The long-term objective of this project is to evaluate the role of estrogen in modulating different types of memory and to understand the neural mechanisms underlying cognitive effects produced by estrogen as a function of aging. Ovarian steroids affect the brain throughout the life span and their effects are not limited to the areas primarily involved in reproduction, but also include the areas relevant to memory. Despite evidence that estrogen affects the brain, however, there have been no studies that directly test the effects of estrogen on memory as a function of aging. Our preliminary studies have indicated that ovariectomy (OVX) has a more rapid effect on cognition in older rats than in young. This has led to our main hypothesis that memory systems are more dependent on estrogens in aged rats. The main aims proposed in this application are to test the working hypothesis that with aging or long-term deficiency of estrogen, cognitive functions decline, and therefore, become more dependent on estrogens. Furthermore, it can be predicted that the types of memory that decline most with aging are most sensitive to estrogen. These studies will test these hypotheses in extended behavioral analyses that will produce detailed information on the interactions of aging and estrogen effects on cognition and the role of IGF-1 as a possible mediating mechanism for estrogen effects in the brain. The four specific aims that will be tested are whether 1) specific cognitive functions are more sensitive to estrogen, 2) with longer estrogen withdrawal cognition will decline more and effects of estrogen will depend upon the duration of the withdrawal, 3) estrogen effects differ as a function of aging, and 4) IGF-1 effects on NMDA receptors mediate the estrogen induced effects on cognition. The results of these studies will be the first to critically analyze the effects of estrogen on cognition as a function of aging, duration of estrogen deficiency and type of cognitive task and will also, test a potential neuroendocrine mechanism. Therefore, the data will be of importance in the understanding of age related changes in cognitive function and will have important clinical relevance.
