CENTRAL NEURONAL-GLIAL MECHANISMS AND NEUROHUMORAL ACTIVATION IN HYPERTENSION

摘要 虽然交感神经系统和神经内分泌系统的协调活动对于适当的 维持心血管（CV）稳态，持续的交感体液激活是高度 有害，导致CV疾病，包括高血压。因此，阐明机制 调节交感体液激活对于预防和更有效地治疗 高血压下丘脑室旁核（PVN）在神经元的生成中起着关键作用。 交感体液反应这个核团内的神经元活动是由一种平衡控制的， 内在属性和外在突触输入。在最近的研究中，我们发现A型K+ 电流（IA）抑制PVN放电活动，并且钝化的IA功能有助于增强的神经元放电。 高血压的活动。高血压的另一个主要致病因素是谷氨酸NMDA增加 受体功能然而，这两种不同的机制是否在功能上和因果关系上 目前，尚不清楚。使用多学科方法结合体外和体内 研究中，我们获得了令人兴奋的初步数据，支持突触外NMDAR之间的因果关系， 和IA介导高血压时神经元活动增加和交感神经激活。 此外，我们发现星形胶质细胞是影响eNMDAR-IA偶联的功效的关键参与者。 在这项提议中，我们将测试中心假设，即eNMDAR的过度激活及其负面影响。 与IA偶联是神经元活性增加的主要促成因素， 高血压中交感体液激活。本申请的主要目的是表征 eNMDAR-IA偶联的信号传导机制。此外，我们的目的是阐明 （a）改变的神经胶质功能和（B）内在神经元机制对过度激活的相对贡献 的eNMDAR-IA偶联，并增加神经元活性和交感体液激活， 高血压大鼠使用肾血管性高血压动物模型，我们提出了以下具体建议： 目的：目的1-表征eNMDAR和IA之间的功能偶联;目的2-确定是否 改变的胶质细胞功能有助于增强高血压大鼠的eNMDAR-IA偶联;目的3- To 确定改变的神经元机制是否有助于增强高血压患者的eNMDAR-IA偶联 大鼠我们希望这项工作能扩大我们对神经生物学基本原理的了解， 产生稳态神经体液反应。更重要的是，我们希望找到关键的 病理生理学脑机制有助于适应性神经体液反应， 高血压我们希望我们的工作将有助于开发新的和更有效的治疗方法 治疗高血压疾病的策略。

Abstract While coordinated activities of the sympathetic and neuroendocrine systems are essential for proper maintenance of cardiovascular (CV) homeostasis, sustained sympathohumoral activation is highly detrimental, contributing to CV disorders including hypertension. Thus, elucidating mechanisms regulating sympathohumoral activation is critical for the prevention and more efficient treatment of hypertension. The hypothalamic paraventricular (PVN) nucleus plays pivotal roles in the generation of sympathohumoral responses. Neuronal activity within this nucleus is controlled by a balance between intrinsic properties and extrinsic synaptic inputs. In recent studies, we showed that the A-type K+ current (IA) inhibits PVN firing activity, and that blunted IA function contributes to enhanced neuronal activity in hypertension. Another major pathogenic factor in hypertension is increased glutamate NMDA receptor function. However, whether these two distinct mechanisms are functionally and causally coupled, is at present unknown. Using a multidisciplinary approach combining in vitro and in vivo studies, we obtained exciting preliminary data supporting a causal link between extrasynaptic NMDARs and IA in mediating increased neuronal activity and sympathoumoral activation in hypertension. Moreover we found astrocytes to be pivotal players influencing the efficacy of the eNMDAR-IA coupling. In this proposal, we will test the central hypothesis that over-activation of eNMDARs and its negative coupling to IA is a major contributing factor underlying increased neuronal activity and sympathohumoral activation in hypertension. The main objective of this application is to characterize the signaling mechanisms underlying the eNMDAR-IA coupling. Moreover, we aim to elucidate the relative contribution of (a) altered glial function and (b) intrinsic neuronal mechanisms to overactivation of the eNMDAR-IA coupling, and increased neuronal activity and sympathohumoral activation in hypertensive rats. Using a renovascular hypertensive animal model, we propose the following Specific Aims: Aim 1- To characterize the functional coupling between eNMDARs and IA; Aim 2- To determine if altered glial function contributes to enhanced eNMDAR-IA coupling in hypertensive rats; and Aim 3- To determine if altered neuronal mechanisms contribute to enhanced eNMDAR-IA coupling in hypertensive rats. We expect this work to expand our knowledge on basic neurobiological principles implicated in the generation of homeostatic neurohumoral responses. More importantly, we expect to identify key pathophysiological brain mechanisms contributing to maldaptive neurohumoral responses in hypertension. We hope our work will help in the development of novel and more efficient therapeutic strategies for the treatment of hypertensive conditions.