Estrogen is known to play a fundamental role in sculpting the developing nervous system. The ultimate goal of this research will be to understand the profound impact of estrogen on the developing mammalian brain. Perinatal estrogen exposure, derived from estrogenic metabolites of circulating testosterone, permanently masculinizes the morphology, connectivity, and chemistry of many regions of the central nervous system. Many behaviors and physiological functions also permanently acquire a male-typical pattern in response to perinatal estrogen. The most dramatic effects of estrogen in development occur in neural circuits that, in the adult, contain estrogen target cells and participate in reproductive behavior and physiology. Abnormal hormone secretion or neurotransmission during early development may affect estrogen-induced differentiation of the brain, possibly disrupting neural control of reproduction or other brain functions. Estrogen binds to estrogen-specific receptors that act as transcription factors, importantly altering protein synthesis. The hypothesis that is central to the proposed studies is that estrogen receptor-containing neurons in the developing brain receive and transduce the estrogenic signal and so are crucial to estrogen-induced differentiation. The experiments performed will determine when estrogen receptor-containing neurons are born, when they begin to express functional estrogen receptor, whether they are subject to selective cell death in the presence or absence of estrogen, and whether selected synaptic and hormonal signals interact to affect the survival of estrogen target neurons. The analyses will initially concentrate on the development of estrogen target cells in the rat preoptic area. This reproductively relevant brain region has documented. hormone-dependent differences in morphology and receptor distribution. Histochemical techniques to detect estrogen receptors, birthdate markers, cell death markers, developing neural connections, and other markers of neuronal differentiation will be employed to identify selected subsets of estrogen receptor-expressing cells from early embryonic stages through adulthood.
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