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 阻塞性睡眠呼吸暂停（OSA）患者可能有数百个周期的夜间气道丧失 扩张器运动张力和气道阻塞，然后是呼吸暂停，最后是觉醒，其中有 EEG去极化伴随气道扩张肌张力恢复、气道开放和再狭窄。 建立通风。EEG唤醒引起睡眠片段化和睡眠丧失，导致认知障碍。 以及代谢和心血管后果。我们假设通过增强大脑 保持气道开放同时抑制EEG唤醒的电路，我们可以防止这些结果。我们 我发现脑电唤醒依赖于两个回路，即臂旁神经元中表达CGRP的神经元， 核（PBCGRP细胞），以及向其提供输入的中缝背核5-羟色胺神经元。的增加 部分通过颏舌肌（GG）张力的气道扩张器张力允许OSA患者重新开始呼吸， 依赖于两种不同的回路：PB中的FoxP 2神经元（PBFoxP 2神经元）和延髓5-羟色胺神经元 神经支配延髓呼吸控制系统。项目1将研究对通风的影响， 真实的PBFoxP 2神经元光遗传学激活或抑制的GG-EMG和PBFoxP 2神经元放电 基线和CO2暴露期间的钙成像时间。然后它将使用化学遗传学来增强 PBFoxP 2神经元和呼吸机的放电（潮气量，呼吸率）和GG-EMG反应，而 抑制CO2暴露时PBCGRP神经元和EEG唤醒。项目2和项目3将同时进行， 识别前脑输入到PBCGRP和PBFoxP 2神经元，在EEG唤醒期间激活它们。他们的 一个共同的策略是确定PB细胞上对CO2有反应的药物受体， 其可用于在CO2暴露期间增强PBFoxP 2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， 结合通道视紫红质辅助电路映射，确定其输入，然后GCaMP 6纤维 光度测定以确定这些输入中的哪一个在伴随CO2的EEG唤醒期间被激活 exposure.项目4检查了从延髓血清素到呼吸控制系统的输入 神经元产生对CO2的反射和GG-EMG反应。它利用 识别神经支配感觉和运动的髓5-羟色胺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，以确定哪些激活它们，以及在CO2 exposure.最后，项目5将使用项目1-4中的信息，这些信息确定了可药用受体， 增加气道扩张器张力，同时抑制睡眠呼吸暂停期间的EEG觉醒。我们希望通过改进 在需要刺激或抑制的受体类型中，我们可以设计药物组合， 气道开放，同时防止导致OSA长期有害后果的EEG唤醒。

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