Mechanisms of State Switching in Sleep and Sleep Apnea

睡眠和睡眠呼吸暂停的状态转换机制

• 批准号: 8435424
• 负责人: CLIFFORD B SAPER
• 金额: $ 226.86万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435424
• 关键词: Apnea; Arousal; Auditory; Brain; Breathing; Cardiovascular Diseases; Cardiovascular system; Cerebral cortex; Cognitive; Continuous Positive Airway Pressure; Dilator; Disease; Electroencephalography; Event; Glutamates; Health; Hypercapnia; Hypothalamic structure; Hypoxia; Impaired cognition; Knock-out; Lateral; Mus; Muscle; Nature; Neurons; Neurotransmitters; Nodal; Obstructive Sleep Apnea; Output; Patients; Pharmaceutical Preparations; Play; Prosencephalon; Rattus; Role; Sensory; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Testing; Work; basal forebrain; hypnotic; hypocretin; improved; novel; parabrachial nucleus; receptor; respiratory; response; therapy design; translational study

DESCRIPTION (provided by applicant): Patients with obstructive sleep apnea (OSA) suffer from repetitive collapse of the airway, resulting in apnea, hypercarbia, and hypoxia, resulting in increased respiratory drive and arousal, with BEG activation and a surge in sympathetic activity and tone in the airway dilator muscles. This cycle re-establishes airway patency, but also causes sleep fragmentation and cardiovascular disease. Despite the critical nature of these events, the brain circuitry that underlies respiratory, EEG, and autonomic arousals during OSA remains unknown. In this PPG, we hypothesize that the parabrachial nucleus (PB) plays a key role in arousals in OSA, as a nodal point in receiving sensory input during apnea, and activating arousal responses. Projects 1 and 5 will examine the circuitry underlying EEG and autonomic (Project 1) and respiratory (Project 5) arousals directly, by tracing the inputs and outputs from PB neurons that respond to hypercarbia. These projects will also use a conditional knockout strategy to test whether the PB neurons that cause arousal use glutamate as their main neurotransmitter. Project 4 will test the role of the PB neurons in arousal, and examine their relationship with the basal forebrain neurons that play a major role in relaying the PB arousal influence to the cerebral cortex. It will test antidromic and orthodromic activation of PB and basal forebrain neurons recorded across wake-sleep states in unrestrained rats, and determine how their firing rate changes during both hypercarbic and auditory arousals. Project 3 will focus on the role of the orexin neurons in the lateral hypothalamus in relaying the arousal influence from the PB. By using mice with conditional knockouts for the orexin type 1 and 2 receptors, the role of the different orexin receptors at specific forebrain targets in producing arousal will be tested. Project 2 is a translational study that tests whether some patients with OSA have a high threshold for arousal, permitting greater hypoxia during airway collapse. It will test whether this threshold is altered by CPAP treatment and whether a novel treatment with a non-myorelaxant hypnotic drug can stabilize breathing in a subset of OSA patients with lower arousal thresholds. This work will help to design interventions for improving the health of patients with OSA.

描述（由申请人提供）： 患有阻塞性睡眠呼吸暂停（OSA）的患者遭受气道的反复塌陷，导致呼吸暂停、高碳酸血症和缺氧，从而导致呼吸驱动和觉醒增加，伴随BEG激活以及气道扩张肌中交感神经活动和张力的激增。这个循环重新建立了气道通畅，但也导致睡眠碎片和心血管疾病。尽管这些事件的关键性质，大脑回路的呼吸，脑电图和自主觉醒在阻塞性睡眠呼吸暂停仍然未知。在这个PPG中，我们假设臂旁核（PB）在OSA的觉醒中起着关键作用，作为在呼吸暂停期间接收感觉输入和激活觉醒反应的节点。项目1和项目5将通过追踪对高碳酸血症做出反应的PB神经元的输入和输出，直接检查EEG和自主神经（项目1）和呼吸（项目5）唤醒的潜在电路。这些项目还将使用条件性敲除策略来测试引起唤醒的PB神经元是否使用谷氨酸作为其主要神经递质。项目4将测试PB神经元在唤醒中的作用，并检查它们与基底前脑神经元的关系，基底前脑神经元在将PB唤醒影响传递到大脑皮层中起主要作用。它将测试PB和基底前脑神经元的逆向和顺向激活记录在未受约束的大鼠的觉醒-睡眠状态，并确定他们的放电率如何变化在高碳酸和听觉觉醒。项目3将集中在下丘脑外侧的食欲素神经元在传递PB的唤醒影响中的作用。通过使用具有食欲素1型和2型受体的条件性敲除的小鼠，将测试特定前脑靶点处的不同食欲素受体在产生唤醒中的作用。项目2是一项转化研究，旨在测试某些OSA患者是否具有高唤醒阈值，从而在气道塌陷期间允许更大的缺氧。它将测试CPAP治疗是否改变了这个阈值，以及使用非肌松催眠药物的新治疗是否可以稳定具有较低唤醒阈值的OSA患者的呼吸。这项工作将有助于设计改善OSA患者健康的干预措施。