Hypothalamic Role in Hypertension

描述(由申请人提供)：这项建议集中在下丘脑室旁核(PVN)中自主神经前神经元在高血压疾病的病理生理学中的作用。交感神经系统功能亢进常见于高血压病患者，自主神经失衡程度是决定患者预后的主要因素。通过与传入内脏感觉和传出运动自主神经中枢的相互联系，室旁核是高血压交感神经驱动改变的潜在神经底物。越来越多的证据表明，室旁核是参与高血压病理生理学的神经元回路的重要组成部分。总的来说，高血压期间神经元兴奋性改变所涉及的细胞机制尚不清楚。由于室旁核同时含有自主神经前副交感神经元和交感神经元，我们建议将其作为一个模型来研究导致高血压特征的不平衡自主神经流出的细胞机制。我们假设，在高血压中，支配不同自主神经靶点的PVN自主神经前神经元的细胞特性发生了不同的改变，从而导致了自主神经驱动的改变。我们的初步数据表明，我们有能力进行实验来检验这些假说，并支持和改变这些神经元在高血压中的功能。我们将采用体外电生理记录与免疫组织化学和原位杂交技术相结合的多方面方法，回答以下问题：1)控制PVN自主前神经元神经元兴奋性的主要内在和外部因素是什么？2)参与控制副交感和自主神经功能的PVN自主前神经元的细胞特性在高血压时是否受到不同的影响？3)高血压时兴奋性改变的细胞机制是什么？

DESCRIPTION (provided by applicant): 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?