Synaptic mechanisms regulating sympathetic drive

描述(申请人提供)：在高血压动物模型和原发性高血压患者中，来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，它通过投射到脑干和脊髓的交感神经相关部位。在之前的资助期间，我们发现，在高血压动物模型中，增加谷氨酸能输入有助于增强PVN前交感神经元的兴奋性，并提高交感血管舒张性。然而，高血压患者下丘脑室旁核谷氨酸能输入持续增加的分子机制尚不清楚。我们最近的研究表明，PVN中的I组代谢性谷氨酸受体(MGluRs)在高血压交感神经流出增加的支持中起重要作用。在这个相互竞争的更新方案中，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动物模型来验证我们的中心假设，即I组mGluR在突触前和突触后上调，导致高血压时PVN交感前神经元谷氨酸能输入增加和兴奋性增加。我们的具体目的是确定(1)突触前I组mGluRs在高血压发展过程中PVN内mGluRs表达和分布的变化；(2)突触前I组mGluRs对高血压时PVN前交感神经元谷氨酸能突触输入增加的贡献；(3)高血压时通过激活突触后I组mGluRs介导PVN交感前神经元兴奋性增加的下游机制；以及(4)高血压时PVN内钙调神经磷酸酶活性的变化及其对I组mGluR和NMDA通道活性增加的贡献。I组mGluRs和钙调神经磷酸酶在PVN谷氨酸能输入增加中的重要作用还没有被认识到。我们提出的研究有望揭开导致高血压患者交感血管舒缩张力持续增加的一系列分子事件。这一新信息应该会对我们理解原发性和继发性高血压发生的基本神经发生机制以及设计新的高血压治疗方法产生重大影响。 公共卫生相关性：这项建议将研究高血压时下丘脑兴奋性神经传递变化的细胞和分子机制。该项目将提供有关大脑如何参与高血压发育的新信息，并将为高血压患者开发新的治疗方法提供理论基础。

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. PUBLIC HEALTH RELEVANCE: This proposal will study the cellular and molecular mechanisms of changes in the excitatory neuro-transmission in the hypothalamus in hypertension. This project will provide new information about how the brain is involved in hypertension development and will provide a rationale for developing new treatments for patients with hypertension.