Synaptic Mechanisms Regulating Sympathetic Drive

在高血压动物模型和高血压患者中， 高血压下丘脑室旁核（PVN）是一个重要的控制部位 交感神经流出通过其投射到脑干和脊髓中的交感神经相关部位 线.在上一个资助期间，我们已经证明，增强的神经元输入有助于 动物PVN前交感神经元兴奋性增加和交感血管紧张度升高 高血压模型。然而，关于这些细胞和分子机制知之甚少。 高血压时室旁核交感神经能输入的可塑性和交感神经流出的持续增加。 我们的初步数据表明，I组代谢型谷氨酸受体（mGluR，包括mGluR 1和mGluR 2）， mGluR 5）调节对PVN前交感神经元的谷氨酸能输入，并参与PVN前交感神经元的突触传递。 自发性高血压大鼠交感神经流出量升高的维持。在这次竞争激烈的续约中 本研究拟利用自发性高血压大鼠作为原发性高血压动物模型， 中心假设：室旁核中的mGluR 1和mGluR 5有助于交感神经血管扩张的增加， 高血压的音调。本项目的具体目的是确定（1）研究mGluR 1的作用， 高血压患者交感神经张力升高时室旁核中mGluR 5的表达;（2）测定 高血压对室旁核中mGluR 1和mGluR 5控制交感神经流出的功能作用的影响。 I组mGluRs在持续增加交感神经传入和交感神经流出中的重要作用， 高血压以前没有被认识到。这些研究将提供大量新的 关于突触可塑性的机制和持续增加的信息 高血压中的交感神经驱动。这些新的信息也将是必不可少的，为我们了解的作用， 自主神经系统在高血压的发展和设计更有效的 治疗高血压。

The sympathetic drive emanating from the brain is increased in animal models of hypertension and in patients with hypertension. The paraventricular nucleus (PVN) of the hypothalamus is an important site for the control of sympathetic outflow through its projections to the sympathetically related sites in the brainstem and spinal cord. During the previous funding period, we have shown that augmented glutamatergic input contributes to increased excitability of PVN presympathetic neurons and elevated sympathetic vasomotor tone in an animal model of hypertension. However, little is known about the cellular and molecular mechanisms underlying the plasticity of glutamatergic input to the PVN and the sustained increase in sympathetic outflow in hypertension. Our preliminary data suggest that group I metabotropic glutamate receptors (mGluRs, including mGluR1 and mGluR5) in the PVN regulate glutamatergic input to PVN presympathetic neurons and are involved in the maintenance of elevated sympathetic outflow in spontaneously hypertensive rats. In this competitive renewal proposal, we will use spontaneously hypertensive rats as an animal model of essential hypertenSion to test the central hypotheSiS that mGluR1 and mGluR5 in the PVN contribute to the increase in sympathetic vasomotor tone in hypertension. The specific aims of this project are to determine (1) study the role of mGluR1 and mGluR5 in the PVN in elevated sympathetic vasomotor tone in hypertenSion and (2) determine the influence of hypertension on the functional role of mGluR1 and mGluR5 in the PVN in the control of sympathetic outflow. The important role of group I mGluRs in sustained increases in glutamatergic input and sympathetic outflow in hypertenSion has not been recognized previously. The proposed studies will provide substantial novel information about the mechanisms underlying glutamatergic synaptic plasticity and the persistent increase in sympathetic drive in hypertension. This new information also will be essential for our understanding of the role of the autonomic nervous system in the development of hypertension and for the design of more effective treatments for hypertension.