Mechanisms of sleep and sleep apnea

睡眠和睡眠呼吸暂停的机制

• 批准号: 10491067
• 负责人: CLIFFORD B SAPER
• 金额: $ 264.68万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491067
• 关键词: Address; Apnea; Arousal; Atherosclerosis; Back; Basic Science; Brain; Breathing; Calcium; Carbon Dioxide; Cardiovascular system; Cell Nucleus; Cells; Cognitive; Diabetes Mellitus; Dilator; Dorsal; Drowsiness; Drug Combinations; Drug Design; Electroencephalography; FOXP2 gene; Fiber; Goals; Human; Hypertension; Image; Impaired cognition; Lateral; Maps; Mediating; Metabolic; Motor; Muscle; Muscle Tonus; Myocardial Infarction; Neurons; Obstructive Sleep Apnea; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Photometry; Physiological; Play; Population; Process; Prosencephalon; Recording of previous events; Relaxation; Research Personnel; Respiratory Muscles; Role; Running; Seminal; Sensory; Serotonergic System; Serotonin; Site; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Fragmentations; Stroke; System; Tidal Volume; Time; Translating; Ventilator; Work; airway muscle; airway obstruction; brain circuitry; cell type; diabetes risk; dorsal raphe nucleus; falls; follow-up; forkhead protein; genioglossus muscle; indexing; lens; optogenetics; parabrachial nucleus; prevent; programs; rabies viral tracing; receptor; respiratory; response; single-cell RNA sequencing; synergism; transcriptome sequencing; ventilation

Summary - Overall Patients with obstructive sleep apnea (OSA) may have hundreds of cycles over the night of loss of airway dilator motor tone and airway obstruction, followed by apnea, which is ended by an arousal, in which there is EEG desynchronization accompanied by return of airway dilator muscle tone, opening of the airway, and re- established ventilation. The EEG arousals cause sleep fragmentation and sleep loss, resulting in cognitive impairment, and metabolic and cardiovascular consequences. We hypothesize that by augmenting brain circuits that keep the airway open while suppressing the EEG arousals, we can prevent these outcomes. We have found that the EEG arousal depends on two circuits, the CGRP-expressing neurons in the parabrachial nucleus (PBCGRP cells), and the dorsal raphe serotonin neurons that provide input to them. The increase in airway dilator tone, in part through genioglossus muscle (GG) tone, allows breathing to restart in OSA, and relies on two different circuits: FoxP2 neurons in the PB (PBFoxP2 neurons) and medullary serotonin neurons that innervate the medulllary respiratory control system. Project 1 will examine the effects on ventilation and GG-EMG of activating or inhibiting the PBFoxp2 neurons optogenetically and the firing of PBFoxP2 neurons in real time with calcium imaging,.at baseline and during CO2 exposure. It will then use chemogenetics to enhance the firing of the PBFoxP2 neurons and ventilator (tidal volume, respiratory rate) and GG-EMG response, while inhibiting the PBCGRP neurons and EEG arousal during CO2 exposure. Project 2 and 3 will run in parallel to identify the forebrain inputs to the PBCGRP and PBFoxP2 neurons that activate them during EEG arousal. Their shared strategy is to identify druggable receptors on the PB cells that respond to CO2, to suggest therapies that can be used to augment firing of PBFoxP2 neurons and suppress PBCGRP neurons during CO2 exposure. They will use single cell RNA-Seq to identify the receptors on these neurons, and rabies virus tracing combined with channelrhodopsin-assisted circuit mapping to determine their inputs, and then GCaMP6 fiber photometry to determine which of these inputs is activated during the EEG arousal that accompanies CO2 exposure. Project 4 examines the inputs to the respiratory control system from the medullary serotonin neurons that are required to produce the ventilatory and GG-EMG response to CO2. It takes advantage of identifying genetically distinct subsets of medullary serotonin neurons that innervate the sensory and motor components of the respiratory control system. It will then identify the forebrain inputs to these different serotonin neurons, to determine which ones activate them, and with what receptor types, during CO2 exposure. Finally, Project 5 will use information from Projects 1-4 that identifies druggable receptors that increase airway dilator tone, while suppressing EEG arousals during sleep apnea. We expect with refinement of the receptor types that need to be stimulated or inhibited, we can design drug combinations to keep the airway open while preventing the EEG arousals that result in the long term deleterious consequences of OSA.

摘要--总体 阻塞性睡眠呼吸暂停(OSA)患者可能在失去呼吸道的当晚有数百个周期 扩张器运动张力和呼吸道阻塞，然后是呼吸暂停，以觉醒结束，其中有 脑电去同步化伴随着气道扩张器肌张力的恢复，呼吸道的开放，以及 已建立通风系统。脑电波的唤醒会导致睡眠碎片和睡眠缺失，从而导致认知 损害、新陈代谢和心血管后果。我们假设通过增强大脑 在抑制脑电唤醒的同时保持呼吸道畅通的回路，我们可以防止这些结果。我们 已发现脑电的觉醒依赖于臂旁核内CGRP表达神经元的两个回路 核团(PBCGRP细胞)和为它们提供输入的中缝背侧5-羟色胺神经元。这一增长 部分通过颧舌肌(GG)张力的呼吸道扩张器张力，允许OSA患者重新开始呼吸，以及 依赖于两个不同的回路：PB中的FoxP2神经元(PBFoxP2神经元)和延髓5-羟色胺神经元 支配着髓质的呼吸控制系统。项目1将检查对通风和 光遗传学激活或抑制PBFoxP2神经元的GG-EMG和真实PBFoxP2神经元的放电 在基线和二氧化碳暴露期间进行钙质成像的时间。然后，它将使用化学遗传学来增强 PBFoxP2神经元和呼吸机的放电(潮气量、呼吸频率)和GG-EMG反应，而 抑制外周CGRP神经元和脑电觉醒。项目2和项目3将并行运行 识别在脑电唤醒过程中激活它们的PBCGRP和PBFoxP2神经元的前脑输入。他们的 共同的策略是识别外周血细胞上对二氧化碳做出反应的可药物受体，以建议治疗方法 这可以用来增强PBFoxP2神经元的放电，并在二氧化碳暴露时抑制PBCGRP神经元。 他们将使用单细胞RNA-Seq来识别这些神经元上的受体，并追踪狂犬病病毒 结合通道视紫红质辅助回路标测确定其输入，然后GCaMP6纤维 光度法确定在伴随二氧化碳的脑电唤醒过程中，这些输入中的哪一个被激活 曝光。项目4检查了延髓5-羟色胺对呼吸控制系统的输入。 对二氧化碳产生呼吸和GG-EMG反应所需的神经元。它利用了 鉴定支配感觉和运动的延髓5-羟色胺神经元的不同亚群 呼吸控制系统的组件。然后，它将识别前脑输入到这些不同的 5-羟色胺神经元，以确定哪些神经元在二氧化碳中激活它们，以及通过什么受体类型激活它们 曝光。最后，项目5将使用项目1-4中的信息，识别可用药受体， 增加呼吸道扩张器张力，同时抑制睡眠呼吸暂停时的脑电唤醒。我们精益求精地期待 在需要刺激或抑制的受体类型中，我们可以设计药物组合来保持 呼吸道开放，同时防止脑电波唤醒，导致OSA的长期有害后果。