Neurobiological Mechanisms of Sympathetic Regulation in Sleep Apnea

描述（由申请人提供）：本研究的长期目标是确定阻塞性睡眠呼吸暂停（OSA）引起的心血管（CV）发病率/死亡率显著和独立风险的神经生物学机制。交感神经异常激活是阻塞性睡眠呼吸暂停的一个病理生理学特征，但其在睡眠-觉醒状态下调节交感神经活动的神经生物学机制却知之甚少。这种知识的缺乏阻碍了为OSA的CV后果设计特定治疗策略的尝试。我的研究主要集中在脚桥被盖核（PPT），在脑桥吻侧的神经元集群。PPT在控制快速眼动（REM）睡眠（一种与自主神经不稳定相关的状态）方面具有公认的作用。我们的实验室开发了新的数据，表明PPT神经元的局部刺激可激发CV和交感神经兴奋活动（例如，血压升高、心动过速和肾交感神经活动增加）。我假设有一个交感神经调制区的PPT（即，PPT-SMR），其在睡眠-觉醒状态（例如REM睡眠）中显著且差异性地调节交感神经活动，并且OSA中改变的PPT-SMR功能代表OSA与交感神经系统的异常激活之间的机制联系。我有一个强大的基础知识/能力相关的研究CV病理生理学，并在这个途径独立奖申请我建议在神经科学和CV反射的评估，这将是重要的启动一个创新的R00调查，以确定如何PPT-SMR调节CV功能在OSA的实验模型的行为状态的额外培训两年。在K99阶段，我将在麻醉大鼠中进行实验，以确定PPT-SMR神经元的位置、神经化学表型和投射。我还将定义的PPT-SMR神经元在调解/调节交感神经对急性缺氧的反应的作用。在R00阶段，我将确定PPT-SMR病变和慢性间歇性缺氧（CIH）对大鼠在不同行为状态（非REM睡眠、REM睡眠和觉醒）下CV功能的影响。K99和R00阶段的研究都是我未来R01计划的重要基础，以确定OSA CV后果的神经生物学。

DESCRIPTION (provided by applicant): The long-term objective of my research is to determine the neurobiological mechanisms underlying the significant and independent risk for cardiovascular (CV) morbidity/mortality resulting from obstructive sleep apnea (OSA). Aberrant sympathetic activation is a pathophysiologic hallmark of OSA, but the neurobiological mechanisms that regulate sympathetic activities across sleep-wake states are poorly understood. This lack of knowledge has thwarted attempts to devise specific therapeutic strategies for the CV consequences of OSA. My research is focused on the pedunculopontine tegmental nucleus (PPT), a cluster of neurons in the rostral pons. The PPT has a well-established role in controlling rapid eye movement (REM) sleep, a state associated with autonomic instability. Our laboratory developed novel data indicating that local stimulation of PPT neurons elicits CV and sympathoexcitatory activities (e.g., elevated blood pressure, tachycardia, and increased renal sympathetic nerve activity). I hypothesize that there is a sympathetic modulating region of the PPT (i.e., a PPT- SMR) that significantly and differentially regulates sympathetic activities across sleep-wake states (such as REM sleep) and that altered PPT-SMR function in OSA represents a mechanistic link between OSA and aberrant activation of the sympathetic nervous system. I have a strong foundation of knowledge/competency relevant to studying CV pathophysiology, and in this Pathway to Independence Award application I propose two years of additional training in neuroscience and the assessment of CV reflexes, which will be important for launching an innovative R00 investigation to determine how the PPT-SMR modulates CV function across behavioral states in an experimental model of OSA. In the K99 phase, I will conduct experiments in anesthetized rats to determine the location(s), neurochemical phenotype, and projections of PPT-SMR neurons. I will also define the role of PPT-SMR neurons in mediating/modulating sympathetic responses to acute hypoxia. In the R00 phase, I will determine the impact of PPT-SMR lesion and chronic intermittent hypoxia (CIH) on CV function across behavioral states (non-REM sleep, REM sleep, and wakefulness) in rats. Both the K99 and R00 phase investigations represent important foundations for my future R01 initiatives to define neurobiology of the CV consequences of OSA.