The decrease in upper airway muscle tone that occurs during sleep (particularly rapid eye movement [REM] sleep) is a major cause of upper airway collapse and sleep apnea syndrome, which affects 2-5% of the adult population. Both the tonic muscle tone and its respiratory modulation are reduced during REM sleep. Our results show that the state-related inhibition of hypoglossal (XII) motoneurons (m-ns), important airway dilators, is not mediated by glycine or GABA, the two common inhibitory transmitters.
The aim of this project is to identify and study the major responsible mechanism. The decrease in the activity of serotonergic neurons is to identify and study the major responsible mechanism. The decrease in the activity of serotonergic neurons of the raphe system, their projections to oral motor nuclei, and the excitatory effects of serotonin (5HT) on orofacial m-ns are the basis for the major hypothesis of this project: the depression of upper airway muscle tone results from a REM sleep related withdrawal of 5HT-mediated excitatory input to upper airway m-ns. We will test our hypothesis by activating the pathways responsible for the REM sleep postural atonia and upper airway depression by applications of a cholinergic stimulant, carbachol, into the pontine tegmentum of a decerebrate cat. By microinjections of specific agonists and antagonists into the XII nucleus we will identify the 5HT receptor type involved in the mediation of excitation to XII m- ns. Then, we will attempt to interfere with the depression of XII nerve activity induced by pontine cholinergic stimulation by counteracting it with specific 5HT receptor agonists. To identify the source of state- dependent and 5HT-mediated input to XII m-ns, raphe neurons that project to the XII motor nucleus will be located using microelectrode recording and antidromic microstimulation techniques and their behavior during the experimentally induced atonia will be studied. Subsequently, the connectivity between individual raphe cells and XII m-ns will be determined using the electrophysiological technique of spike-triggered averaging. Because 5HT facilitates synaptic transmission in excitatory pathways to m-ns, the hypothesis will be tested that this mechanism controls the magnitude of the phasic respiratory input to XII m-ns. To achieve this, brainstem inspiratory neurons that make synaptic contacts with inspiratory-modulated XII m-ns will be identified and their behavior during the atonia studied. Subsequently, the modulatory effects mediated by 5HT receptors on the strength of the connectivity between inspiratory-modulated premotor neurons and inspiratory XII m-ns will be evaluated by combining microinjections of serotonergic drugs into the XII nucleus with an assessment of the strength of the connectivity using electrophysiological techniques. The results of this project should provide a better understanding of the mechanisms underlying upper airway atonia and guide pharmacological approaches to the prevention of airway occlusions during sleep.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Biology and Pathology Study Section (LBPA)
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University of Pennsylvania
Schools of Veterinary Medicine
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Kubin, Leszek; Mann, Graziella L (2018) Hypoglossal motoneurons are endogenously activated by serotonin during the active period of circadian cycle. Respir Physiol Neurobiol 248:17-24
Herr, Kate B; Mann, Graziella L; Kubin, Leszek (2018) Modulation of Motoneuronal Activity With Sleep-Wake States and Motoneuronal Gene Expression Vary With Circadian Rest-Activity Cycle. Front Integr Neurosci 12:32
Hicks, Amelia; Cori, Jennifer M; Jordan, Amy S et al. (2017) Mechanisms of the deep, slow-wave, sleep-related increase of upper airway muscle tone in healthy humans. J Appl Physiol (1985) 122:1304-1312
Kubin, Leszek (2016) Neural Control of the Upper Airway: Respiratory and State-Dependent Mechanisms. Compr Physiol 6:1801-1850
Kubin, Leszek; Jordan, Amy S; Nicholas, Christian L et al. (2015) Crossed motor innervation of the base of human tongue. J Neurophysiol 113:3499-510
Kubin, Leszek (2014) Sleep-wake control of the upper airway by noradrenergic neurons, with and without intermittent hypoxia. Prog Brain Res 209:255-74
Stettner, Georg M; Rukhadze, Irma; Mann, Graziella L et al. (2013) Respiratory modulation of lingual muscle activity across sleep-wake states in rats. Respir Physiol Neurobiol 188:308-17
Herr, Kate Benincasa; Stettner, Georg M; Kubin, Leszek (2013) Reduced c-Fos expression in medullary catecholaminergic neurons in rats 20 h after exposure to chronic intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 304:R514-22
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
Duffin, James; Kubin, Leszek; Mateika, Jason H (2013) Sleep and breathing. Foreword. Respir Physiol Neurobiol 188:231-2

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