The long term goal of these studies is to define the molecular mechanisms involved in adrenal glucocorticoid regulation of brain development. The studies proposed here will begin by studying the expression and development of glucocorticoid- (GR) and mineralocorticoid- (MR) receptors and identifying proteins that are regulated by glucocorticoids in hippocampal neurons and glial cells. In the future, these studies promise to lead to the cloning and sequencing of those genes and gene products that are regulated by glucocorticoids at the transcriptional level in specific classes of neurons and glia. Our previous work on glucocorticoid effects on neural development and glucocorticoid receptor expression in the brain places us in a position to address these issues. An interdisciplinary approach using primary cell culture, immunocytochemistry, in situ hybridization, and quantitative analysis of proteins separated by ultra-high resolution giant 2-D gel electrophoresis will be applied. Specifically, the proposed studies seek to a) describe the initial expression and ontogeny of GRs and MRs and their corresponding mRNAs in the fetal and postnatal rat brain, b) determine which classes of glia express GRs or MRs, c) study the possible co-expression of GRs and MRs within the same cell, d) identify proteins regulated by glucocorticoids in astrocytes, oligodendrocytes, hippocampal neurons and HT4 cells, an immortalized clonal neuronal cell line derived from hippocampus e) investigate whether glucocorticoid effects on the metabolism of specific proteins are mediated by the MR or the GR, or both, and f) determine whether glucocorticoid regulation of specific proteins occurs at the level of mRNA. More generally, these studies address current issues in developmental neurobiology concerning the role of extracellular factors in cell differentiation and regulation. These studies will increase our understanding of mechanisms through which hormones derived from the periphery influence differentiation of neurons and glia and cellular regulation in the adult brain. Moreover, these studies promise to elucidate loci where changes in the hormonal milieu of cells in the brain, elicited by disease, steroid therapy or aging, may lead to behavioral abnormalities. Such knowledge may contribute to our understanding of birth defects, senility and depression in the human and ultimately lead to therapeutic approaches to treat these disorders.
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