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）是一个主要的健康负担和慢性间歇性缺氧（CIH）是一个标志性的表现 的SA。项目2的总体目标是确定CIH如何作用于关键中枢神经系统（CNS） 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 在呼吸周期的吸气后阶段表现出明显的交感神经激活。 而室旁核（PVN）接受来自CB的感觉输入，并且是CB的主要调节器。 同情的语气。我们最近发现了一个神经网络，它介导了吸气后的活动， 脑干：吸气后复合体（皮科）。我们检验了皮科和PVN是主要CNS的假设 这些区域对于CIH介导CB反射依赖性交感神经兴奋至关重要。我们测试这种可能性 在大鼠和小鼠上使用生理学、电生理学和光遗传学方法的组合 暴露于CIH，以及在小鼠的睡眠呼吸暂停模型，和脑干切片。AIM 1确定 CIH是否会增加皮科的兴奋性。AIM 2决定CIH是否改变了 通过皮科. AIM 3中的实验解决了 CIH对PVN与皮科相互作用的影响。AIM 4确定了皮科的功能作用， PVN介导CIH引起的交感神经冲动增强。AIM 5检查了皮科和PVN的作用 在表现出自发睡眠的HO-2缺失小鼠中介导交感神经驱动和呼吸暂停增加 呼吸暂停项目2的主要概念和技术创新包括：a）确定皮科在以下方面的作用： 通过CIH介导增加的交感神经活性，B）描绘完整的神经回路 负责CIH增加的交感神经活性，c）使用最先进的光遗传学方法， 确定不同神经元回路参与的方法，和d）中枢运动前区的检查 在一个新的小鼠模型中控制交感神经张力的电路，该模型表现出自发性呼吸暂停。成员 调查小组在拟议办法方面有长期的经验和专门知识， 第一个发现皮科，并有多年合作的良好记录，如 联合出版物。项目2的顺利完成预计将建立一个谅解框架， 中枢神经系统回路引起交感神经激活增加，并可能导致新的有效治疗， 减轻CB反射依赖的交感神经激活。