Neurobiological Mechanisms of Sympathetic Regulation in Sleep Apnea

描述（由申请人提供）：我研究的长期目标是确定阻塞性睡眠呼吸暂停（OSA）导致心血管（CV）发病率/死亡率的显著和独立风险的神经生物学机制。异常的交感神经激活是OSA的病理生理特征，但调节睡眠-觉醒状态交感神经活动的神经生物学机制尚不清楚。这种知识的缺乏阻碍了为OSA的心血管后果设计特定治疗策略的尝试。我的研究重点是桥脚被盖核（PPT），这是一组位于桥喙侧的神经元。PPT在控制快速眼动（REM）睡眠（一种与自主神经不稳定有关的状态）方面已经确立了良好的作用。我们的实验室开发了新的数据，表明局部刺激PPT神经元会引起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）。我假设在睡眠-觉醒状态（如REM睡眠）中存在一个PPT-SMR的交感调节区域（即PPT-SMR），该区域对交感神经活动具有显著和差异的调节作用，并且OSA中PPT-SMR功能的改变代表了OSA与交感神经系统异常激活之间的机制联系。我在研究心血管病理生理学方面有很强的知识/能力基础，在这份通往独立之路奖的申请中，我提议在神经科学和心血管反射评估方面进行两年的额外培训，这对于启动一项创新的R00调查非常重要，该调查旨在确定在OSA实验模型中，PPT-SMR如何调节跨行为状态的心血管功能。在K99期，我将对麻醉大鼠进行实验，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PPT-SMR神经元在介导/调节急性缺氧交感反应中的作用。在R00期，我将确定PPT-SMR损伤和慢性间歇性缺氧（CIH）对大鼠跨行为状态（非快速眼动睡眠、快速眼动睡眠和清醒）CV功能的影响。K99期和R00期的研究都为我未来的R01期研究奠定了重要的基础，以确定OSA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.