The Role of Excitatory Input into the PVN on Increased Sympathetic Drive in Heart

心力衰竭患者和所有心力衰竭动物模型都表现出交感神经增加。 激活，这增加了心力衰竭期间的死亡风险。这些基础上的核心机制 人们对异常现象知之甚少。我们之前已经观察到，大脑中的神经元激活 下丘脑室旁核(PVN)可能参与神经体液驱动的增强。这个 这种激活的机制和来源仍有待于清楚地描述。最近我们发现了增强版 兴奋机制可能是由来自高级前脑区域的改变的输入所介导的，例如 MnPO/SFO和/或上行去甲肾上腺素能输入以及改变的醛固酮-RAS机制 涉及ACE2。这些数据加在一起，表明改变了的下降和上升 室旁核内去甲肾上腺素能输入和激活的醛固酮-RAS系统(与 这些涉及nNOS的机制可能参与了这种交感兴奋。这项提案考验着 假设MnPO/SFO的激活和去甲肾上腺素的上升机制与 醛固酮-RAS的激活和ACE2的失活在心力衰竭交感神经驱动增加中的作用 我们建议确定1)哪些因素，激活MnPO/SFO，上升去甲肾上腺素能通路或 Alodosterone-RAS机制主要负责下调PVN和 心衰大鼠随后的交感神经兴奋和2)IF EXT，使nNOS和 抑制系统，也正常化或减少增强的中枢激活和醛固酮-RAS 系统。这一目标将通过利用多学科方法来实现，从完整的研究到 从动物到研究大脑核，再到单个细胞再到单分子。我们将使用各种 补充技术包括神经解剖学，免疫组织化学，电生理， 分子、细胞和腺病毒/兰蒂病毒基因转移技术。这一结果将提供重要的新的 关于交感神经兴奋的中枢机制的信息，特别是涉及下行 在增加的交感神经中，上行输入以及醛固酮-RAS系统到室旁核 在HF状态下激活。了解这些中央机制的作用，迄今尚未进行研究 调节交感神经驱动的增加将增强我们治疗心力衰竭的能力及其 心血管并发症。 相关性(请参阅说明)： 慢性心力衰竭(HF)的一个特征是交感神经动力增强。这种异常增加了风险。 心力衰竭期间的死亡率。虽然在阐明外周机制方面已经取得了一些进展 涉及到这些异常，到目前为止发现的机制并不能完全解释 心衰时的神经-体液驱动。了解中枢机制的作用及其治疗价值 运动训练将提高我们治疗心力衰竭及其全身并发症的能力。到目前为止 越来越多的证据表明，运动训练是有益的，但其中涉及的核心机制是 仍有待阐明。

Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of mortality during HF. The central mechanisms that underlie these abnormalities are poorly understood. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanisms that may be mediated by an altered input from higher forebrain areas such as MnPO/SFO and/or ascending noradrenergic input as well as an altered Aldosterone-RAS mechanism involving ACE2. These data, taken together, suggest that altered descending as well as ascending noradrenergic input and an activated Aldosterone-RAS system within the PVN (with interactions between these mechanisms involving nNOS) may be involved in this sympatho-excitation. This proposal tests the hypothesis that activation of MnPO/SFO and ascending noradrenergic mechanisms in combination with the activation of Aldosterone-RAS and inactivation of ACE2 contribute to the increased sympathetic drive in HF We propose to determine 1) which factors, activation of MnPO/SFO, ascending noradrenergic pathways or Alodosterone-RAS mechanisms are primarily responsible for the down-regulation of nNOS in the PVN and subsequent sympatho-excitation in rats with HF and 2) if ExT, which normalizes levels of nNOS and the inhibitory system, also normalizes or reduces the enhanced central activation and the Aldosterone-RAS system. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact animals to studies in brain nuclei to individual cells to single molecules. We will use a variety of complementary techniques involving neuroanatomical, immunohistochemical, electrophysiological, molecular, cellular, and Adeno/Lenti viral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of the descending and ascending input as well as the Aldosterone-RAS system to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date mediating increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications. RELEVANCE (See instructions): A hallmark of chronic heart failure (HF) is increased sympathetic drive. This abnormality increases the risk of mortality during HF. While there has been some progress in elucidating the peripheral mechanisms involved in these abnormalities, the mechanisms thus far identified do not totally account for the elevated neuro-humoral drive during HF. Understanding the role of central mechanisms and the therapeutic value of exercise training will enhance our ability to treat the HF condition and its systemic complications. To date there is growing evidence that exercise training is beneficial however the central mechanisms involved are remain to be elucidated.