About 5% of adults suffer from the obstructive sleep apnea syndrome (OSAS). OSAS patients have predisposing upper airway anatomy that requires increased levels of activity in those muscles that maintain the upper airway open. Sleep-related decrements of that activity result in intermittent upper airway obstructions, sleep loss, impaired alertness, hypertension and metabolic disorders. Endogenous noradrenergic (NE) drive determines the level of activity in hypoglossal (XII) motoneurons (mns) that innervate the genioglossus, a muscle that plays a key role in the maintenance of upper airway patency in OSAS. This drive originates in neuronal groups that have decrements of activity during sleep and from one NE group that our recent data suggest is not state-dependent, the medullary A1 group. We hypothesize that the A1 group contributes to the increased levels of activity in upper airway muscles during wakefulness, a well established adaptation in OSAS that may be caused by the chronic-intermittent hypoxia(CIH) that OSAS patients experience as a result of the disorder. Another important source of wake-related excitation of XII mns is the posterior, lateral hypothalamus. This excitation is thought to originate in the neurons that synthesize the peptide orexin (ORX) and is believed to be relayed to mns by brainstem NE neurons. However, we found that aminergic pathways are not required. This leads us to hypothesize that hypothalamic excitatory input to XII mns is mediated by direct projections of ORX neurons to the XII nucleus or by non-aminergic pontomedullary XII-premotor neurons. To address these hypotheses, we propose four Specific Aims. (1) Determine the magnitude of the excitatory drive to XII mns that originates in NE XII-premotor neurons of the A1 group. In urethane-anesthetized rats, we will measure the effect of silencing of these neurons on XII nerve activity. We will also record from A1 XII-premotor cells to determine whether their activity is altered during pharmacologically induced REM sleep-like state. (2) Determine whether the activity of A1 neurons is increased in rats exposed to chronic-intermittent hypoxia (CIH), whether there is a concomitant increase of catecholaminergic markers in the ventrolateral medulla and increased density of NE terminals in the XII nucleus. (3) Determine whether CIH increases the magnitude of the excitatory drive to XII mns from the A1 region and increases expression of the excitatory a -adrenergic receptors in the XII nucleus. (4) 1 Determine whether the wake-related excitatory drive to XII mns that originates in ORX neurons is mediated by their direct projections to the XII nucleus or by XII-premotor neurons with ORX receptors. We will pharmacologically activate ORX neurons and antagonize ORX receptors in the XII nucleus while measuring XII nerve activity and examine Fos expression in pontomedullary XII-premotor neurons following stimulation of ORX neurons with and without systemic antagonism of ORX receptors. Thus, we will characterize two major sources of excitatory drive to XII mns and assess the impact of CIH on one of these inputs. This will advance our understanding of the mechanisms leading to altered by OSAS control of the upper airway.

Public Health Relevance

About 5% of adults suffer from the obstructive sleep apnea syndrome (OSAS), a disorder that causes sleep loss and fragmentation, impaired alertness, arterial hypertension and metabolic disorders. We plan to use a rodent model to study the neural pathways responsible for increased activity in the muscles that keep the airway open in OSAS patients and to determine whether chronically occurring decrements of blood oxygen levels, like those experienced by OSAS patients, alter the central neural control of the upper airway. This should help understand the pathophysiology of OSAS and identify potential therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL047600-19
Application #
8312558
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
1992-09-21
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
19
Fiscal Year
2012
Total Cost
$396,000
Indirect Cost
$148,500
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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; Lei, Yanlin; Benincasa Herr, Kate et al. (2013) Evidence that adrenergic ventrolateral medullary cells are activated whereas precerebellar lateral reticular nucleus neurons are suppressed during REM sleep. PLoS One 8:e62410
Volgin, Denys V; Stettner, Georg M; Kubin, Leszek (2013) Circadian dependence of receptors that mediate wake-related excitatory drive to hypoglossal motoneurons. Respir Physiol Neurobiol 188:301-7
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
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
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
Stettner, Georg M; Fenik, Victor B; Kubin, Leszek (2012) Effect of chronic intermittent hypoxia on noradrenergic activation of hypoglossal motoneurons. J Appl Physiol (1985) 112:305-12
Mody, Pari; Rukhadze, Irma; Kubin, Leszek (2011) Rats subjected to chronic-intermittent hypoxia have increased density of noradrenergic terminals in the trigeminal sensory and motor nuclei. Neurosci Lett 505:176-9
Rukhadze, Irma; Fenik, Victor B; Benincasa, Kate E et al. (2010) Chronic intermittent hypoxia alters density of aminergic terminals and receptors in the hypoglossal motor nucleus. Am J Respir Crit Care Med 182:1321-9

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