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

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）的一种症状。在未经治疗的OSA中，过度嗜睡被认为是睡眠呼吸暂停相关觉醒的结果。然而，用经鼻持续气道正压通气治疗OSA，虽然改善了嗜睡，但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）导致未治疗的OSA患者睡眠不良，而慢性间歇性缺氧（CIH）导致治疗后白天警觉性持续不足。上一个资助期的工作确定了大脑皮层视前区（POA）中GABA能睡眠调节神经元的数量。 下丘脑的POA神经元和觉醒相关的神经元，包括组胺（HA）和下丘脑（Hcrt）神经元之间的解剖和功能的相互作用。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唤醒系统之间的失调。我们预测，这种失调将反映在破坏正常模式的c-fos蛋白免疫反应（IR）中观察到的GABA，HA和HCRT含神经元在清醒和睡眠。我们将量化暴露于AIH的大鼠的自发睡眠和EEG异常。我们将确定AIH患者的睡眠是否比常氧状态下的睡眠在恢复24小时睡眠剥夺期间积累的睡眠深度方面效率更低。我们将确定AIH诱导的自发和恢复性睡眠异常是否与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， 在CIH期间和从CIH返回到常氧条件后，大鼠下丘脑神经元中的fos-IR。我们预测，CIH将导致持续增加总睡眠时间在活跃期，这将与增加的fos-IR的GABA能神经元的POA，减少fos-IR的HA和Hcrt神经元。人类的睡眠呼吸障碍与特定脑区的神经元丢失有关（见项目1）。大鼠CIH与中枢神经系统病理学有关（见项目2-5）。本文提出的工作将确定AIH和CIH是否通过影响下丘脑睡眠和觉醒调节神经元系统引起睡眠功能的持续异常。