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

Abstract

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.

Catecholaminergic A1/C1 neurons contribute to the maintenance of upper airway muscle tone but may not participate in NREM sleep-related depression of these muscles

“…Yet the neuronal circuitry underlying the upper airway muscle depression during NREM sleep and REM sleep has not been fully identified and characterized. The research conducted to date has been largely focused on the mechanisms mediating REM sleep-related depression of XIImns, as XIImns innervate the muscles of the upper airway (Zauerland and Harper, 1976; Remmers, 1978; Mezzanotte et al, 1992; Fenik et al, 2004, 2005b; Saboisky et al, 2007; Kubin, 2014, 2016). Two major competing theories have argued that REM sleep-related depression of activity in upper airway muscles results from either postsynaptic inhibition (increased glycine and/or GABA hyperpolarization) or disfacilitation (decreased serotonergic and noradrenergic excitation) of XIImns.…”

“…For example, depression of XII nerve activity during carbachol-elicited REM sleep-like state can be pharmacologically abolished by microinjections of combination of GABA, glycine, NA and 5HT antagonists into XIImns in urethane anesthetized rats (Fenik et al, 2004). It has also been shown that a combination of NA and 5HT antagonists is both necessary and sufficient to abolish depression of XII nerve activity during REM sleep-like state (Fenik et al, 2005a), with the contribution of NA being larger than 5HT (Fenik et al, 2005a; Kubin, 2014, 2016; Fenik, 2015). These findings were confirmed by reports that NA has a significant contribution to REM sleep-related depression of GG muscle activity in naturally sleeping behaving rats (Chan et al, 2006) whereas the contribution of 5HT was minimal (Sood et al, 2005).…”

“…As the contribution of NA to depression of XII nerve activity during REM sleep-like state was determined to be relatively stronger than 5HT in both, anesthetized (Fenik et al, 2005a; Fenik, 2015; Kubin, 2014, 2016) and behaving rats (Sood et al, 2005; Chan et al, 2006), our research activity has focused most intensively on NA mechanisms. The role of different pontine NA neurons was assessed in functional studies, which have concluded that among the NA groups tested (A5, A7, SubC and LC) A7 neurons provide the major NA excitatory drive to XIImns (Fenik et al, 2002, 2008, 2012).…”

Caracterización del Fenotipo Cardiorrespiratorio de los Ratones “conexina-36 knockout” : un Modelo de Muerte Súbita de la Infancia y de Apneas de Sueño en el Adulto

“…durante el NREM se produce un reducción de la frecuencia respiratoria y de la amplitud ventilatoria y aumenta la regularidad del ritmo respiratorio (Kubin, 2016), asociados a una reducción en el consumo de O 2 y en la producción de CO 2 (Coote, 1982). Por el contrario, durante el REM se produce un aumento fásico de la frecuencia, la amplitud ventilatoria disminuye y la respiración se vuelve irregular (Fraigne y Orem, 2011;Aserinsky y Kleitman, 1953).…”

“…La mayor frecuencia respiratoria que se produce en vigilia podría ser secundaria a la acidosis respiratoria que desarrollan estos ratones (Tabla 3). Durante sueño NREM se produce una disminución fisiológica de la frecuencia respiratoria que se ha atribuido a la reducción de las entradas excitadoras procedentes de distintas estructuras sobre el centro respiratorio y de los quimiorreceptores periféricos (Kubin, 2016;Li et al, 1999), pasando la respiración a depender en estas condiciones más de su propia capacidad ritmogénica y de su regulación por el NRT (Li et al, 1999;Burke et al, 2015). La menor frecuencia respiratoria que muestras los ratones Cx36KO en NREM podría deberse a la disminución de la sensibilidad al CO 2 que ocurre en estos ratones en la edad adulta y probablemente también una capacidad ritmogénica reducida.…”