The goal of this research proposal is to elucidate the mechanisms underlying LHRH release from hypothalamic neurons and its regulation by steroid hormones. Our working hypothesis (conceived as a result of our studies conducted during the period of previous grant support) is that copper, released from neurons impinging on LHRH neurons, is taken up by the LHRH neuron, interacts with the secretory granules and this interaction leads to release of the peptide. Steroids regulate LHRH release by modifying copper action on LHRH neuron and/or copper release from other neurons. Our first objective is to elucidate the biochemical mechanism of the process of copper-stimulated release of LHRH, using explants of the median eminence as a model system. To achieve this goal, we will characterize the time course, dose response and the requirements for energy, Na+, and granule -SH. The second objective is to elucidate the mechanisms by which steroids regulate LHRH release from LHRH neurons of female and male rats. To achieve this goal, we will study the effects of steroids on the process of copper-stimulated release of LHRH. To examine the specificity of this effect of steroids, we will examine in parallel, the effects of steroids on K+-stimulated release of LHRH; a process distinct from that stimulated by copper. The third objective is to define the biochemical mechanisms underlying copper homeostasis in the brain. To achieve this goal, using K+-stimulated release from brain slices as a model, we will characterize the process of copper release and its regional distribution in the brain. In addition, we will investigate the uptake, subcellular distribution and release of newly taken up [Cu64]. Once these biochemical parameters are defined, we will utilize them to achieve the goals of our fourth objective - to elucidate the mechanism by which steroids (gonadal and adrenal) regulate copper homeostasis in the brain. An understanding of the mechanisms by which steroids regulate LHRH release, through regulation of the process of copper-stimulated release of LHRH and of copper release per se, will provide insight into integrative regulatory processes in the brain and hence, into developmental and hormonally regulated brain functions.
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