This project is designed to test the hypothesis that brain neuronal circuits develop through the complex interaction of specific neurotransmitters and trophic factors. In particular, we hypothesize that glial and neuronal target cells are stimulated by neurotransmitters of specific brain pathways to regulate expression of the very trophic factor(s) and cognate receptor(s) responsible for the development and maintenance of those pathways. Previous work from our laboratory and others indicates that trophic factors regulate normal brain ontogeny. We now will examine the contention that impulse activity regulates trophic factor expression and action through the mediation of specific transmitters. In particular, we will use well-characterized neuronal, glial, and neuronal-glial cultures to 1) define the role of neuronal activity in the regulation of NGF gene expression, 2) define molecular mechanisms underlying the regulation of NGF receptor gene expression, 3) characterize regulation of expression of other members of the NGF gene family in the brain and the actions of these agents. Using this strategy we hope to identify molecular mechanisms governing brain systems formation and function, and define loci where disease processes may intervene, resulting in such abnormalities as cognitive disorders during development.
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