of delayed estrogen treatment would be different from the effects of immediate estrogen treatment.

The effects of estradiol on cognitive performance are, at least in part, mediated by the cholinergic system (Daniel and Dohanich, 2001, Lam and Leranth, 2003). In line with the prediction of the critical period hypothesis, we recently found that the ability of estradiol to affect protein levels of the cholinergic marker choline acetyltransferase (ChAT) and estrogen receptor alpha (ERα) are altered if treatment is initiated 5 months following ovariectomy (Bohacek et al., 2008, Bohacek and Daniel, 2009). Specifically, 5 months of ovarian hormone deprivation reduced the responsiveness of both ChAT and ERα to subsequent estradiol treatment in the hippocampus, but increased responsiveness in the prefrontal cortex. The observation that the effects of delayed estrogen treatment vary in these brain regions raises the possibility that different cognitive functions might differentially respond to delayed estrogen treatment. Further, based on the observation of region-specific alteration in ChAT levels following delayed estrogen treatment (Bohacek et al., 2008), we presented animals with systemic cholinergic drug challenges, the muscarinic receptor antagonist scopolamine, and the nicotinic antagonist mecamylamine, while performing the 5-CSRTT. We hypothesized that if the effects of estrogen on prefrontal cortex function are mediated by the cholinergic system, estrogen should be able to attenuate performance impairments induced by anti-cholinergic drugs as observed in hippocampus-sensitive memory tasks (e.g. Dohanich et al., 1994, Fader et al., 1998). Further, we predicted that delayed estrogen treatment would alter the responsiveness to cholinergic drug challenges compared to immediate estrogen treatment.

Section snippets

Subjects

Twenty female Long-Evans hooded rats, approximately 2 months of age, were purchased from Harlan Sprague–Dawley (Indianapolis, IN). Rats were individually housed under a 12-h light/dark cycle, and tested during the light phase of the cycle. Rats were maintained on a balanced maintenance diet manufactured and fortified with nutrients specifically for rodents (Teklad Diet 2016, Harlan, IN). All animals were weighed daily following behavioral training and food was provided in their home cages to

Experiment 1

One animal in the Immediate E group died during the course of the experiment and was excluded from all analyses, resulting in the following final group numbers: Cholesterol (n = 10), Immediate E (n = 9). All animals successfully acquired the task as indicated by criterion level performance within 60 training sessions before undergoing ovariectomies at the age of 4 months.

Discussion

The current work demonstrates for the first time that chronic estradiol treatment can enhance performance of the prefrontal cortex sensitive 5-choice serial reaction time task (5-CSRTT) when task difficulty is increased by unpredictably shortening the intertrial interval (Short ITI). Most importantly, this estradiol-induced effect is dependent on the timing of treatment initiation following ovariectomy, such that estradiol treatment initiated following a 5-month period of ovarian hormone

Role of funding source

Funding for this study was provided by National Science Foundation Grant 0715725 (J.M.D.). The NSF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

We gratefully acknowledge Brandon Parker, Nicole Ulrich, and Richard Silbert for their help in animal training and testing. We thank Drs. Gary Dohanich, Laura Schrader, and Paul Colombo for helpful discussions throughout the course of the study.

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