Hypothalamic Role in Hypertension

描述（由申请人提供）：本提案关注下丘脑室旁核（PVN）中前自主神经元在高血压疾病病理生理学中的作用。原发性高血压患者普遍存在交感神经系统功能亢进，自主神经功能紊乱的程度是决定患者预后的主要因素。由于与内脏感觉传入和传出运动自主神经中枢的相互联系，PVN是高血压交感神经驱动改变的潜在神经基质。越来越多的证据表明室旁核是参与高血压病理生理的神经回路的重要组成部分。一般而言，高血压期间神经元兴奋性改变的细胞机制仍不清楚。由于PVN包含前自主神经副交感神经和交感神经元，我们建议使用它作为一个模型来研究改变细胞机制，有助于不平衡的自主神经流出，高血压的特点。我们假设，PVN前自主神经元的细胞特性支配功能不同的自主目标是差异性改变高血压，有助于改变自主驱动。我们的初步数据表明，我们有能力进行实验来测试这些假设，并支持和改变这些神经元在高血压中的功能。使用多方面的方法结合体外电生理记录与免疫组织化学和原位杂交技术，我们将回答以下问题：1）什么是主要的内在和外在因素控制神经元兴奋性PVN前自主神经元？2)室旁核前自主神经元参与控制副交感和交感自主神经功能的细胞特性是否在高血压时受到不同的影响？3)高血压期间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?