Brainstem Neural Mechanisms Mediating Sympathetic Activation by Chronic Intermittent Hypoxia

慢性间歇性缺氧介导交感神经激活的脑干神经机制

• 批准号: 10409554
• 负责人: Jan M. Ramirez
• 金额: $ 49.38万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409554
• 关键词: Address; Alleles; Animals; Apnea; Area; Blood Pressure; Brain Stem; Carotid Body; Catecholamines; Chronic; Complex; Data; Electrophysiology (science); Exhibits; Experimental Models; Exposure to; Female; Glutamates; Goals; Halorhodopsins; Health; Hypoxia; In Vitro; Injections; Joints; Kidney; Knockout Mice; Lead; Lesion; LoxP-flanked allele; Maps; Mediating; Membrane; Motor; Motor Neurons; Mus; Nerve; Nervous system structure; Neuraxis; Neurons; Norepinephrine; Oxytocin; Patients; Phase; Physiological; Plasma; Population; Property; Publications; Rattus; Reflex action; Rodent; Role; Sleep Apnea Syndromes; Slice; Techniques; Technology; Testing; Toxin; Transgenic Organisms; Vasopressins; Virus; base; designer receptors exclusively activated by designer drugs; effective therapy; experience; experimental study; in vivo; innovation; kainate; male; member; mouse model; neural circuit; neural network; neuromechanism; neuronal circuitry; novel; optogenetics; paraventricular nucleus; receptor; relating to nervous system; respiratory; sensory input

Project Summary- Project 2 Sleep apnea (SA) is a major health burden and chronic intermittent hypoxia (CIH) is a hallmark manifestation of SA. The overall goal of Project 2 aims at determine how CIH acting on key central nervous system (CNS) structures mediate sympathetic activation through the carotid body (CB). SA patients and CIH exposed rodents exhibit pronounced sympathetic nerve activation during the post-inspiratory phase of the respiratory cycle. While the Paraventricular nucleus (PVN) receives sensory input from the CB and is a major regulator of sympathetic tone. We recently discovered a neural network that mediates post-inspiratory activity in the brainstem: the post-inspiratory complex (PiCo). We test the hypothesis that PiCo and PVN are the major CNS areas that are critical for mediating CB reflex-dependent sympathetic excitation by CIH. We test this possibility using a combination of physiological, electrophysiological, and optogenetic approaches on rats and mice exposed to CIH, as well as in a mouse of model of sleep apnea, and brainstem slices. AIM 1 determines whether CIH increases excitability in PiCo. AIM 2 determines whether CIH alters the excitability of rostroventrolateral medulla sympathetic pre-motoneurons via PiCo. Experiments in AIM 3 addresses the influence of CIH on the interaction between PVN and PiCo. AIM 4 determines the functional role of PiCo and PVN in mediating the increased sympathetic drive caused by CIH. AIM 5 examines the role of PiCo and PVN in mediating increased sympathetic drive and apneas in HO-2 null mice which exhibit spontaneous sleep apnea. Major conceptual and technical innovations of Project 2 include: a) identification for role of PiCo in mediating increased sympathetic nerve activity by CIH, b) the delineation of a complete neural circuit responsible for increased sympathetic nerve activity by CIH, c) use of the state-of-the-art optogenetic approaches to determine the involvement of different neuronal circuits, and d) examination of central pre-motor circuits controlling sympathetic tone in a novel mouse model that exhibits spontaneous apneas. Members of the investigative team have long-standing experience and expertise with the proposed approaches, were the first to identify PiCo, and have an excellent track record of working together for number years as evidenced by joint publications. Successful completion of Project 2 is anticipated to establish a framework of understanding the CNS circuits causing increased sympathetic nerve activation and may lead to novel effective therapies for mitigating CB reflex- dependent sympathetic activation.

项目摘要 - 项目2 睡眠呼吸暂停（SA）是主要的健康负担，慢性间歇性缺氧（CIH）是标志性的表现 SA。项目2的总体目标旨在确定CIH在关键中枢神经系统（CNS）上的作用 结构通过颈动脉体（CB）介导交感神经激活。 SA患者和CIH暴露啮齿动物 在呼吸周期的启动后培训阶段表现出明显的交感神经激活。 室室核（PVN）从CB接收感觉输入，是 同情的语气。我们最近发现了一个神经网络，该网络介导 脑干：启发性络合物（PICO）。我们检验了PICO和PVN是主要中枢神经系统的假设 对于通过CIH介导CB反射依赖性的交感激发至关重要的区域。我们测试了这种可能性 结合大鼠和小鼠的生理，电生理和光遗传学方法的结合 暴露于CIH以及睡眠呼吸暂停模型和脑干切片中。 AIM 1确定 CIH是否增加了PICO的兴奋性。 AIM 2确定CIH是否改变了兴奋性 Rostroventrolololal外侧延髓通过PICO交感神经元。 AIM 3中的实验解决了 CIH对PVN和PICO之间相互作用的影响。 AIM 4确定PICO和 PVN在介导CIH引起的交感神经驱动力增加时。 AIM 5检查了PICO和PVN的作用 在介导HO-2 NULL小鼠中的同情驱动和呼吸暂停的增加时，该小鼠表现出自发的睡眠 呼吸暂停。项目2的主要概念和技术创新包括：a）识别pico在 介导CIH的增加交感神经活动，b）完整的神经回路的描述 负责通过CIH提高交感神经活动，c）使用最先进的光遗传学 确定不同神经元电路的参与的方法，d）检查中央前运动剂 在表现出自发呼吸暂停的新型小鼠模型中控制交感神经的电路。成员 调查团队在拟议方法中具有长期的经验和专业知识，是 首先要识别PICO，并在数年中共同努力的良好记录，这证明了这一点 联合出版物。预计成功完成项目2将建立一个理解框架 中枢神经系统电路导致同情神经激活增加，并可能导致新的有效疗法 减轻CB反射依赖性交感神经激活。