Obstructive sleep apnea (OSA) affects about 5% of adults in industrialized countries. Chronic, recurrent nocturnal sleep disruption and arterial bloo oxygen desaturations cause, or exacerbate arterial hypertension and metabolic disorders, increase the risk of stroke, and contribute to fatal accidents. OSA occurs in individuals whose upper airway anatomy predisposes them to upper airway collapse when the airway is not protected by sufficient activation of upper airway dilator muscles. Distinct neurotransmitter systems responsible for the maintenance of upper airway muscle tone during wakefulness and its decline during sleep have been identified using as a model hypoglossal (XII) motoneurons that innervate important upper airway dilators. Norepinephrine is a major wake- related modulator that drives upper airway muscle tone. The most relevant premotor noradrenergic neuronal groups are the A7, sub-coeruleus (subC), A5, A2 and A1, but their relative contributions to activation of XII and other motoneurons, to the central respiratory and cardiovascular activation, and to the arousal response differ. In this segment of our project, we will employ transgenic rats with Cre element expressed in tyrosine hydroxylase- synthesizing neurons, which allows us to directly and selectively activate distinct groups of brainstem noradrenergic neurons by means of optogenetic stimulation. Because we have previously identified the pontine A7 group as a major source of wake-related excitatory drive to XII motoneurons, we hypothesize that activation of A7 neurons will have the most selective and strongest effect, but our goal is to measure the relative contributions of A7 and other noradrenergic groups to activation of upper airway muscles vs. cardiorespiratory activation and systemic arousal.
Our Specific Aim (SA) #1 is to measure the magnitude of XII motoneuronal activation elicited by graded optogenetic stimulation of different noradrenergic neuronal groups and measure any concurrent effects at other motor, cardiorespiratory and arousal-related outputs. These experiments will be conducted under anesthesia to ensure stable experimental conditions and allow us to verify the neurochemical nature of the responses by delivering appropriate neurotransmitter receptor antagonists to selected output sites within the studied networks. Our SA #2 is to determine the differential effects of optogenetic stimulation of distinct groups of noradrenergic neurons on activity of lingual muscles, including the genioglossus, sleep-wake behavior, and respiratory rate and depth in chronically instrumented, behaving rats. To achieve this, we shall stimulate different pontomedullary noradrenergic groups during different sleep-wake states. Our SA #3 is to determine how the contributions of different noradrenergic neuronal groups to upper airway muscle tone are altered in rats exposed to chronic intermittent hypoxia used as a model of a major component of OSA. Collectively, these studies will characterize the key sources of noradrenergic drive to upper airway motoneurons and establish the basis for targeting different components of the central noradrenergic system with potentially therapeutic interventions for sleep-disordered breathing.

Public Health Relevance

Obstructive sleep apnea syndrome (OSA) has severe consequences for many regulatory systems, including cardiovascular, metabolic and cognitive. In order to breathe adequately, OSA patients need to generate a high level of activity in their upper airway muscles but they cannot achieve this during sleep and sleep becomes disrupted. Our goal is to determine, in an animal model, how different groups of neurons that use noradrenaline as their transmitter contribute to activation of upper airway muscles.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL047600-20A1
Application #
8960764
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
1992-09-21
Project End
2019-04-30
Budget Start
2015-07-15
Budget End
2016-04-30
Support Year
20
Fiscal Year
2015
Total Cost
$400,000
Indirect Cost
$150,000
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; 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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