Brainstem Neural Mechanisms Mediating Sympathetic Activation by Chronic Intermittent Hypoxia

项目总结-项目2 睡眠呼吸暂停 (SA) 是一种主要的健康负担，慢性间歇性缺氧 (CIH) 是一种标志性表现 南澳。项目2的总体目标旨在确定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。 虽然室旁核 (PVN) 接收来自 CB 的感觉输入，并且是 同情的语气。我们最近发现了一种神经网络，可以介导吸气后活动 脑干：吸气后复合体（PiCo）。我们检验 PiCo 和 PVN 是主要 CNS 的假设 这些区域对于介导 CIH 引起的 CB 反射依赖性交感神经兴奋至关重要。我们测试一下这种可能性 在大鼠和小鼠身上结合使用生理学、电生理学和光遗传学方法 暴露于 CIH、睡眠呼吸暂停模型小鼠和脑干切片。 AIM 1 决定 CIH 是否会增加 PiCo 的兴奋性。 AIM 2 确定 CIH 是否改变了兴奋性 延髓头腹外侧交感前运动神经元通过 PiCo。 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 决定了 PiCo 的功能作用和 PVN 介导 CIH 引起的交感神经驱动力增强。 AIM 5 研究 PiCo 和 PVN 的作用 介导表现出自发睡眠的 HO-2 缺失小鼠交感神经驱动和呼吸暂停的增加 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) 完整神经回路的描绘 负责 CIH 增加交感神经活动，c) 使用最先进的光遗传学 确定不同神经元回路参与情况的方法，以及 d) 中枢前运动检查 在表现出自发性呼吸暂停的新型小鼠模型中控制交感神经张力的电路。成员 调查小组对拟议的方法拥有长期的经验和专业知识，如果 第一个发现 PiCo，并拥有多年合作的良好记录，如下所示： 联合出版物。项目 2 的成功完成预计将建立一个理解框架 中枢神经系统回路导致交感神经激活增加，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。

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.