Mechanisms of sleep and sleep apnea

睡眠和睡眠呼吸暂停的机制

• 批准号: 10674855
• 负责人: CLIFFORD B SAPER
• 金额: $ 264.22万
• 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/10674855
• 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; Genetic; Goals; Human; Hypertension; Image; Impaired cognition; Lateral; Legal patent; Maps; Mediating; Metabolic; Motor; Muscle; Muscle Tonus; Myocardial Infarction; Neurons; Obstructive Sleep Apnea; Outcome; Patients; Pharmaceutical Preparations; 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; pharmacologic; prevent; programs; rabies viral tracing; receptor; respiratory; response; single nucleus RNA-sequencing; single-cell RNA sequencing; synergism; 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.

总结 - 总体 患有阻塞性睡眠呼吸暂停 (OSA) 的患者可能会在夜间经历数百个周期的气道丧失 扩张器运动音调和气道阻塞，然后是呼吸暂停，最后以唤醒结束，其中有 脑电图去同步伴随着气道扩张器肌张力的恢复、气道的开放以及重新 建立通风。脑电图唤醒会导致睡眠碎片和睡眠缺失，从而导致认知能力下降 损害以及代谢和心血管后果。我们假设通过增强大脑 通过保持气道开放同时抑制脑电图唤醒的回路，我们可以防止这些结果。我们 研究人员发现，脑电图的唤醒取决于两个回路，即臂旁臂中表达 CGRP 的神经元。 细胞核（PBCGRP 细胞）和中缝背侧血清素神经元为它们提供输入。增加的 气道扩张器音调（部分通过颏舌肌 (GG) 音调）允许 OSA 患者重新开始呼吸，并且 依赖于两种不同的回路：PB 中的 FoxP2 神经元（PBFoxP2 神经元）和髓质血清素神经元 支配髓质呼吸控制系统。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以及真实PBFoxP2神经元的放电 基线和二氧化碳暴露期间的钙成像时间。然后它将利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，同时 在 CO2 暴露期间抑制 PBCGRP 神经元和 EEG 唤醒。项目2和项目3将同时进行 识别在脑电图唤醒期间激活它们的 PBCGRP 和 PBFoxP2 神经元的前脑输入。他们的 共同的策略是识别 PB 细胞上对 CO2 做出反应的可成药受体，以提出治疗建议 可用于在 CO2 暴露期间增强 PBFoxP2 神经元的放电并抑制 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 结合视紫红质通道辅助电路映射来确定其输入，然后使用 GCaMP6 光纤 光度测定法确定在伴随 CO2 的脑电图唤醒过程中哪些输入被激活 接触。项目 4 检查髓质血清素对呼吸控制系统的输入 产生对 CO2 的通气和 GG-EMG 反应所需的神经元。它利用了 识别支配感觉和运动的髓质血清素神经元的遗传上不同的子集 呼吸控制系统的组成部分。然后它会识别这些不同的前脑输入 血清素神经元，以确定在 CO2 过程中哪些神经元激活它们，以及激活它们的受体类型 接触。最后，项目 5 将使用项目 1-4 中的信息来识别可成药受体， 增加气道扩张器音调，同时抑制睡眠呼吸暂停期间的脑电图唤醒。我们期待精益求精 对于需要刺激或抑制的受体类型，我们可以设计药物组合来保持 打开气道，同时防止脑电图唤醒，从而导致 OSA 的长期有害后果。

项目成果

Reboxetine Plus Oxybutynin for OSA Treatment: A 1-Week, Randomized, Placebo-Controlled, Double-Blind Crossover Trial.

• DOI: 10.1016/j.chest.2021.08.080
• 发表时间: 2022-01
• 期刊: CHEST
• 影响因子: 9.6
• 作者: Perger, Elisa;Montemurro, Luigi Taranto;Rosa, Debora;Vicini, Stefano;Marconi, Mariapaola;Zanotti, Lucia;Meriggi, Paolo;Azarbarzin, Ali;Sands, Scott A.;Wellman, Andrew;Lombardi, Carolina;Parati, Gianfranco
• 通讯作者: Parati, Gianfranco

Stereotaxic Surgical Approach to Microinject the Caudal Brainstem and Upper Cervical Spinal Cord via the Cisterna Magna in Mice.

• DOI: 10.3791/63344
• 发表时间: 2022-01-21
• 期刊: JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
• 影响因子: 1.2
• 作者: Joshi, Krutika;Kirby, Alana;Niu, Jianguo;VanderHorst, Veronique
• 通讯作者: VanderHorst, Veronique

Effect of Pimavanserin on the Respiratory Arousal Threshold from Sleep: A Randomized Trial.

匹马范色林对睡眠呼吸唤醒阈值的影响：随机试验。

• DOI: 10.1513/annalsats.202205-419oc
• 发表时间: 2022
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Messineo,Ludovico;Gell,Laura;Calianese,Nicole;Sofer,Tamar;Vena,Dan;Azarbarzin,Ali;Labarca,Gonzalo;Taranto-Montemurro,Luigi;Yang,HyungChae;Wang,Tsai-Yu;Kim,Molly;Smith,Hannah;White,David;Sands,Scott;Wellman,Andrew
• 通讯作者: Wellman,Andrew