Neurobiological Mechanisms of Sympathetic Regulation in Sleep Apnea

描述(申请人提供)：我的研究的长期目标是确定阻塞性睡眠呼吸暂停(OSA)导致的心血管(CV)发病率/死亡率的显著和独立风险背后的神经生物学机制。异常的交感神经激活是阻塞性睡眠呼吸暂停综合征的一个病理生理标志，但调节睡眠-觉醒状态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阻塞性睡眠呼吸暂停综合征的心血管后果制定具体治疗策略的努力。我的研究重点是桥脑脚盖核(PPT)，这是脑桥吻部的一群神经元。PPT在控制快速眼动(REM)睡眠方面具有公认的作用，REM睡眠是一种与自主神经不稳定相关的状态。我们的实验室发展了新的数据，表明局部刺激PPT神经元可以引起CV和交感兴奋活动(例如，血压升高、心动过速和肾交感神经活动增加)。我假设，在睡眠-觉醒状态(如REM睡眠)中，PPT-SMR存在一个交感调节区，它显著地和不同地调节交感活动，而OSA中PPT-SMR功能的改变代表了OSA和交感神经系统异常激活之间的机制联系。我拥有与学习心血管病理生理学相关的知识/能力的坚实基础，在这份独立之路奖的申请中，我建议进行两年的神经科学额外培训和CV反射的评估，这对于启动一项创新的R00调查将是重要的，以确定PPT-SMR如何在阻塞性睡眠呼吸暂停综合征的实验模型中调节心血管功能。在K99时相，我将在麻醉大鼠身上进行实验，以确定PPT-SMR神经元的位置(S)、神经化学表型和投射。我还将确定PPT-SMR神经元在介导/调节对急性缺氧的交感反应中的作用。在R00阶段，我将确定PPT-SMR损伤和慢性间歇性低氧(CIH)对大鼠不同行为状态(非REM睡眠、REM睡眠和清醒)的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，以定义阻塞性睡眠呼吸暂停综合征的心血管后果的神经生物学。

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.