Effects of Intermittent Hypoxia on Sleep-Wake Control

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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.