Estrogenic modulation of place and response learning via specific receptor-mediated mechanisms

Estrogens are best known for their roles in reproductive behavior and physiology, but they also contribute substantially to normal brain function. The effects of estrogens on brain and cognitive health are particularly important because should they live long enough, all women will undergo a dramatic loss of estrogen and progesterone through menopause. While the results of human studies remain mixed due to a variety of confounding factors, a large body of basic science research has shown that estrogens indeed modulate learning and memory. Importantly, estrogens do not globally improve cognition but have bi-directional effects depending on the cognitive task and neural systems engaged. Estrogens generally enhance learning and memory for tasks that are sensitive to function of the hippocampus but impair the performance of tasks that tap the dorsal striatum. These memory systems do not act in isolation but rather appear to interact extensively when an animal attempts to learn a given task, with estrogens acting to shift the relative contributions of each neural structure for the acquisition and performance of cognitive tasks. Specifically, estrogens promote the use of hippocampus-sensitive spatial strategies and impede the use of striatum-sensitive egocentric strategies. Additionally, estrogens act through a variety of receptor subtypes, which are expressed in the hippocampus and striatum with varying densities and localizations, to exert these behavioral effects. As women are increasingly exposed to substances with distinct estrogen receptor (ER) affinities, such as selective estrogen receptor modulators and botanical phytoestrogen supplements, it is important to characterize the role of each ER in estrogenic cognitive shifts. The present work examines the contributions of ER subtypes to shifts in learning and memory in ovariectomized female rats. Endogenous estrogen levels were eliminated through the surgical removal of ovaries in young adult or middle-aged rats. Two days prior to cognitive testing, rats were treated with either estradiol benzoate, isoflavones, or compounds that selectively target ERα, ERβ, or GPER. Rats then underwent maze training on a hippocampus-sensitive place task or dorsal striatum-sensitive response task. Our results reveal that treatment with estradiol, the isoflavone genistein, or selective agonists for ERα, ERβ, or GPER were all sufficient to enhance place learning and impair response learning. These findings emphasize that multiple receptor-mediated pathways contribute to estrogenic shifts in cognition, and that independent activation of a single receptor appears sufficient to induce these mnemonic changes. Importantly, a consistent feature of our results was the appearance of inverted-U dose response functions, whereby behavioral effects emerged at an optimal dose of estrogens but lower and higher doses were ineffective or produced opposing effects. This finding emphasizes the need for careful consideration of dose-response functions in experiment and treatment design. Lastly, activation of MAPK signaling was examined in the hippocampi and striata of rats used in prior experiments. Phosphorlyation of ERK, a member of the MAPK cascade, appears to play a critical role in both learning and estrogen signaling in the brain. Results from quantitative Western blot analyses show that patterns of estrogen-regulated ERK activation are nuanced, varying according to the level of learning task performance and the ER subtype targeted. Together, the findings of these studies elucidate some of the neurobiological mechanisms that underlie estrogen-induced shifts in learning and memory and may have implications for the development of new treatments aimed at preserving cognitive function over the lifespan