This proposal focuses on the role of preautonomic neurons in the paraventncular nucleus (PVN) of the hypothalamus in the pathophysiology of hypertensive disorders. Hyperactivity of the sympathetic nervous system is commonly present in patients with essential hypertension, and the level of autonomic disbalance is a major determinant of patients' prognosis. By virtue of reciprocal connections with afferent visceroceptive and efferent motor autonomic centers, the PVN stands as a potential neural substrate underlying altered sympathetic drive in hypertension. Accumulating evidence implicates the PVN as an important component in the neuronal circuit involved in the pathophysiology of hypertension. In general, the cellular mechanisms involved in altered neuronal excitability during hypertension remain unknown. Since the PVN contains both preautonomic parasympathetic and sympathetic neurons, we propose to use it as a model to study altered cellular mechanisms contributing to unbalanced autonomic outflow, characteristic of hypertension. We hypothesize that the cellular properties of PVN preautonomic neurons innervating functionally different autonomic targets are differentially altered in hypertension, contributing to altered autonomic drive. Our preliminary data shows our ability to conduct experiments to test these hypotheses, and supports and altered function of these neurons in hypertension. Using a multifaceted approach combining in vitro electrophysiological recordings with immunohistochemical and in situ hybridization techniques we will answer the following questions: 1) What are the main intrinsic and extrinsic factors controlling neuronal excitability in PVN preautonomic neurons? 2) Are the cellular properties of PVN preautonomic neurons involved in the control of the parasympathetic and sympathetic autonomic function differentially affected during hypertension? 3) What are the cellular mechanisms underlying altered excitability during hypertension?
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