Lateral Hypothalamic Regulation of Sympathetic Nerve Activity and Blood Pressure

 描述（由申请人提供）：肥胖和高血压是严重的公共卫生问题。人口研究表明，至少三分之二的高血压患病率可直接归因于肥胖。肥胖引起的高血压与交感神经过度活跃有关，有证据表明，通过瘦素受体和黑皮质素-4受体的信号传导对这一过程至关重要。然而，这种关联的潜在神经基础仍然不完全清楚。我们的长期目标是描绘出介导肥胖引起的交感神经过度活跃和高血压的神经回路。这项拟议研究的基本原理是，了解特定的大脑瘦素和黑皮质素回路，介导交感神经流出和血压将有助于开发更有选择性的药理学策略，使高血压和肥胖症的有效治疗。我们最近发现了一个独特的亚群神经元在外侧下丘脑区，共同表达瘦素受体和黑皮质素-4受体。中心假设是，在肥胖症和高瘦素血症的背景下，瘦素受体和黑皮质素-4受体信号在下丘脑外侧区神经元的这个亚群中被增强，引起交感神经过度活跃和高血压。为了直接测试该假设的组成部分，已经产生了以下具体目的：1）确定LHA中的MC 4 R信号传导是否是调节肾SNA和介导肥胖相关的血压升高所必需和足够的;和2）确定LHA中的LepR信号传导是否是调节肾SNA和介导肥胖相关的血压升高所必需和足够的;和3）测试LHA LepR+神经元活性的选择性光遗传学调节是否调节肾SNA并改善肥胖相关的血压升高。我们将测试是否操纵瘦素和黑皮质素信号和神经元活动的LHA在肥胖的背景下影响交感神经流出和心血管功能。这项研究具有创新性，因为它将联合收割机结合多种最先进的技术，包括Cre/loxP，光遗传学，交感神经活动的直接多纤维记录和血压的无线电遥测测量，以测试一种新的大脑回路，该回路有助于肥胖诱导的交感神经麻痹和高血压。这项研究意义重大，因为它将提高我们对肥胖引起的高血压的分子和神经基础的理解，并确定有效治疗与肥胖发展相关的高血压的新治疗机会。我们相信，这项工作将有助于更好地了解大脑网络和信号通路如何导致神经源性高血压的发展。

 DESCRIPTION (provided by applicant): Obesity and hypertension are serious public health concerns. Population studies indicate that at least two- thirds of the prevalence of hypertension can be directly attributed to obesity. Obesity-induced hypertension is associated with sympathetic overactivity and evidence indicates that signaling through both leptin receptor and melanocortin-4 receptor is critical for this process. However, the underlying neural basis of this association remains incompletely understood. Our long-term goal is to delineate the neural circuits that mediate obesity- induced sympathetic overactivity and hypertension. The rationale for this proposed research is that understanding the specific brain leptin and melanocortin circuits that mediate sympathetic outflow and blood pressure will help to develop more selective pharmacologic strategies that will allow effective treatment of hypertension and obesity. We have recently identified a unique subpopulation of neurons in the lateral hypothalamic area that co-express both leptin receptor and melanocortin-4 receptor. The central hypothesis is that, in the context of obesity and hyperleptinemia, both leptin receptor and melanocortin-4 receptor signaling in this subpopulation of lateral hypothalamic area neurons is augmented to cause sympathetic overactivity and hypertension. In order to directly test the components of this hypothesis, the following Specific Aims have been generated: 1) To determine if MC4R signaling in the LHA is necessary and sufficient to regulate renal SNA and mediates obesity-associated increases in blood pressure; and 2) To determine if LepR signaling in the LHA is necessary and sufficient to regulate renal SNA and mediates obesity-associated increases in blood pressure; and 3) To test if selective optogenetic modulation of activity of LHA LepR+ neurons regulates renal SNA and ameliorates obesity-associated increases in blood pressure. We will test if manipulating leptin and melanocortin signaling and neuronal activity in the LHA in the context of obesity affect sympathetic outflow and cardiovascular function. The proposed research is innovative because it will combine multiple state-of-the-art techniques, including Cre/loxP, optogenetics, direct multi-fiber recording of sympathetic nerve activity and radiotelemetry measurement of blood pressure, to test a novel brain circuit that contributes to obesity-induced sympathetic overdrive and hypertension in mice. The proposed research is significant because it will improve our understanding of the molecular and neural basis of obesity-induced hypertension and identifies novel therapeutic opportunities to effectively treat hypertension associated with the development of obesity. We believe that this work will contribute to a better understanding of how brain networks and signaling pathways lead to the development of neurogenic hypertension.