Neuronal Control Mechanisms of the Ascending Sleep Arousal Pathway

阻塞性睡眠呼吸暂停（OSA）是一种常见的睡眠障碍，其特征是频繁的觉醒， 由上气道塌陷和导致的高碳酸血症/低氧血症引起的睡眠。频繁觉醒 从睡眠干扰正常睡眠的结构，减少深度睡眠，并损害恢复/ 睡眠的认知益处尽管为了改善睡眠质量， 虽然数百万患有OSA的美国人的睡眠质量，但对神经控制机制知之甚少 在阻塞性睡眠呼吸暂停综合征中介导觉醒最近使用解剖学方法的研究表明，脑干 接受内脏和呼吸输入的臂旁复合体（PB/PC）的交感神经能神经元， 重要的是通过它们的投射到基底前脑（BF），一个区域， 皮质投射和觉醒促进神经元。然而，这些发现还没有被 由一个基本元素补充，记录这个回路中的神经元。该项目通过使用PB/PC和BF神经元在自然睡眠周期期间以及在由高碳酸血症引起的慢波睡眠（非REM睡眠）和REM睡眠的觉醒期间的四极/多个单个单元记录来解决这一需求，从而模仿OSA的刺激。为了模拟睡眠呼吸暂停的觉醒，将大鼠暴露于10%的二氧化碳中以将其从睡眠中唤醒。我们假设，在睡眠呼吸暂停觉醒中看到的皮层激活是由PB/PC到BF的投射介导的。由于PB神经元接收有关二氧化碳水平和呼吸努力的输入，我们预测，PB/PC神经元将表现出增加的放电活动之前皮层激活时，从睡眠中的觉醒产生的二氧化碳，但不是当觉醒是自发的，或由声刺激引起的。PB/PC的可逆蝇蕈醇失活将进一步测试PB/PC在觉醒中的作用。我们预测，所有类型的觉醒从睡眠和伴随的皮层激活将与BF觉醒促进神经元的放电升高。该项目的精确信息的神经元激活相对于高碳酸血症的时间将补充和加强该计划的项目赠款的其他项目。

Obstructive sleep apnea (OSA) is a common sleep disorder that is characterized by frequent arousals from sleep caused by the collapse of the upper ainway and resulting hypercarbia/hypoxemia. Frequent arousals from sleep interfere with the architecture of normal sleep, reduce deep sleep, and impair the restorative/ cognitive benefits of sleep. Despite the importance of preventing arousals from sleep in order to improve sleep quality for millions of Americans with OSA, very little is known about the neural control mechanisms that mediate arousals during OSA. Recent work using anatomical methods suggests that the brainstem glutamatergic neurons of the parabrachial complex (PB/PC), which receive visceral and respiratory input, are important for arousal during OSA via their projections to the basal forebrain (BF), a region containing cortically projecting & wakefulness promoting neurons. However, these findings have not yet been complemented by an essential element, the recording of neurons in this circuit. This project addresses this need by using tetrode/multiple single unit recordings of PB/PC and BF neurons during natural sleep cycles and during arousals from both slow wave sleep (non-REM sleep) and REM sleep provoked by hypercarbia, thus mimicking the stimuli from OSA. To model the arousals of sleep apnea, rats will be exposed to 10% carbon dioxide to awaken them from sleep. We hypothesize that the cortical activation seen in the arousals of sleep apnea is mediated by the projection from PB/PC to BF. Since PB neurons receive input about levels of carbon dioxide and respiratory effort, we predict that PB/PC neurons will exhibit an increase in discharge activity that precedes cortical activation when the arousals from sleep are produced by carbon dioxide, but not when the arousals are spontaneous, or induced by acoustic stimulation. Reversible muscimol inactivation of PB/PC will further test the role of PB/PC in arousals. We predict that all types of arousals from sleep & the accompanying cortical activation will correlate with the elevated discharge of BF wakefulness promoting neurons. This project's precise information on the timing of neuronal activation relative to hypercarbia will complement and enhance the other projects of this program project grant.