The objective of this research program is to determine the role of neurotransmitters, neuropeptides, ion fluxes, and second messenger systems in the regulation of vasopression (VP) mRNA in neurons of the supraoptic nuclei during chronic dehydration. Organ-cultured explants of the hypothalamo-neurohypophyseal system (HNS) will be utilized in these studies. The HNS explant includes the VP neurons located in the supraoptic nuclei, their axons extending caudally through the median eminence, and their axon terminals in the neural lobe. HNS explants reliably increase VP release into the culture medium in response to hypertonicity as well as acetylcholine, phenylephrine, bicuculline, and angiotensin II. Thus, these explants provide the opportunity to determine the extracellular and intracellular signals which regulate the length and content of VPmRNA in these neurons.
The specific aims of this proposal are: 1. To further characterize the effect of hypertonicity on VP mRNA size and content in HNS explants. 2. To determine whether the effect of hypertonicity on VPmRNA size and content in SON neurons reflects osmotically induced depolarization or synaptically mediated activation of the neuron. 3. To evaluate the role of specific neurotransmitters/neuropeptides in inducing the increase in VPmRNA content and size in response to hypertonicity. 4. To evaluate the role ion fluxes in hypertonicity and neurotransmitter/neuropeptide induced increases in VP mRNA size or content. 5. To evaluate the role of intracellular second messenger systems in the increases in VPmRNA size or content induced by hypertonicity and neurotransmitters/neuropeptides. Identification of the intracellular signals utilized by extracellular stimuli to regulate gene expression is of crucial importance to understanding the molecular basis of transmembrane control of peptide synthesis in neurons. Abnormalities in these coupling processes may underlie some neuropathological conditions. Therefore, the proposed approaches to studying the mechanisms regulating VP synthesis and release may provide important insight into normal and pathological conditions in the nervous system.
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