REM Sleep–like Atonia of Hypoglossal (XII) Motoneurons Is Caused by Loss of Noradrenergic and Serotonergic Inputs

Fenik, Victor B.; Davies, Richard O.; Kubin, Leszek

doi:10.1164/rccm.200412-1750oc

Cited by 171 publications

(264 citation statements)

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“…This wake-related aminergic drive is derived from NE and 5-HT cells of the brainstem (14)(15)(16). NE excites XII motoneurons through a 1 -adrenergic receptors (23,51,52) and antagonism of these receptors in the rat XII nucleus causes a profound decrease of XII motoneuronal activity (12,13). Therefore, our finding of an increased density of NE terminals and XII motoneurons expressing a 1 -adrenergic receptors suggests that exposure to CIH may enhance the endogenous NE excitatory input to XII motoneurons.…”

Section: Functional Implicationsmentioning

confidence: 72%

“…Data from healthy animals show that sleep-related withdrawal of aminergic (NE and 5-HT) activation is a major mechanism responsible for sleep-related depression of upper airway muscle activity (9,(11)(12)(13)20). This wake-related aminergic drive is derived from NE and 5-HT cells of the brainstem (14)(15)(16).…”

Section: Functional Implicationsmentioning

confidence: 99%

“…Sleep-related decrements of lingual muscle activity facilitate the occurrence of sleep-related upper airway obstructions (6)(7)(8). Data from healthy animals show that endogenous excitation mediated by norepinephrine (NE) and serotonin (5-HT) is an important contributor to the maintenance of upper airway muscle tone during wakefulness (9)(10)(11)(12)(13). This drive is derived from pontomedullary NE and 5-HT cells (14)(15)(16) that have state-dependent levels of activity, maximal during wakefulness, moderate during non-REM sleep, and minimal or absent during REM sleep (17)(18)(19).…”

mentioning

confidence: 99%

“…This drive is derived from pontomedullary NE and 5-HT cells (14)(15)(16) that have state-dependent levels of activity, maximal during wakefulness, moderate during non-REM sleep, and minimal or absent during REM sleep (17)(18)(19). The sleep-related withdrawal of aminergic (NE and 5-HT) activation has been identified as a major mechanism underlying sleep-related depression of upper airway muscle activity (9,12,13,20). The excitatory effects of NE and 5-HT on XII motoneurons are mediated by a 1 -adrenergic and 5-HT 2A receptors that are abundantly expressed in XII motoneurons (9,(21)(22)(23).…”

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confidence: 99%

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Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

Rukhadze

Fenik

Benincasa

et al. 2010

Am J Respir Crit Care Med

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Rationale: Patients with obstructive sleep apnea (OSA) adapt to the anatomical vulnerability of their upper airway by generating increased activity in upper airway-dilating muscles during wakefulness. Norepinephrine (NE) and serotonin (5-HT) mediate, through a 1 -adrenergic and 5-HT 2A receptors, a wake-related excitatory drive to upper airway motoneurons. In patients with OSA, this drive is necessary to maintain their upper airway open. We tested whether chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, affects aminergic innervation of XII motoneurons that innervate tongue-protruding muscles in a manner that could alter their airway-dilatory action. Objectives: To determine the impact of CIH on neurochemical markers of NE and 5-HT innervation of the XII nucleus. Methods: NE and 5-HT terminal varicosities and a 1 -adrenergic and 5-HT 2A receptors were immunohistochemically visualized and quantified in the XII nucleus in adult rats exposed to CIH or room air exchanges for 10 h/d for 34 to 40 days. Measurements and Main Results: CIH-exposed rats had approximately 40% higher density of NE terminals and approximately 20% higher density of 5-HT terminals in the ventromedial quadrant of the XII nucleus, the region that controls tongue protruder muscles, than sham-treated rats. XII motoneurons expressing a 1 -adrenoceptors were also approximately 10% more numerous in CIH rats, whereas 5-HT 2A receptor density tended to be lower in CIH rats. Conclusions: CIH-elicited increase of NE and 5-HT terminal density and increased expression of a 1 -adrenoceptors in the XII nucleus may lead to augmentation of endogenous aminergic excitatory drives to XII motoneurons, thereby contributing to the increased upper airway motor tone in patients with OSA.Keywords: chronic-intermittent hypoxia; hypoglossal motoneurons; obstructive sleep apnea; norepinephrine; serotonin Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of upper airway narrowing or collapse, which lead to reduced ventilation or apnea, blood oxygen (O 2 ) desaturations, and sleep fragmentation (1, 2). Subjects with OSA adapt to the anatomical vulnerability of their upper airway by generating a higher level of activity in their upper airway-dilating muscles during wakefulness than healthy subjects (3-5). This allows them to maintain airway patency, but the mechanisms underlying this adaptation are unknown.Hypoglossal (XII) motoneurons innervate the genioglossus and other muscles of the tongue whose active contraction is important for the maintenance of upper airway patency in patients with OSA (2, 6). Sleep-related decrements of lingual muscle activity facilitate the occurrence of sleep-related upper airway obstructions (6-8). Data from healthy animals show that endogenous excitation mediated by norepinephrine (NE) and serotonin (5-HT) is an important contributor to the maintenance of upper airway muscle tone during wakefulness (9-13). This drive is derived from pontomedullary NE and 5-HT cells (14-16) that have state-depende...

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Section: Functional Implicationsmentioning

confidence: 72%

Section: Functional Implicationsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

Rukhadze

Fenik

Benincasa

et al. 2010

Am J Respir Crit Care Med

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“…Two recent studies suggest that inspiratory genioglossus muscle activity is suppressed during REM sleep because noradrenergic excitation of hypoglossal motoneurons is withdrawn during this state (Fenik et al, 2005;Chan et al, 2006). If loss of an excitatory noradrenergic drive at nonrespiratory motor pools is also responsible for suppressing basal muscle tone during REM sleep, then pharmacologically activating trigeminal motoneurons should reverse REM atonia.…”

Section: Glutamatergic Control Of Muscle Tone During Phasic and Tonicmentioning

confidence: 99%

An Endogenous Glutamatergic Drive onto Somatic Motoneurons Contributes to the Stereotypical Pattern of Muscle Tone across the Sleep–Wake Cycle

Burgess¹,

et al. 2008

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Skeletal muscle tone is modulated in a stereotypical pattern across the sleep-wake cycle. Abnormalities in this modulation contribute to most of the major sleep disorders; therefore, characterizing the neurochemical substrate responsible for transmitting a sleep-wake drive to somatic motoneurons needs to be determined. Glutamate is an excitatory neurotransmitter that modulates motoneuron excitability; however, its role in regulating motoneuron excitability and muscle tone during natural sleep-wake behaviors is unknown. Therefore, we used reverse-microdialysis, electrophysiology, pharmacological, and histological methods to determine how changes in glutamatergic neurotransmission within the trigeminal motor pool contribute to the sleep-wake pattern of masseter muscle tone in behaving rats. We found that blockade of non-NMDA and NMDA glutamate receptors (via CNQX and D-AP-5) on trigeminal motoneurons reduced waking masseter tone to sleeping levels, indicating that masseter tone is maximal during alert waking because motoneurons are activated by an endogenous glutamatergic drive. This wake-related drive is switched off in non-rapid eye movement (NREM) sleep, and this contributes to the suppression of muscle tone during this state. We also show that a functional glutamatergic drive generates the muscle twitches that characterize phasic rapid-eye movement (REM) sleep. However, loss of a waking glutamatergic drive is not sufficient for triggering the motor atonia that characterizes REM sleep because potent activation of either AMPA or NMDA receptors on trigeminal motoneurons was unable to reverse REM atonia. We conclude that an endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone during wakefulness, NREM sleep, and phasic REM sleep but not during tonic REM sleep.

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Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

Kubin

2016

Comprehensive Physiology

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Upper airway muscles subserve many essential for survival orofacial behaviors, including their important role as accessory respiratory muscles. In the face of certain predisposition of craniofacial anatomy, both tonic and phasic inspiratory activation of upper airway muscles is necessary to protect the upper airway against collapse. This protective action is adequate during wakefulness, but fails during sleep which results in recurrent episodes of hypopneas and apneas, a condition known as the obstructive sleep apnea syndrome (OSA). Although OSA is almost exclusively a human disorder, animal models help unveil the basic principles governing the impact of sleep on breathing and upper airway muscle activity. This article discusses the neuroanatomy, neurochemistry, and neurophysiology of the different neuronal systems whose activity changes with sleep-wake states, such as the noradrenergic, serotonergic, cholinergic, orexinergic, histaminergic, GABAergic and glycinergic, and their impact on central respiratory neurons and upper airway motoneurons. Observations of the interactions between sleep-wake states and upper airway muscles in healthy humans and OSA patients are related to findings from animal models with normal upper airway, and various animal models of OSA, including the chronic-intermittent hypoxia model. Using a framework of upper airway motoneurons being under concurrent influence of central respiratory, reflex and state-dependent inputs, different neurotransmitters, and neuropeptides are considered as either causing a sleep-dependent withdrawal of excitation from motoneurons or mediating an active, sleep-related inhibition of motoneurons. Information about the neurochemistry of state-dependent control of upper airway muscles accumulated to date reveals fundamental principles and may help understand and treat OSA.

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REM Sleep–like Atonia of Hypoglossal (XII) Motoneurons Is Caused by Loss of Noradrenergic and Serotonergic Inputs

Cited by 171 publications

References 49 publications

Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

An Endogenous Glutamatergic Drive onto Somatic Motoneurons Contributes to the Stereotypical Pattern of Muscle Tone across the Sleep–Wake Cycle

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

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