The hippocampus is a brain region regulating two (2) divergent but related life functions;learning and memory and regulation of the hypothalamatic-pituitary-adrnenal stress axis. The rodent provides a powerful model for investigating the importance of the hippocampus in both these responses. In the adult, the hippocampus is a sensitive target organ for both gonadal and adrenal steroids. Estradiol modulates synaptic plasticity in the CA1 region and improves cognitive functioning on spatial learning tasks. The effects of estradiol on hippocampal development have been less intensively studied and largely framed in the context of sexual differentiation of the brain. In this scenario, neonatal androgens of testicular origin are locally aromatized to estradiol by neurons and thereby exert a masculinizing effect on the neuroarchitechture. However, we recently discovered that contrary to expectation, the developing female hippocampus possesses high levels of estradiol. This lead us to speculate that the developing female hippocampus synthesizes estradiol de novo from cholesterol and this results in levels similar to that of males produced from testicular androgens, thereby reducing sex differences in cognitive functioning in adults. This tenet can be deconstructed into 3 testable hypotheses: 1) The developing female hippocampus makes estradiol de novo from cholesterol. 2) The developing male hippocampus does not make estradiol de novo from cholesterol but instead derives estradiol from testicular androgen. 3) Developmental estradiol synthesis in females reduces sex differences in cognitive function. We will test each of these hypotheses via three (3) specific aims that involve characterizing the source of estradiol, determining the functional significance of estradiol action to hippocampal development and identification of cellular endpoints modulated by estradiol. These results will be informative to normal hippocampal development and may serve as an entry point into understanding adult sex differences in learning and memory and stress responding.
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