Upper airway control during disrupted and misaligned sleep

睡眠中断和失调期间的上呼吸道控制

• 批准号: 8705579
• 负责人: LESZEK K KUBIN
• 金额: $ 39.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705579
• 关键词: Adult; Affect; Agonist; Animal Model; Animals; Breathing; Cardiovascular system; Cell Nucleus; Chemicals; Circadian Rhythms; Cognitive; Depressed mood; Electroencephalography; Event; Genes; Genetic Transcription; Goals; Housing; Hypoxia; Immunohistochemistry; Knowledge; Lead; Light; Maintenance; Measures; Mediating; Messenger RNA; Metabolic; Molecular; Motor; Motor Neurons; Motor output; Muscle; Muscle hypotonia; Obstruction; Obstructive Sleep Apnea; Pathway interactions; Patients; Pattern; Phase; Physiological; Polymerase Chain Reaction; Procedures; Process; Proteins; REM Sleep; RNA; Rattus; Recurrence; Regulation; Research; Rest; Reverse Transcription; Role; Secondary to; Serotonin; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Slow-Wave Sleep; System; Time; Tongue; Wakefulness; Western Blotting; adverse outcome; airway obstruction; awake; design; follow-up; instrument; neurochemistry; neurophysiology; pressure; public health relevance; receptor; receptor expression; relating to nervous system; research study; sleep regulation

DESCRIPTION (provided by applicant): Obstructive sleep apnea syndrome (OSA) affects about 5% of adults and has severe adverse consequences for many regulatory systems (cardiovascular, metabolic, cognitive). Active contraction of upper airway muscles allows OSA patients to keep the airway open and breathe adequately during wakefulness but is insufficient during sleep; hence sleep-disordered breathing occurs. Great progress has been made towards the understanding of the mechanisms responsible for the maintenance of upper airway muscle activity during wakefulness and its decline during normal sleep in healthy subjects. However, with the exception of studies with recurrent hypoxia, our understanding of upper airway control in sleep-disordered breathing is limited. In this project, we plan to study how upper airway muscle activity is altered as a result of sleep disruption, sleep loss and circadian misalignment. We find that serotonin type 2A (5-HT ) receptors which mediate wake-related drive to upper airway (hypoglossal-XII) 2A motoneurons have higher levels in the XII motor nucleus at the onset of active period when compared to the rest period, that the magnitude of upper airway muscle activation during both wakefulness and rapid eye movement sleep differs between the rest and active periods, and that it is depressed by sleep loss or when the circadian rhythm of sleep is abolished. This leads us to hypothesize that circadian rhythm, intensity of prior muscle activation, and sleep drive importantly determine the level of activity in upper airway muscles and that 5-HT receptors 2A contribute to this process. Our research plan has three Specific Aims: (1) Measure lingual electromyographic (EMG) activity levels over the entire circadian cycle in normally sleeping rats, rats with circadian regulation of sleep abolished by housing in constant light, and rats subjected to sleep deprivation. We will also determine the time course of lingual EMG changes during state transitions (sleep entries and awakenings) because they represent the critical events during which upper airway obstructions begin and are resolved, and measure the endogenous, 5-HT receptor-mediated drive in XII motoneurons at different phases of the circadian cycle. (2) Determine the 2A normal circadian time course of 5-HT receptor expression in the XII nucleus using quantitative reverse 2A transcription-polymerase chain reaction, Western blots and immunohistochemistry to identify its phase relationship within the circadian cycle and then follow up with mRNA microarrays to identify targets and pathways unique to the XII nucleus. (3) Differentiate between the intrinsic (activity-dependent) and sleep/circadian rhythm-dependent effects on lingual EMG across sleep-wake states in chronically instrumented rats with stimulated use of the tongue and in anesthetized rats with direct activation of XII motoneurons with 5-HT. These studies will, for the first time, quantify upper airway muscle activity across sleep-wake states during normal, disrupted and misaligned sleep, and establish the contributions of circadian regulation, muscle activation, sleep loss, and 5-HT receptors to this control. As such, they will fill a major gap in our understanding of state-dependent control of the upper airway under conditions highly relevant to OSA.

描述（由申请人提供）：阻塞性睡眠呼吸暂停综合征 (OSA) 影响约 5% 的成年人，并对许多调节系统（心血管、代谢、认知）产生严重的不良后果。上气道肌肉的主动收缩使 OSA 患者在清醒时保持气道开放并充分呼吸，但在睡眠时则不足；因此会发生睡眠呼吸障碍。在了解健康受试者清醒期间维持上呼吸道肌肉活动以及正常睡眠期间上呼吸道肌肉活动下降的机制方面，已经取得了巨大进展。然而，除了反复缺氧的研究之外，我们对睡眠呼吸障碍的上气道控制的理解是有限的。在这个项目中，我们计划研究上呼吸道肌肉活动如何因睡眠中断、睡眠不足和昼夜节律失调而改变。我们发现，与休息期相比，在活跃期开始时，介导与唤醒相关的上呼吸道（舌下-XII）2A运动神经元驱动的血清素2A型（5-HT）受体在XII运动核中的水平较高，在清醒和快速眼动睡眠期间，上呼吸道肌肉的激活程度在休息和活动期间有所不同，并且由于睡眠不足或睡眠昼夜节律紊乱而受到抑制。废除了。这使我们假设昼夜节律、先前肌肉激活的强度和睡眠驱动力重要地决定上呼吸道肌肉的活动水平，并且 5-HT 受体 2A 有助于这一过程。我们的研究计划有三个具体目标：（1）测量正常睡眠大鼠、因长期光照而取消睡眠昼夜节律调节的大鼠以及睡眠剥夺的大鼠在整个昼夜节律周期内的舌肌电图（EMG）活动水平。我们还将确定状态转换（入睡和觉醒）期间舌肌电图变化的时间过程，因为它们代表上呼吸道阻塞开始和解决的关键事件，并测量 XII 中内源性 5-HT 受体介导的驱动昼夜节律周期不同阶段的运动神经元。 (2) 利用定量逆向2A转录聚合酶链反应、Western blotting和免疫组化确定XII核中5-HT受体表达的2A正常昼夜时程，以确定其在昼夜周期内的相位关系，然后用mRNA微阵列进行随访以确定 XII 核特有的靶点和途径。 (3) 区分长期使用仪器刺激舌头使用的大鼠和用 5 直接激活 XII 运动神经元的麻醉大鼠在睡眠-觉醒状态下对舌肌电图的内在（活动依赖性）和睡眠/昼夜节律依赖性影响-HT。这些研究将首次量化正常、睡眠中断和失调睡眠期间睡眠-觉醒状态下的上呼吸道肌肉活动，并确定昼夜节律调节、肌肉激活、睡眠缺失和 5-HT 受体对此控制的贡献。因此，它们将填补我们在与 OSA 高度相关的条件下对上呼吸道的状态依赖性控制的理解上的一个重大空白。