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，其特征是从睡眠中频繁唤醒 由于上主干道塌陷而导致的高碳酸血症/低氧血症引起的睡眠。频繁的唤醒 睡眠干扰正常睡眠结构，减少深度睡眠，并损害恢复力/ 睡眠对认知的益处。尽管为了改善睡眠而防止唤醒很重要 数百万患有阻塞性睡眠呼吸暂停的美国人的睡眠质量，对神经控制机制知之甚少 在阻塞性睡眠呼吸暂停时调节唤醒。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谷氨酸能神经元(PB/PC)是 在阻塞性睡眠呼吸暂停时通过投射到基底前脑(BF)对觉醒很重要，这一区域包含 大脑皮层投射和觉醒促进神经元。然而，这些发现还没有被 与此相补充的是一个基本要素，即记录这个回路中的神经元。该项目通过在自然睡眠周期以及从慢波睡眠(非REM睡眠)和高碳酸血症引起的REM睡眠中唤醒PB/PC和BF神经元的Tetrode/多个单单位记录来满足这一需求，从而模拟OSA的刺激。为了模拟睡眠呼吸暂停的觉醒，大鼠将暴露在10%的二氧化碳中以将它们从睡眠中唤醒。我们推测睡眠呼吸暂停患者觉醒时的皮质激活是由PB/PC向BF的投射介导的。由于PB神经元接受有关二氧化碳水平和呼吸努力的输入，我们预测，当从睡眠中产生的觉醒是由二氧化碳产生时，PB/PC神经元将表现出先于皮质激活的放电活动增加，但当唤醒是自发的或由声刺激诱导时，则不会。PB/PC可逆灭活蝇蝇酚将进一步检验PB/PC在觉醒中的作用。我们预测，所有类型的睡眠唤醒&伴随而来的大脑皮层激活将与促进觉醒的BF神经元放电增加相关。该项目关于高碳酸血症相关神经元激活时间的准确信息将补充和加强该计划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.