It is now well accepted that gonadal steroids exert potent influences in the brain during critical developmental periods and into adulthood by organizing and reorganizing the circuitry involved in neuroendocrine and behavioral functions. More recently, estradiol has also been shown to act in regions outside the neuroendocrine axis and to exert neuroprotective and neurotrophic actions on neurons. These effects are especially prominent in postmenopausal women where hormonal replacement ameliorates cognitive decline and decreases the incidence and delays the onset of several neurodegenerative diseases. With the demonstration by the Women's Health Initiative Study that current gonadal hormone replacement regimens lead to adverse effects and cancellation of one major treatment arm, it has become critical to understand how estrogen exerts its positive actions in the brain (and other tissues) and to design better hormone replacement regimens. Proposed experiments will utilize rat and mice models to investigate enhancement of recognition memory (visual and place) by estrogens and androgens. Hormones and drugs will be utilized to determine which estrogen receptors mediate the short term (non-genomic) and long term (genomic effects) enhancements of object recognition (visual memory) and object placement (spatial memory). Mice lacking specific receptors for estrogen will also be examined with these memory tasks. Mechanisms mediating estrogen-dependent enhancements in memory will be determined by use of Golgi techniques to determine hormonal effects on dendritic morphology and spine density in cortical and hippocampal neurons which are known to be important for memory. Whether gonadal hormones contribute to memory function in males will also be examined by the same behavioral and anatomical techniques. Proposed studies have enormous health relevance since age and disease related dementia is growing in the U.S. due to the aging of post war """"""""baby boom"""""""" generations. Proposed experiments should provide better understanding of the mechanisms for gonadal hormone action and thereby provide insights for designing new hormones/drugs for the prevention and treatment of age and neurodegenerative disease related memory impairments.
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