Neuroendocrine neuropeptides such as vasopressin, oxytocin, and neurotensin serve as neurohormones, and neurotransmitters in the mammalian brain. The expression of the genes which encode these peptides, and their receptors, in brain neurons is regulated by steroid hormones such as estrogen, corticosteroids, and testosterone. This laboratory has for several years attempted to understand the importance of this hormonal modulation in the function of these neuropeptide systems, has used them to understand the cellular and molecular events which mediate the effects of steroids on neurotransmitter gene transcription in brain neurons. Data gathered in neuroblastoma cells, in primary neuronal cultures, and in the rat and mouse brain in vivo suggests that estrogen acts not only through the """"""""classical"""""""" mechanism of action involving nuclear hormone receptor dimerization and binding to consensus hormone response elements, but also via """"""""cross-talk"""""""" with other protein kinase-dependent signal transduction pathways such as protein kinase A, and the mitogen activated protein kinases. The studies proposed in this renewal application will test the hypothesis that estrogenic regulation of neuropeptide gene expression in vitro and in vivo. They will also investigate the relative roles of estrogen receptor-subtypes (ERalpha and the newly identified ERbeta) in these responses involves a mix of """"""""classical"""""""" and protein kinase-dependent transcriptional actions. It is, thus, the combination of these effects which confer the dramatic effects of hormones such as estrogen on the brain involved in neuroendocrine regulation, reproductive behavior, as well as neurotropic effects in the developing and aging. The approach will involve identification of signal transduction cascades which respond to estrogen, determination of their ability to enhance transcription of neuropeptide/receptor promoter-reporter gene constructs in vitro, and profiling their sensitivity to estrogen receptor agonists and antagonists. Local implantation of ER agonists and antagonists, and pharmacologic agents which activate or inhibit the relevant signal transduction pathways will be used.
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