The primary goal of this Program Project is to reveal the important interactions between the brain and female reproductive senescence, with particular attention to the impact of these evens on memory, cognition, and attention. While animal studies have demonstrated clearly that changes in circulating estrogen levels affect cellular and molecular attributes of certain neural circuits, the link between such observations and the human data on peri- and post-menopausal memory impairment, beneficial neurobehavioral effects of estrogen replacement therapy (ERT), and potential decreased risk of Alzheimer's disease with ERT are far from clear. It is our strong conviction that the Program Project mechanism, as implemented in this proposal, is required to analyze the spectrum of mechanistic analyses from the in vitro level to an in depth structural and functional assessment of the effects of ERT on behaviorally characterized non-human primates. Though tight interactions between projects 1, 2, and 3, studies in rodents will extend from a) mechanistic analyses of estrogen's role in synaptogenesis and neurodegeneration to b) estrogen- and age-induced alterations in the circuits that directly control reproductive function and c) estrogen and age-induced plasticity in the circuits that mediate memory. The rodent analyses, particularly the in vitro studies of Project 1, will be a crucial testing ground for revealing novel molecular and cellular links to estrogen-brain interactions that could be pursued in the primate model. Core A as well as Projects 2, 3, 4, and 5 will converge on the non-human primate model. They will evaluate the structural (hippocampal, glutamate, cholinergic, basal forebrain, and dopaminergic mesocortical systems) and functional (behavioral assays of memory, cognition, and attention) consequences of ERT in young and aged Rhesus monkeys, as well as provide a detailed assessment of endocrine status and hypothalamic regulation of reproductive function. Rhesus monkeys of different ages that have been surgically ovariectomized with and without ERT as well as those that have transitioned through age-related menopause will be employed in this Program Project. These animals will be the object of detailed endocrine, neurobiological, and behavioral analyses in an integrated effort to reveal the effects of interactions of estrogen and aging in the brain. These studies will lay the groundwork for more informed approaches to ERT in humans in order to help ameliorate neurodegenerative processes, as well as to promote successful brain aging.
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