Synaptic Mechanisms Regulating Sympathetic Drive

在高血压动物模型和患者中，从大脑发出的交感神经驱动增加 患有高血压。下丘脑室旁核(PVN)是调控的重要部位 交感神经流出通过其投射到脑干和脊髓的交感神经相关部位 电源线。在之前的资助期间，我们已经表明，增加谷氨酸能输入有助于 动物下丘脑室旁核前交感神经元兴奋性增强和交感血管舒缩张力升高 高血压模型。然而，人们对其背后的细胞和分子机制知之甚少。 高血压患者下丘脑室旁核谷氨酸能输入的可塑性和交感神经流出的持续性增加。 我们的初步数据表明，I组嗜代谢性谷氨酸受体(mGluRs，包括mGluR1和mGluR1) 下丘脑室旁核中的mGluR5)调节下丘脑室旁核前交感神经元的谷氨酸能传入，并参与 自发性高血压大鼠交感神经流出增加的维持。在这场竞争性的更新中 建议，我们将使用自发性高血压大鼠作为高血压的动物模型，以测试 中枢假说：室旁核中的mGluR1和mGluR5参与交感血管运动的增加 高血压患者的声调。本项目的具体目标是确定(1)研究mGluR1和mGluR1的作用 MGluR5在下丘脑室旁核交感血管舒缩张力升高中的作用 高血压对下丘脑室旁核mGluR1和mGluR5控制交感神经流出的作用。 I组mGluRs在脑内谷氨酸能输入和交感神经流出持续增加中的重要作用 高血压以前没有被认识到。拟议的研究将提供大量的新奇 谷氨酸能突触可塑性及其持续增加机制的研究进展 高血压患者的交感神经驱动力。这一新信息也将是我们理解这一角色的关键 自主神经系统在高血压发展中的作用及为设计更有效 高血压的治疗。

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.