Synaptic mechanisms regulating sympathetic drive

描述（由申请人提供）：在高血压动物模型和原发性高血压患者中，源自大脑的交感神经驱动增加。下丘脑室旁核（PVN）是控制交感神经流出的重要部位，通过其投射到脑干和脊髓的交感神经相关部位。在上一个资助期间，我们发现，增强的交感神经输入有助于增加PVN前交感神经元的兴奋性和高血压动物模型中的交感血管紧张素升高。然而，很少有人知道的分子机制，潜在的持续增加的多巴胺能输入的PVN在高血压。我们最近的研究表明，I组代谢型谷氨酸受体（mGluRs）在室旁核是至关重要的，在高血压的交感神经流出的支持。在这个竞争性的更新建议中，我们将使用自发性高血压大鼠和肾血管性高血压大鼠作为高血压的动物模型来测试我们的中心假设，即I组mGluRs在突触前和突触后位点上调，这导致高血压中PVN前交感神经元的兴奋性和兴奋性增加。我们的具体目的是确定（1）在高血压的发展过程中，PVN中I组mGluRs的表达和分布的变化;（2）突触前I组mGluRs对高血压时增强PVN前交感神经元的突触能输入的贡献;（3）高血压时通过激活突触后I组mGluRs介导PVN前交感神经元兴奋性增加的下游机制;（4）高血压时室旁核钙调神经磷酸酶活性的变化及其对I组mGluR和NMDA通道活性增加的作用。I组mGluRs和钙调神经磷酸酶在PVN中增加的谷氨酸能输入中的重要作用以前没有被认识到。我们提出的研究有望解开一个级联的分子事件负责持续增加交感血管紧张素在高血压。这些新的信息将对我们理解原发性和继发性高血压发展的基本神经机制以及设计新的高血压治疗方法产生重大影响。

DESCRIPTION (provided by applicant): The sympathetic drive emanating from the brain is increased in animal models of hypertension and in patients with primary hypertension. The paraventricular nucleus (PVN) of the hypothalamus is an important site for the control of sympathetic outflow through its projections to sympathetically related sites in the brainstem and spinal cord. During the previous funding period, we showed that augmented glutamatergic input contributes to increased excitability of PVN presympathetic neurons and elevated sympathetic vasomotor tone in the animal model of hypertension. However, little is known about the molecular mechanisms underlying the sustained increase in glutamatergic input to the PVN in hypertension. Our recent study suggests that group I metabotropic glutamate receptors (mGluRs) in the PVN are critically involved in the support of elevated sympathetic outflow in hypertension. In this competing renewal proposal, we will use spontaneously hypertensive rats and renovascular hypertensive rats as animal models of hypertension to test our central hypothesis that group I mGluRs are upregulated at presynaptic and postsynaptic sites, which leads to increased glutamatergic input and excitability of PVN presympathetic neurons in hypertension. Our specific aims are to determine (1) the changes in the expression and distribution of group I mGluRs in the PVN during the development of hypertension; (2) the contribution of presynaptic group I mGluRs to augmented glutamatergic synaptic input to PVN presympathetic neurons in hypertension; (3)the downstream mechanisms mediating increased excitability of PVN presympathetic neurons by activation of postsynaptic group I mGluRs in hypertension; and (4) the changes in calcineurin activity and their contribution to increased group I mGluR and NMDA channel activity in the PVN in hypertension. The important roles of group I mGluRs and calcineurin in increased glutamatergic input in the PVN have not been recognized previously. Our proposed studies are expected to unravel a cascade of molecular events responsible for the sustained increase in sympathetic vasomotor tone in hypertension. This new information should have a major impact on our understanding of the fundamental neurogenic mechanisms underlying the development of primary and secondary hypertension and on the design of new treatments for hypertension.