Effects of Intermittent Hypoxia on Sleep-Wake Control

间歇性缺氧对睡眠-觉醒控制的影响

• 批准号: 6820298
• 负责人: Ronald Szymusiak
• 金额: $ 12.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-08 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820298
• 关键词: electroencephalography; electromyography; fos protein; gamma aminobutyrate; histamine; hypothalamus; hypoxia; immunocytochemistry; laboratory rat; neurons; orexin; preoptic areas; respiratory airflow disorder; sleep apnea; electroencephalography; electromyography; fos protein; gamma aminobutyrate; histamine; hypothalamus; hypoxia; immunocytochemistry; laboratory rat; neurons; orexin; preoptic areas; respiratory airflow disorder; sleep apnea

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.

白天嗜睡是人类阻塞性睡眠呼吸暂停综合征（OSA）的症状。在未处理的OSA中，据信过度嗜睡是与呼吸暂停相关的唤醒的结果。但是，用鼻连续的阳性气道压力治疗OSA，同时改善了嗜睡，并不能使白天的警觉性恢复到正常水平。我们假设急性间歇性缺氧（AIH）在未经治疗的OSA中有助于睡眠不足，并且暴露于慢性间歇性缺氧（CIH）治疗后白天警报中持续缺陷。前一期资金期的工作确定了peroptic区域（POA）的GABA能睡眠调节性神经元的种群 下丘脑并在后下丘脑（pH）中表现出POA神经元和唤醒相关的神经元之间的解剖和功能相互作用，包括组胺（HA）和降囊蛋白（HCRT）神经元。我们假设AIH和CIH对睡眠的影响是由于POA睡眠调节性神经元和PH唤醒系统的失调引起的。我们预测，这种失调将反映在醒来和睡眠期间在含GABA，HA-和HCRT神经元中观察到的C-FOS蛋白免疫反应性（IR）的正常模式。我们将量化暴露于AIH的大鼠中的自发睡眠和脑电图异常。我们将确定与正常氧的睡眠相比，AIH的睡眠是否在恢复睡眠24小时内积累的睡眠部门效率较低。我们将确定自发性和恢复睡眠中AIH诱导的异常是否与GABA，HA和HCRT神经元中FOS-IR的异常模式相关。我们将检查睡眠效果的数量和模式 CIH期间大鼠下丘脑神经元的FOS-IR以及从CIH返回到常氧状况之后。我们预测，CIH会导致活跃期间的总睡眠时间持续增加，并且这将与POA中GABA能神经元中的FOS-IR增加相关，并减少HA和HCRT神经元中的FOS-IR。人类呼吸的睡眠失调与特定大脑区域的神经元丧失有关（请参阅项目1）。大鼠中的CIH与中枢神经系统病理有关（参见项目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性神经元系统的影响来导致睡眠功能持续异常。