Lateral hypothalamic regulation of sympathetic nerve activity and blood pressure

 描述(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以直接归因于肥胖。肥胖性高血压与交感神经过度活动有关，有证据表明，通过瘦素受体和黑素皮质素-4受体的信号在这一过程中起着关键作用。然而，这种联系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动和高血压的神经回路。这项拟议研究的基本原理是，了解调节交感神经流出和血压的特定大脑瘦素和黑素皮质素回路将有助于开发更具选择性的药物策略，从而有效治疗高血压和肥胖症。我们最近在下丘脑外侧区发现了一个独特的神经元亚群，它们同时表达瘦素受体和黑素皮质素-4受体。中心假设是，在肥胖和高瘦素血症的背景下，下丘脑外侧区神经元亚群中的瘦素受体和黑素皮质素-4受体信号都被增强，从而导致交感神经过度活动和高血压。为了直接测试这一假说的组成部分，已经产生了以下具体目标：1)确定LHA中的MC4R信号是否必要且充分地调节肾脏SNA并调节肥胖相关的血压升高；以及2)确定LHA中的Lepr信号是否必要且充分地调节肾脏SNA并调节肥胖相关的血压升高；以及3)测试LHA Lepr神经元活动的选择性光遗传调制是否调节肾脏SNA并改善肥胖相关的血压升高。我们将测试在肥胖的情况下，操纵LHA中的瘦素和黑素皮质素信号和神经元活动是否会影响交感神经流出和心血管功能。这项拟议的研究具有创新性，因为它将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，以测试一种导致肥胖诱导的交感神经过度驱动和高血压的新大脑电路。这项拟议的研究具有重要意义，因为它将提高我们对肥胖性高血压的分子和神经基础的理解，并确定有效治疗与肥胖症发展相关的高血压的新的治疗机会。我们相信，这项工作将有助于更好地理解大脑网络和信号通路如何导致神经原性高血压的发展。

 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.