Neuronal Control Mechanisms of the Ascending Sleep Arousal Pathway

$388,465P01FY2013HLNIH

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

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.

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