Effects of Intermittent Hypoxia on Sleep-Wake Control

白天嗜睡是人类阻塞性睡眠呼吸暂停综合征(OSA)的一种症状。在未经治疗的阻塞性睡眠呼吸暂停综合征患者中，过度嗜睡被认为是睡眠中与呼吸暂停相关的唤醒的结果。然而，鼻腔持续正压治疗阻塞性睡眠呼吸暂停综合征，虽然可以改善嗜睡，但并不能将白天的警觉恢复到正常水平。我们假设急性间歇性低氧(AIH)导致未经治疗的阻塞性睡眠呼吸暂停综合征(OSA)患者睡眠不佳，而暴露于慢性间歇性低氧(CIH)是治疗后持续的白天警觉性缺陷的原因。上一个资金时期的工作确定了大脑前区(POA)内GABA能睡眠调节神经元的数量 并展示了POA神经元和下丘脑后部觉醒相关神经元(包括组胺(HA)和下丘脑下丘脑(Hcrt)神经元)之间的解剖和功能相互作用。我们假设AIH和CIH对睡眠的影响是由于POA睡眠调节神经元和PH觉醒系统之间的失调所致。我们预测，这种失调将反映在清醒和睡眠中观察到的含有GABA、HA和HCrt的神经元中c-fos蛋白免疫反应(IR)的正常模式的破坏。我们将量化暴露于AIH的大鼠的自发睡眠和脑电异常。我们将确定AIH患者的睡眠在恢复24小时睡眠剥夺期间积累的睡眠方面的效率是否低于常氧睡眠。我们将确定AIH诱导的自发睡眠和恢复睡眠的异常是否与GABA、HA和Hcrt神经元中FOS-IR的异常模式相关。我们将研究睡眠觉醒的数量和模式 脑出血大鼠下丘脑神经元中FOS-IR的表达。我们预测，CIH将导致活动期总睡眠时间持续增加，这可能与POA内GABA能神经元FOS-IR增加、HA和Hcrt神经元FOS-IR减少有关。人类睡眠呼吸障碍与特定大脑区域的神经元丢失有关(见项目1)。大鼠脑出血与中枢神经系统病理有关(见项目2-5)。这里提出的工作将确定AIH和CIH是否通过对下丘脑睡眠和唤醒调节神经系统的影响而导致睡眠功能的持续性异常。

Daytime sleepiness is a symptom of obstructive sleep apnea syndrome (OSA) in humans. In untreated OSA, excessive sleepiness is believed to be a consequence of apnea-related arousals from sleep. However, treatment of OSA with nasal continuous positive airway pressure, while improving sleepiness, does not restore daytime alertness to normal levels. We hypothesize that acute intermittent hypoxia (AIH) contributes to poor sleep in untreated OSA and that exposure to chronic intermittent hypoxia (CIH) is responsible for persistent deficits in daytime alertness following treatment. Work from the previous funding period identified populations of GABAergic sleep-regulatory neurons in the preoptic area (POA) of the hypothalamus and demonstrated anatomical and functional interactions among POA neurons and arousal-related neurons in the posterior hypothalamus (PH), including histamine (HA) and hypocretin (Hcrt) neurons. We hypothesize that effects of AIH and CIH on sleep are due to dysregulation among POA sleep-regulatory neurons and PH arousal systems. We predict that this dysregulation will be reflected in disruption of the normal pattern of c-fos protein immunoreactivity (IR) observed in GABA-, HA- and HCrt-containing neurons during waking and sleep. We will quantify the spontaneous sleep and EEG abnormalities present in rats exposed to AIH. We will determine if sleep in AIH is less efficient in restoring sleep dept accumulated during 24 hours of sleep deprivation, compared to sleep in normoxia. We will determine if AIH-induced abnormalities in spontaneous and recovery sleep are correlated with abnormal patterns of fos-IR in GABA, HA, and Hcrt neurons. We will examine sleep-wake amounts and patterns of fos-IR in hypothalamic neurons in rats during CIH and following a return from CIH to normoxic conditions. We predict that CIH will cause persistent increases in total sleep time during the active period, and that this will be correlated with increased fos-IR in GABAergic neurons in the POA, and diminished fos-IR in HA and Hcrt neurons. Sleep disordered breathing in humans is associated with neuronal loss in specific brain regions (see Project 1). CIH in rats is associated with central nervous system pathology (see Projects 2-5). Work proposed here will determine if AIH and CIH cause persistent abnormalities in sleep function via effects on hypothalamic sleep-and arousal-regulatory neuronal systems.