Sleepiness is a major consequence of the obstructive sleep apnea syndrome (OSA), a debilitating disorder affecting 3-5% of adults. The long-term goal of this project is to determine the mechanisms responsible for detrimental effects of sleep loss on the central nervous system and respiratory control. We focus on the cellular processes resulting from sleep loss that occur in the perifornical (PF) region of the posterior hypothalamus because this region is involved in respiratory regulation and sleep. We found that, in rats, sleep loss leads to increased GABA receptor-mediated inhibition of wake-promoting cells in the PF region and that antagonism of this inhibition in the PF region activates hypoglossal (XII) motoneurons, which in OSA patients play an important role in the control of upper airway patency. We now propose to identify those hypothalamic cells in which sleep loss induces these changes and study the pathways that relay these effects to upper airway motoneurons. We hypothesize that hypothalamic neurons that have sleep deprivation-induced upregulation of certain subunits of GABA receptors contribute to the regulation of sleep and mediate hypothalamic excitatory effects on XII motoneurons.
In Specific Aim (SA) 1, we shall use chronically instrumented, behaving rats to characterize the interaction between sleep deprivation and antagonism of GABA receptor-mediated inhibition in the PF region, as it occurs at the level of upper airway (genioglossal) muscles. In SA 2, we shall identify the patterns of GABA A receptor subunit mRNA expression in PF cells with different neurotransmitter phenotypes and axonal projections to XII motoneurons and wake-related brainstem neurons. In SA 3, we shall test whether activation of XII motoneurons elicited by disinhibition of PF neurons requires activation of orexin-containing PF neurons and whether it is mediated by brainstem serotonergic and/or noradrenergic neurons. In SA 4, we shall determine whether sleep deprivation and treatments of hypothalamic slices in vitro that neurochemically model sleep and wake conditions lead to distinct changes in mRNA levels for GABA receptor subunits in hypothalamic cells having different projections and neurotransmitter phenotypes. These studies will characterize the neural substrates of the """"""""sleepiness signal,"""""""" which include dynamic changes in GABA receptor-mediated inhibition. They will also define the role of hypothalamic inhibitory mechanisms in sleep loss-related changes in the control of the upper airway. Since both stimulants and sleep-promoting treatments are considered as adjunct therapies for OSA, our studies will provide the mechanistic basis for potential effectiveness of such treatments.

Public Health Relevance

Sleepiness is a major consequence of the obstructive sleep apnea syndrome (OSA), a debilitating disorder affecting 3-5% of adult Americans. Sleep loss may exacerbate OSA symptoms, but the neural substrate(s) of the brain """"""""sleepiness signal"""""""" are unknown. The goal of this project is to assess how selected brain regions and transmitters interact in their control of breathing under the condition of increased drive for sleep.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Laposky, Aaron D
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University of Pennsylvania
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Kubin, Leszek (2016) Neural Control of the Upper Airway: Respiratory and State-Dependent Mechanisms. Compr Physiol 6:1801-1850
Volgin, Denys V; Lu, Jackie W; Stettner, Georg M et al. (2014) Time- and behavioral state-dependent changes in posterior hypothalamic GABAA receptors contribute to the regulation of sleep. PLoS One 9:e86545
Laitman, Benjamin M; Gajewski, Nicholas D; Mann, Graziella L et al. (2014) The ?1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats. Prog Neuropsychopharmacol Biol Psychiatry 49:7-15
Stettner, Georg M; Kubin, Leszek; Volgin, Denys V (2013) Loss of motoneurons in the ventral compartment of the rat hypoglossal nucleus following early postnatal exposure to alcohol. J Chem Neuroanat 52:87-94
Stettner, Georg M; Kubin, Leszek (2013) Antagonism of orexin receptors in the posterior hypothalamus reduces hypoglossal and cardiorespiratory excitation from the perifornical hypothalamus. J Appl Physiol (1985) 114:119-30
Volgin, Denys V; Kubin, Leszek (2012) Reduced sleep and impaired sleep initiation in adult male rats exposed to alcohol during early postnatal period. Behav Brain Res 234:38-42
Kubin, L (2011) Mechanisms and networks of motoneuronal control during sleep: introduction. Arch Ital Biol 149:323-4
Stettner, Georg M; Kubin, Leszek; Volgin, Denys V (2011) Antagonism of orexin 1 receptors eliminates motor hyperactivity and improves homing response acquisition in juvenile rats exposed to alcohol during early postnatal period. Behav Brain Res 221:324-8
Rukhadze, I; Kamani, H; Kubin, L (2011) Quantitative differences among EMG activities of muscles innervated by subpopulations of hypoglossal and upper spinal motoneurons during non-REM sleep - REM sleep transitions: a window on neural processes in the sleeping brain. Arch Ital Biol 149:499-515
Lu, Jackie W; Kubin, Leszek (2009) Electromyographic activity at the base and tip of the tongue across sleep-wake states in rats. Respir Physiol Neurobiol 167:307-15

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