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: 10612097
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612097
• 关键词: Address; Alleles; Anesthesia procedures; Animals; Apnea; Area; Blood Pressure; Brain Stem; Carotid Body; Catecholamines; Central Nervous System; Chronic; Complex; Data; Electrophysiology (science); Exhibits; Experimental Models; Exposure to; Female; Glutamates; Goals; Halorhodopsins; Health; Hypoxia; In Vitro; Injections; Joints; Kidney; Knockout Mice; Lesion; LoxP-flanked allele; Maps; Mediating; Membrane; Motor; Motor Neurons; Mus; Nerve; Neurons; Norepinephrine; Oxytocin; Patients; Phase; Physiological; Plasma; Property; Publications; Rattus; Reflex action; Research; Rodent; Role; Sleep Apnea Syndromes; Slice; Structure; Techniques; Technology; Testing; Toxin; Transgenic Organisms; Vasopressins; Virus; designer receptors exclusively activated by designer drugs; effective therapy; experience; experimental study; in vivo; innovation; kainate; male; member; mouse model; neural; neural circuit; neural network; neuromechanism; neuronal circuitry; novel; optogenetics; paraventricular nucleus; receptor; 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)是一种主要的健康负担，慢性间歇性低氧(CIH)是其显著表现 来自SA的。项目2的总体目标是确定CIH如何作用于关键的中枢神经系统(CNS) 结构通过颈动脉小体(CB)介导交感神经的激活。SA患者和接触CIH的啮齿动物 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，是中枢神经系统的主要调节器。 同情的语气。我们最近发现了一种神经网络，它可以调节吸气后活动。 脑干：吸气后复合体(Pico)。我们检验了Pico和PVN是主要中枢神经系统的假设 在介导CB反射依赖的交感神经兴奋中起关键作用的区域。我们测试了这一可能性 采用生理学、电生理学和光遗传学相结合的方法对大鼠和小鼠进行研究 并以小鼠睡眠呼吸暂停模型和脑干脑片为模型。目标1决定 CIH是否增加了皮科的兴奋性。目标2确定CIH是否改变脑组织兴奋性 吻侧延髓腹外侧区交感前运动神经元通过Pico。AIM 3中的实验解决了 氯仿对PVN与Pico相互作用的影响目标4确定了Pico的功能角色和 下丘脑室旁核在脑出血所致交感神经冲动增强中的作用目标5研究了Pico和PVN的作用 在介导HO-2基因缺失小鼠表现出自发睡眠的交感神经驱动增加和呼吸暂停中 呼吸暂停。项目2的主要概念和技术创新包括：a)确定PICO在 通过CIH介导交感神经活动增加，b)描绘完整的神经回路 负责通过CIH增加交感神经活性，c)使用最先进的光遗传 确定不同神经元回路受累的方法，以及d)中枢运动前状态检查 控制交感神经张力的回路在一种表现出自发性呼吸暂停的新小鼠模型中。成员： 调查小组对拟议的方法具有长期的经验和专业知识， 第一个识别Pico，并有多年合作的良好记录，这一点可以证明 联合出版物。项目2的成功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兴奋。