Mechanisms of State Switching in Sleep and Sleep Apnea

描述(由申请人提供)： 阻塞性睡眠呼吸暂停(OSA)患者反复出现呼吸道塌陷，导致呼吸暂停、高碳酸血症和低氧，导致呼吸动力和觉醒增加，BEG激活，呼吸道扩张肌交感神经活动和张力激增。这一循环重新建立了呼吸道通畅，但也会导致睡眠障碍和心血管疾病。尽管这些事件的性质很关键，但阻塞性睡眠呼吸暂停期间呼吸、脑电和自主神经觉醒背后的大脑回路仍然未知。在这个PPG中，我们假设臂旁核(PB)在OSA的觉醒过程中起着关键作用，它是呼吸暂停时接收感觉输入和激活觉醒反应的结点。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，直接检查脑电和自主神经(项目1)和呼吸(项目5)觉醒背后的电路。这些项目还将使用条件基因敲除策略来测试引起觉醒的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神经元在觉醒中的作用，并检查它们与基底前脑神经元的关系，后者在将PB唤醒影响传递到大脑皮层方面发挥主要作用。它将测试自由状态下记录的PB和基底前脑神经元的逆行和顺行激活，并确定它们在高碳水化合物和听觉唤醒期间的放电率如何变化。项目3将集中在下丘脑外侧的食欲素神经元在传递PB的唤醒影响方面的作用。通过使用条件基因敲除增食欲素1型和2型受体的小鼠，将测试特定前脑目标上不同的增食欲素受体在产生觉醒方面的作用。项目2是一项转化性研究，旨在测试一些OSA患者是否有较高的唤醒阈值，从而允许在呼吸道崩溃期间出现更严重的缺氧。它将测试CPAP治疗是否改变了这一阈值，以及一种新的非肌松剂催眠药物治疗是否可以稳定觉醒阈值较低的OSA患者的子集的呼吸。这项工作将有助于设计改善阻塞性睡眠呼吸暂停综合征患者健康的干预措施。

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.