Role of presympathetic neurons of the hindbrain in cardiovascular control

后脑交感前神经元在心血管控制中的作用

• 批准号: 10116460
• 负责人: Stephen Abbott
• 金额: $ 54.28万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116460
• 关键词: Acute; Animals; Blood Pressure; Brain; Brain Stem; Cardiovascular Diseases; Cardiovascular system; Carotid Body; Cell Nucleus; Cells; Cessation of life; Chemoreceptors; Chronic; Data; Development; Essential Hypertension; Functional disorder; Generations; Genetic Transcription; Heart Diseases; Heart failure; Human; Hyperactivity; Hypertension; Hypoxemia; Hypoxia; Mediating; Methods; Modeling; Molecular Genetics; Multiple System Atrophy; Nerve; Neurons; Norepinephrine; Output; Oxidative Stress; Pathway interactions; Patients; Play; Pontine structure; Rabies virus; Rattus; Regulation; Resistance; Rest; Risk Factors; Rodent; Role; Sleep Apnea Syndromes; Source; Spinal Cord; Stroke; Sympathetic Nervous System; System; Testing; Therapeutic; blood pressure regulation; connectome; excitatory neuron; hindbrain; knock-down; neurogenic hypertension; noradrenergic; optogenetics; prevent; receptor; respiratory; transcriptome; transcriptome sequencing; vesicular monoamine transporter 2

Contact PD/PI: Abbott, Stephen Project summary Hypertension is an important risk factor for the development of cardiovascular disease. Despite major therapeutic advances, hypertension is often treatment resistant and still causes countless deaths from stroke and heart disease. Hypertension may be neurogenic i.e. it is associated with and probably caused by a chronic elevation of sympathetic nerve activity (SNA). This SNA elevation has many suspected causes such as an increase in carotid body activity, brainstem hypoxemia and CNS oxidative stress but the CNS network that ultimately mediates the SNA elevation is not well understood. One reason is our limited understanding of the connections and function of most brainstem pathways implicated in the generation of SNA. This proposal focuses on the contribution of the A5 group of hindbrain noradrenergic neurons to the regulation of SNA and blood pressure (BP). This choice is motivated by four considerations. First, A5 neurons are the main source of noradrenergic input to sympathetic preganglionic neurons. Second, noradrenaline exerts powerful excitatory effects on sympathetic preganglionic neurons. Third, A5 neurons are strongly activated by hypoxia and therefore could mediate some of the effects of hypoxia on SNA and contribute to the adaptive changes elicited by hypoxia. Lastly, the efflux of noradrenaline metabolites from the brain of hypertensive humans (MHPG) is elevated, which suggests that CNS NA-release may be abnormally high. These four considerations suggest that A5 neurons hyperactivity could contribute to neurogenic hypertension. I will test the hypothesis that A5 noradrenergic cells activate the sympathetic nervous system by exciting sympathetic preganglionic neurons via NA-release. Second, I propose to determine the transcriptome and connectome of A5 neurons, and compare them with that of neighboring neurons that control BP in the rostral ventrolateral medulla. And finally, I will test whether A5-dependent NA-release causes sympathetic hyperactivity in a model of sleep apnea (acute intermittent hypoxia). Understanding the hindbrain networks controlling the sympathetic system may benefit the treatment of any condition associated with sympathetic dysfunction, like neurogenic hypertension, heart failure and multiple systems atrophy. Page 6 Project Summary/Abstract

联系PD/PI：Abbott，Stephen 项目总结 高血压是心血管疾病发展的重要危险因素。尽管有重大的 治疗的进展，高血压通常是耐药的，仍然导致无数人死于中风 和心脏病。高血压可能是神经性的，即它与慢性高血压有关，而且可能是由慢性高血压引起的 交感神经活动(SNA)升高。这种SNA升高有许多可疑原因，例如 颈动脉小体活动、脑干低氧血症和中枢神经系统氧化应激增加，但中枢神经系统网络 最终调节SNA上升的机制还不是很清楚。其中一个原因是我们对 大多数脑干通路的连接和功能与SNA的产生有关。 这一建议侧重于A5组后脑去甲肾上腺素能神经元对 SNA和SNA监管 血压(BP)。这一选择是出于四个考虑。首先，A5神经元 是交感节前神经元去甲肾上腺素能输入的主要来源。第二，去甲肾上腺素 对交感神经节前神经元产生强烈的兴奋作用。第三，A5神经元是很强的 被低氧激活，因此可能介导低氧对SNA的一些影响，并有助于 低氧引起的适应性变化。最后，去甲肾上腺素代谢产物从脑组织流出。 高血压人群(MHPG)升高，提示CNS NA释放可能异常高。 这四个方面的考虑表明，A5神经元的过度活动可能与神经源性高血压有关。 我将验证A5去甲肾上腺素能细胞通过兴奋激活交感神经系统的假设 交感神经节前神经元通过NA释放。第二，我建议确定转录组和 A5神经元的连接体，并与嘴端控制BP的相邻神经元的连接体进行比较 延髓腹外侧。最后，我将测试一下 A5依赖NA释放 成因 同情的 多动症在 睡眠呼吸暂停(急性间歇性低氧)模型。理解后脑网络 控制交感神经系统可能有助于任何与交感神经相关的疾病的治疗 功能障碍，如神经性高血压、心力衰竭和多系统萎缩。 第6页 项目摘要/摘要