Neurobiological Mechanisms of Sympathetic Regulation in Sleep Apnea

我研究的长期目标是确定神经生物学机制， 阻塞性睡眠导致心血管（CV）发病率/死亡率的显著独立风险 呼吸暂停（OSA）。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标志，但神经生物学改变是阻塞性睡眠呼吸暂停的一个重要因素。 调节睡眠-觉醒状态下交感神经活动的机制知之甚少。这种缺乏 这些知识阻碍了为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），一群神经元在吻侧 脑桥PPT在控制快速眼动（REM）睡眠方面具有良好的作用，这是一种与睡眠相关的状态。 自主神经不稳定我们的实验室开发了新的数据，表明局部刺激PPT神经元， 兴奋CV和交感神经兴奋活性（例如，血压升高、心动过速和肾功能增加 交感神经活动）。我假设有一个交感神经调制区的PPT（即，一份PPT- SMR），其显著且差异性地调节跨睡眠-觉醒状态（例如， REM睡眠），而OSA中PPT-SMR功能的改变代表了OSA与 交感神经系统的异常激活。我有很强的知识/能力基础 与研究CV病理生理学有关，在这条独立奖的申请中，我建议 两年的神经科学额外培训和CV反射评估，这对于 启动创新的R 00研究，以确定PPT-SMR如何调节CV功能， OSA实验模型中的行为状态。在K99阶段，我将进行以下实验： 麻醉大鼠，以确定PPT-SMR的位置、神经化学表型和投射 神经元我还将定义PPT-SMR神经元在介导/调节交感神经反应中的作用， 急性缺氧在R 00阶段，我将确定PPT-SMR病变和慢性间歇性 缺氧（CIH）对大鼠在行为状态（非REM睡眠、REM睡眠和觉醒）下CV功能的影响。 K99和R 00阶段的研究都是我未来R 01计划的重要基础， 定义OSA的CV后果的神经生物学。

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.