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，从大脑发出的交感驱动增加。下丘脑室旁核（PVN）通过投射到脑干和脊髓的交感神经相关部位，是控制交感神经流出的重要部位。在之前的资助期内，我们发现在高血压动物模型中，增强的谷氨酸能输入有助于PVN前交感神经元的兴奋性增加和交感血管舒缩张力升高。然而，对于高血压患者谷氨酸能输入PVN持续增加的分子机制知之甚少。我们最近的研究表明，PVN中的I组代谢性谷氨酸受体（mGluRs）在高血压患者交感神经流出量升高的支持中起关键作用。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验证我们的中心假设，即I组mGluRs在突触前和突触后位点上调，从而导致高血压中PVN前交感神经元的谷氨酸能输入和兴奋性增加。我们的具体目的是确定(1)高血压发生过程中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PVN前交感神经元谷氨酸能突触输入增强的贡献；(3)高血压患者突触后I组mGluRs激活PVN前交感神经元兴奋性升高的下游机制；(4)高血压患者PVN中钙调磷酸酶活性的变化及其对I组mGluR和NMDA通道活性升高的贡献。I组mGluRs和钙调磷酸酶在PVN谷氨酸能输入增加中的重要作用以前没有被认识到。我们提出的研究有望揭示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。这一新发现将对我们理解原发性和继发性高血压发病的基本神经源性机制以及高血压新疗法的设计产生重大影响。

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.