Comprehensive Physiology Wiley Online Library

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

Full Article on Wiley Online Library



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. © 2016 American Physiological Society. Compr Physiol 6:1801‐1850, 2016.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Schematic representation of a sagittal cross‐section through the upper airway. During inspiration, negative intraluminar pressure pulls three soft tissue elements, the tongue, posterior pharyngeal walls, and soft palate, toward each, thereby reducing the airway lumen in the pharyngeal region. This airway‐collapsing action is opposed by pharyngeal dilator muscles, including the genioglossus, geniohyoid, and tensor and levator veli palatini. Additionally, activation of the pharyngeal constrictors stiffens the airway walls. Arrows show approximate directions of the forces exerted during contraction of these major pharyngeal muscles. Image based on a scan of the upper airway in an OSA patient—courtesy of Dr. Richard J. Schwab at the University of Pennsylvania. (Modified from Fig. 1 in Ref. and republished with permission from Informa Healthcare, a member of the Taylor and Francis Group, obtained via the Copyright Clearance Center, Inc.)
Figure 2. Figure 2. Distribution of the major groups of respiratory neurons in the brainstem and upper spinal cord, as seen in a dorsal view. Brainstem respiratory neurons form longitudinal columns, of which the most prominent one is the VRG located in the ventrolateral medullary reticular formation. The rostralmost part of the VRG, the Bötzinger complex, contains mainly late expiratory neurons. Next region caudally, the pre‐Bötzinger complex, contains pacemaker neurons that, at least in neonatal animals, are capable of producing basic respiratory rhythm under in vitro conditions. Farther caudal is a large group of mainly inspiratory‐modulated neurons, of which many send axons to spinal motoneurons that innervate the diaphragm and external intercostal muscles. Nucleus ambiguus runs parallel to this part of VRG and contains cell bodies of laryngeal motoneurons. Caudal to the inspiratory part of the VRG is an expiratory region whose neurons send axons to spinal expiratory motoneurons that control internal intercostal and abdominal muscles. A spinal extension of the VRG, the C2 and C3 group, again contains inspiratory neurons whose function may be to reinforce the actions of the VRG. The dorsal respiratory group is located in the viscerosensory nucleus of the solitary tract. It contains mostly inspiratory‐modulated neurons, of which some have connections with spinal motoneurons and some receive input from pulmonary and laryngeal receptors. The pontine respiratory group located in the dorsolateral pons comprises cells with different patterns of respiratory modulation. These neurons integrate peripheral and central respiratory and nonrespiratory inputs and have descending projections to medullary respiratory neurons. (Modified from Fig. 2 in Ref. and republished with permission from the American Academy of Sleep Medicine.)
Figure 3. Figure 3. Major sources of pontomedullary afferent projections to the orofacial motor nuclei. (A) Schematic dorsal view of the most prominent afferent pathways common to all orofacial motor nuclei. The medullary IRt is the main source of bilateral projections to the trigeminal (V), facial (VII), hypoglossal (XII), and ambiguus (nA) motor nuclei (red arrows). The projections to these motor nuclei tend to exhibit a distinct rostro‐caudal pattern. The projections to orofacial motor nuclei that originate in the pontine reticular region surrounding the trigeminal motor nucleus (peri‐V), and the ventrolateral medullary gigantocellular region (GCv) tend to be unilateral (blue arrows). (Fig. 12 from Ref. colorized and republished with permission from John Wiley and Sons obtained via the Copyright Clearance Center, Inc.) (B) Major medullary sources of afferent projections to the XII nucleus in relation to the descending spinal collaterals of selected XII premotor neurons, as revealed by large retrograde tracer injections into the XII motor nucleus and ventral horns of the lumbar (L2) spinal cord. The two medullary levels illustrated are located rostral to the XII nucleus. Consistent with data in A, the IRt region contains the largest number of neurons retrogradely labeled with Diamidino Yellow (DY) tracer from the XII nucleus (red dots). Notably, no cells retrogradely labeled with Fast Blue (FB) tracer from the spinal cord (black dots) are located in this region. Additional medullary XII premotor neurons are located along the midline (enlarged images in the middle), the gigantocellular region pars α (GiA), and the lateral paragigantocellular (LPGi) region. A small fraction of cells in these medial and ventral locations has divergent projections to the XII nucleus and lumbar spinal cord (blue triangles). The key to anatomical regions is shown on the right. (Modified from Fig. 3B in Ref. and republished with permission from John Wiley and Sons obtained via the Copyright Clearance Center, Inc.) Additional abbreviations in A and B: Gi, gigantocellular reticular region; mlf, medial longitudinal fasiculus; MVe, medial vestibular nucleus; PCRtA, parvicellular reticular area; PrH, nucleus prepositus hypoglossi; py, pyramidal tract; RMg, Rob, Rpa, raphé magnus, pallidus, and obscurus nuclei; Sp5, spinal trigeminal sensory nucleus; SpVe, spinal vestibular nucleus.
Figure 4. Figure 4. Typical activity patterns during wakefulness and sleep states of selected neurochemically distinct groups of central neurons. Some groups have the highest activity during wakefulness (top/red); others have peaks during both wakefulness and REM sleep or during REM sleep only (middle/yellow), and still others during NREM or REM sleep (bottom/blue). These neuronal groups have direct and indirect connections with central respiratory neurons and upper airway motoneurons through which they impart state‐dependent changes onto the respiratory system.
Figure 5. Figure 5. Schematic representation of the four key neuroanatomically and neurochemically distinct inputs to the XII nucleus. NE afferents originate mainly in the pontine A7 and A5 groups and the SubC region, whereas the largest group of NE neurons, the LC, has negligible projections to the XII nucleus. For clarity, NE projections are shown on one side only; they are bilateral with a minor ipsilateral predominance. 5‐HT afferents come from the medullary raphé pallidus and obscurus nuclei, as well as the lateral wings of the medullary raphé. The medullary IRt contains glutamatergic and cholinergic XII premotor cells; the former provide inspiratory drive to XII motoneurons, and the latter may mediate pre‐ or postsynaptic modulatory influences that are either respiratory or state dependent. The LPGi and the adjacent areas contain cells that have been hypothesized to mediate active inhibitory effects of REM sleep to motoneurons. GABAergic, REM sleep‐active neurons with divergent projections ascending to the pons and descending to the spinal cord have been located in this area (). It is not known whether the same cells also have axonal projections to the XII nucleus. Abbreviations: A, nucleus ambiguus; IO, inferior olive, Po, nucleus pontis oralis; K‐F, Kölliker‐Fuse nucleus; NTS, nucleus of the solitary tract; py, pyramidal tract.
Figure 6. Figure 6. NE‐ and 5‐HT‐containing axon terminals are present throughout the XII nucleus. (A and B) Microscopic images of coronal cross‐sections through the XII nucleus on one side. The section in A was immunostained for dopamine‐ß‐hydroxylase (DBH), which in the XII nucleus labels noradrenergic fibers and terminals (black). The section in B was immunostained for 5‐HT fibers and terminals. In both panels, selected XII motoneurons that innervate the tongue also were labeled by retrograde transport from the base of the tongue (brown). Typical of motoneurons innervating the genioglossus, most labeled motoneurons are located in the ventromedial quadrant of the XII nucleus. Panels A1 and B1 show enlarged details framed in the corresponding panels on the left. The small dark‐brown and black particles in the enlarged images represent fine axonal ramifications and terminals containing NE (in A1) and 5‐HT (in B1). NE terminals are especially numerous in the ventromedial portion of the XII nucleus. CE, central canal. (Unpublished data from the study described in Ref. .)
Figure 7. Figure 7. Different firing rate outcomes resulting from different patterns of convergence of three functionally distinct excitatory inputs onto an upper airway motoneuron. The scheme shows three scenarios of how different combinations of inputs from functionally different sources may shape state‐dependent changes in motoneuronal activity. (A) The three distinct excitatory inputs considered—respiratory, state‐dependent, and reflex—are shown converging on an upper airway motoneuron. In B to D, the depolarizing actions contributed by each of these three inputs summate above the “baseline membrane potential” (black line at the bottom of each panel), which may result in the membrane potential crossing the firing threshold. Of the three distinct drives, the respiratory input is distinctly rhythmic (phasic), the central state‐dependent input is tonic, and the reflex input includes both a phasic respiratory and a tonic component. The respiratory input is assumed to increase during sleep (e.g., to make up for reduced ventilation during NREM sleep, or as a result of central activation during REM sleep). In the three scenarios shown in B to D, different relative magnitudes of the three drives during wakefulness and their different changes at sleep onset result in quantitatively and qualitatively different firing rate outcomes at the motoneuronal level. (B) A case with a moderate phasic respiratory, moderate reflex, and strong central tonic input during wakefulness. A large drop of the tonic input at the onset of sleep is compensated for by an increase in the respiratory input and the associated phasic component of the reflex input. As a result, the motoneuron's activity minimally changes on the transition from wakefulness to sleep. (C) A case with a strong phasic respiratory input and weak central and reflex inputs during wakefulness. The increase in respiratory input during sleep more than makes up for the loss of the reflex and tonic drives. As a result, the motoneuron is more active during sleep than during wakefulness. (D) A case with all three inputs having similar magnitudes during wakefulness and the state‐dependent input being profoundly reduced during sleep. In spite of a prominent increase in the respiratory input and a moderate increase in the reflex input during sleep, the motoneuron becomes silent. (Modified from Fig. 5 in Ref. and republished with permission from Informa Healthcare, a member of the Taylor and Francis Group, obtained via the Copyright Clearance Center, Inc.)
Figure 8. Figure 8. Time course of lingual muscle activity during transition from wakefulness (W) to NREM sleep in healthy humans and rats. (A) In healthy humans, peak firing rate of inspiratory phasic motor units recorded at the base of the tongue significantly declined in association with a transition from quiet wakefulness to NREM sleep (squares). Transitions were defined based on EEG power shift from α‐frequency to Θ‐frequency. Mean data from 29 inspiratory phasic motor units. In contrast, inspiratory tonic motor units (defined as those firing continuously throughout the respiratory cycle with firing rate increases during inspiration) either had minimal declines of firing rate in association with the onset of NREM sleep or were entirely silenced around the time of the transition. Filled circles show data for all 58 inspiratory tonic motor units studied, including those that became silent at NREM sleep onset. Open circles show data for the subset of inspiratory tonic motor units that were not silenced at the onset of NREM sleep; for this group (n = 29), there was only a very small and transient decrease of firing rate. Asterisks indicate significantly lower firing rate after NREM sleep onset when compared to the mean before the transition. (Fig. 2 in Ref. republished with permission from the American Academy of Sleep Medicine obtained via the Copyright Clearance Center, Inc.) (B) Lingual and nuchal EMGs averaged over multiple transitions from W to NREM sleep and from NREM sleep to W in rats. The top graphs show average levels of lingual EMG determined during successive 10 s intervals over 2‐min periods before and after the state transitions, as indicated above the panels. Root mean squares of muscle activity were normalized within each animal and recording session by its average level during W. The middle graphs show the corresponding changes in postural activity recorded from dorsal neck muscles. The bottom panels show the corresponding average changes in cortical delta power which characteristically increases during NREM sleep. Lingual activity is nearly abolished following entry into NREM sleep. Such a low level of activity is maintained throughout the duration of NREM sleep episodes and rapidly returns to the wakefulness level after arousal (right panels). (Modified from Fig. 5 in Ref. and republished with permission from Elsevier.)
Figure 9. Figure 9. Upper airway muscle activity during REM sleep in subjects with fully patent upper airway is dominated by nonrespiratory, phasic bursts that emerge from an otherwise atonic state. (A) Activity of the arytenoid (laryngeal) muscle during REM sleep in a healthy human subject. (Fig. 9 in Ref. republished with permission from the American Physiological Society.) (B) Average time course of lingual muscle activity during transitions from NREM to REM sleep in rats. Lingual and nuchal EMG levels were measured during successive 10 s intervals from 60 s before to 200 s after the state transition (time zero) and averaged over multiple transitions in multiple animals. Root mean squares of muscle activity were normalized within each animal by their average levels during wakefulness. The bottom graph shows the corresponding average time course of the ratio of EEG powers in β‐2 to Δ‐2 bands (the ratio characteristically increases during REM sleep). Lingual and nuchal EMGs follow a different time course during the transition. Whereas nuchal EMG declines prior to the onset of REM sleep and then maintains a low level (atonia), lingual EMG is nearly atonic prior to the onset of REM sleep (see Fig. 8B) and first gradually increases and then declines after REM sleep onset. The relatively smooth time course of the increase and then decline is a result of averaging of many short bursts of activity (twitches) across many NREM to REM sleep transitions. The resulting mean time course indicates that, after the onset of REM sleep, individual twitches first become gradually larger and more frequent and then gradually become smaller and less frequent when the duration of REM sleep episodes extends beyond its mean ( s in rats). (Modified from Fig. 6 in Ref. and republished with permission from Archives Italiennes de Biologie and the University of Pisa.)
Figure 10. Figure 10. REM sleep exerts a powerful excitatory effect on the activity of most brainstem respiratory neurons. In this example, cumulative activity of an augmenting medullary inspiratory neuron was recorded from a chronically instrumented cat over a period covering a transition from NREM to REM sleep and then from REM sleep to awakening. The period of REM sleep is marked by EEG desynchronization, appearance of PGO waves, and a slightly reduced and variable end‐expiratory CO2. The bottom panel shows that the neuron has a distinctly increased activity during REM sleep when compared to either the preceding period of NREM sleep or the period after awakening, as indicated by the slope of cumulative activity. (Fig. 1 in Ref. republished with permission from John Wiley and Sons obtained via the Copyright Clearance Center, Inc.)
Figure 11. Figure 11. REM sleep‐like episodes of depression of XII nerve activity accompanied by the characteristic cortical and hippocampal activation can be elicited by microinjections of a cholinergic agonist, carbachol, into the dorsal mesopontine tegmentum in urethane‐anesthetized, paralyzed, and artificially ventilated rats. (A) Typical REM sleep‐like episode. The moving average of XII nerve activity (top) shows inspiratory bursts of activity. The amplitude of the bursts is reduced and the central respiratory rate declines within less than 2 min following pontine carbachol injection (at arrow). Parallel to the depression of XII nerve activity, there is cortical and hippocampal activation. The second trace from top shows raw signal recorded from the hippocampus. The third trace from top shows the power of hippocampal activity in the 3 to 5 Hz frequency band, which represents theta‐like rhythm under urethane anesthesia. The increase in power of cortical EEG in the 6 to 9 Hz frequency band (bottom) indicates activation relative to the period prior to carbachol injection. The entire episode lasts about 5 min, after which all signals return to their precarbachol levels and patterns. The ability to repeatedly elicit such REM sleep‐like episodes allows one to investigate cellular, neurochemical, and network mechanisms of the interaction between REM sleep and the regulation of breathing and upper airway muscle activity. (Unpublished record from the study described in Ref. .) B: The sites at which carbachol microinjections elicit REM sleep‐like episodes in urethane‐anesthetized rats superimposed onto two standard cross sections of the brainstem from levels 8.3 mm and 8.72 mm caudal to bregma. Abbreviations: LDN, laterodorsal tegmental nucleus; PPN, pedunculopontine tegmental nucleus; scp, superior cerebellar peduncle; VT, ventral tegmental nucleus. (Modified from Fig. 2 in Ref. and republished with permission from Elsevier.)
Figure 12. Figure 12. Antagonism of glycinergic inhibition at the level of the XII motor nucleus did not prevent the REM sleep‐like depression of XII nerve activity elicited in decerebrate, paralyzed, vagotomized, and artificially ventilated cats by pontine microinjections of a cholinergic agonist, carbachol. Strychnine, a blocker of glycinergic receptors, was repeatedly microinjected into the right XII nucleus 3 to 16 min prior to the beginning of the record. The traces show moving averages of activities recorded from both XII nerves (upward deflections represent inspiratory bursts) and a cervical nerve branch that innervates dorsal neck muscles (a marker of postural activity). Pontine carbachol injection made at the marker initiated the REM sleep‐like suppression of activity in both XII nerves and the postural nerve. The activities of both XII nerves were similarly depressed despite the prior injection of strychnine into the right XII nucleus. (Modified from Fig. 2B in Ref. and republished with permission from Elsevier.)
Figure 13. Figure 13. Results from different laboratories and different animal models consistently indicate that antagonism of glycinergic inhibition at the motoneuronal level by strychnine does not abolish the REM sleep‐related depression of activity in orofacial motoneurons. (A) In chronically instrumented, behaving cats, microinjections of strychnine into the trigeminal motor nucleus only marginally diminished the REM sleep‐related depression of reflexly elicited activation of the masseter muscle. (Modified from Fig. 3 in Ref. and republished with permission from Elsevier.) (B) In unanesthetized, decerebrate cats, the REM sleep‐like depression of spontaneous activity of the XII nerve elicited by microinjection of a cholinergic agonist, carbachol, into the dorsomedal pontine tegmentum was well maintained despite microinjections of strychnine into the XII nucleus. (Modified from Fig. 5 in Ref. and republished with permission from Elsevier.) (C) REM sleep atonia of the masseter muscle was not reduced in naturally sleeping rats by continuous microperfusion of strychnine into the trigeminal motor nucleus. QW, quiet wakefulness. (Data extracted and replotted from Fig. 4D in Ref. with the authors' permission.) (C) In naturally sleeping rats, depression of activity of the genioglossus muscle (GG) measured in arbitrary units (A.U.) during the period of REM sleep without muscle twitches (“TONIC”) occurred with a similar magnitude during continuous microperfusion of the XII nucleus region with strychnine and when the nucleus was perfused with a vehicle (Control). (Data extracted and re‐plotted from Fig. 4 in Ref. with the authors' permission.)
Figure 14. Figure 14. Evidence that the REM sleep‐related depression of activity in XII motoneurons is caused by a concurrent withdrawal of endogenous activation mediated by NE and 5‐HT. When a cocktail containing the α1‐adrenergic receptor antagonist, prazosin, and a broad‐spectrum 5‐HT receptor antagonist, methysergide, is injected into the XII nucleus at multiple antero‐posterior levels, spontaneous XII nerve activity is depressed to 20% to 30% of its control level and remains depressed for several hours (line graph at the top). This indicates that XII motoneurons are under a strong endogenous excitatory drive mediated by NE and 5‐HT. The three sets of bar graphs at the bottom show XII nerve activity levels measured just before (B), during (D), and just after (A) REM sleep‐like episodes elicited by pontine microinjections of carbachol. The first set of bars characterizes typical REM sleep‐like depression elicited under the control conditions (before prazosin and methysergide injection into the XII nucleus; see Fig. 11A for a detailed time course and pattern of a typical REM sleep‐like episode). Under these control conditions, XII nerve activity is depressed to 20% to 30% of the control. The second set of bars represents XII nerve activity during REM sleep‐like episodes elicited 40 to 50 min after prazosin and methysergide microinjections, that is, when the antagonists exert maximal effect (cf. top graph). Under these conditions, there is no additional depression of XII nerve activity during the REM sleep‐like episode beyond that already caused by the antagonists. The third set of bars shows XII nerve activity during the REM sleep‐like episodes elicited when XII nerve activity partially recovered from the effect of the antagonists. At this time after the antagonist injections (about 170 min), XII nerve activity is again depressed during the REM sleep‐like episodes. Thus, when endogenous activation of XII motoneurons mediated by NE and 5‐HT is fully blocked (middle set of bars), no depression of XII nerve activity occurs during the REM sleep‐like episodes. This indicates an occlusion between the depression caused by the antagonists and the effect of REM sleep‐like state that takes place at the level of XII motoneurons. (Data from Ref. visualized as Fig. 3 in Ref. and republished with permission from Elsevier.)
Figure 15. Figure 15. Semiquantitative representation of afferent projections to the XII nucleus from distinct groups of pontomedulary NE neurons based on retrograde tracing studies. (A) When expressed relative to the total number of retrogradely labeled NE neurons found throughout the brainstem following tracer injections into the XII nucleus, projections from the A5 group are most prominent, followed by SubC region, and then A1/C1 and A7 groups. (B) When the numbers of NE cells retrogradely labeled from the XII nucleus found in each group are expressed relative to the total numbers of neurons present in this cell group, the A7 group contains the highest percentage of cells sending axons to the XII nucleus, followed by the A5 group and SubC. Regardless of the quantification method, projections from the LC are negligible. In both schemes, arrow thickness is proportional to the corresponding percentage of cells retrogradely labeled from the XII nucleus. (Data from Ref. modified from Fig. 4 in Ref. and republished with permission from Elsevier.)
Figure 16. Figure 16. Pathways transmitting activation from the hypothalamic wake‐active orexin neurons to orofacial motoneurons. Anatomical studies indicate that ACh, 5‐HT, and NE brainstem neurons as well as motoneurons, are among the major targets of axons descending from hypothalamic orexin‐containing neurons. However, physiological and pharmacological studies reveal that nonorexin cells located in the posterior hypothalamic orexinergic region also can significantly influence the respiratory output, including upper airway motoneurons. In particular, neither the combined antagonism of 5‐HT and NE‐mediated excitation at the XII nucleus level (), nor microinjections of a dual orexin receptor antagonist into the XII nucleus (), could significantly attenuate activation of XII motoneurons from the hypothalamic region containing orexin neurons. On the other hand, microinjections of a dual orexin receptor antagonist into the hypothalamic orexin cell field significantly attenuated activation of XII motoneurons from this hypothalamic region (). These results support the presence of an excitatory pathway that descends from the posterior hypothalamus parallel to the orexinergic pathway and targets different components of the respiratory system, including upper airway motoneurons. Additional connections may exist, such as nonorexinergic excitatory hypothalamo‐brainstem pathways to ACh, 5‐HT and NE neurons, and there may be additional orexinergic connections to central respiratory neurons, although specific details are not yet available. Cholinergic effects within the respiratory network may be excitatory or inhibitory (marked with yellow circles).
Figure 17. Figure 17. Effects of microdialysis perfusion of the XII nucleus region with different K+ channel blockers in chronically instrumented, behaving rats. (A) Perfusion with a solution containing barium ions, which primarily block the inwardly rectifying (Kir) channels, resulted in GG muscle activity being elevated in all sleep‐wake states and attaining the highest levels during wakefulness and REM sleep with muscle twitches (REM(+)). (B) During perfusion with an antagonist of the tandem pore domain (TASK) channels, methanandamide, activation was limited to wakefulness. (C) Perfusion with 4‐aminopyridine (4‐AP, a blocker of voltage‐dependent Kv4 channels) or TEA (a blocker of voltage‐dependent Kv2 channels) increased GG activity across all sleep‐wake states, with the strongest activation attained during REM sleep with twitches. Collectively, these experiments demonstrate that closure of certain K+ channels can elevate GG muscle activity during sleep to, or above, the levels seen during wakefulness. In all panels, integrated GG activity was measured during inspiration within different sleep‐wake states using arbitrary units while the XII nucleus region was perfused with a vehicle [artificial cerebrospinal fluid (ACSF) with or without an emulsificant] or with one of the blockers. Symbols in the graphs indicate statistically significant elevation of activity with the blocker when compared to vehicle. (Panels A‐C show Figs. 1E, 2B and 3C, respectively, from Ref. and are republished with permission from the American Academy of Sleep Medicine obtained via the Copyright Clearance Center, Inc.)
Figure 18. Figure 18. Summary of neurochemically distinct pathways that converge on upper airway motoneurons and determine the respiratory and sleep‐wake state‐dependent patterns of motoneuronal activity. Among the many excitatory pathways (shown on the left) the glutamatergic one mediates the respiratory drive, whereas the effects of all the remaining ones are likely to be wakefulness (or wakefulness and REM sleep) related. Among the inhibitory pathways (shown on the right), GABA, and glycine are especially important for shaping the reflex responses and rhythmic activities of orofacial motoneurons, whereas ACh may mediate pre‐ and postsynaptic, state‐dependent inhibitory effects through muscarinic (M) receptors [in addition to the excitatory effects of ACh mediated by nicotinic (N) receptors]. Additional state‐dependent and state‐independent presynaptic effects are exerted on the respiratory (glutamatergic) input to motoneurons by 5‐HT and GABA.
Figure 19. Figure 19. Upper airway muscle activity changes across sleep‐wake states have different patterns in healthy subjects and OSA subjects with anatomically compromised upper airway. The graph compares measurements obtained from recordings of sternohyoid muscle activity in English bulldogs, who present with OSA (especially during REM sleep), and in normal dogs (beagles). During wakefulness, sternohyoid EMG is higher in English bulldogs than in beagles. Furthermore, whereas in bulldogs sternohyoid EMG steadily declines from wakefulness to NREM sleep and then REM sleep, in beagles, there is a decline between wakefulness and NREM sleep and then an increase during REM sleep. The increase during REM sleep is similar to that in rats (), other healthy dogs (), cats (), and healthy humans (). (Graphical representation of numerical data in Ref. published as Fig. 3B in Ref. and republished with permission from Informa Healthcare, a member of the Taylor and Francis Group, obtained via the Copyright Clearance Center, Inc.)
Figure 20. Figure 20. Rats exposed to CIH have increased density of NE terminals in the ventromedial quadrant of the XII nucleus (top section) and increased endogenous excitatory drive to XII motoneurons mediated by α1‐adrenergic receptors (bottom section). (A1 and B1) Comparison of the appearance of NE‐containing terminals in 100 × 100 μm images of the ventromedial quadrant of the XII nucleus in a rat exposed to CIH for 35 days (A1) and a sham‐treated animal (B1). Also visible are several XII motoneurons retrogradely labeled from the base of the tongue (dark brown). (A2 and B2) Graphic renditions of all NE‐containing terminals found in the images shown in A1 and B1. Red dots indicate terminals that were closely apposed to the somatic membrane of retrogradely labeled XII motoneurons (gray), whereas black dots represent the remaining NE terminals. (C) Average numbers of NE terminals (immunostained for dopamine‐β‐hydroxylase) counted in 24 matched for the anteroposterior level pairs of brain sections from eight pairs of CIH/sham‐treated rats. (Panels A‐C modified from Fig. 2 and 3 in Ref. and republished with permission from the American Thoracic Society.) (D) Microinjections of the α1‐adrenergic receptor antagonist, prazosin (PZ), into the XII nucleus caused larger decrements of spontaneous XII nerve activity in anesthetized, paralyzed, and artificially ventilated rats that were earlier exposed to CIH for 35 days than in sham‐treated animals. (E) Prazosin injections did not cause any changes of the central respiratory rate. (Panels D and E modified from Fig. 3 in Ref. and republished with permission from the American Physiological Society.)


Figure 1. Schematic representation of a sagittal cross‐section through the upper airway. During inspiration, negative intraluminar pressure pulls three soft tissue elements, the tongue, posterior pharyngeal walls, and soft palate, toward each, thereby reducing the airway lumen in the pharyngeal region. This airway‐collapsing action is opposed by pharyngeal dilator muscles, including the genioglossus, geniohyoid, and tensor and levator veli palatini. Additionally, activation of the pharyngeal constrictors stiffens the airway walls. Arrows show approximate directions of the forces exerted during contraction of these major pharyngeal muscles. Image based on a scan of the upper airway in an OSA patient—courtesy of Dr. Richard J. Schwab at the University of Pennsylvania. (Modified from Fig. 1 in Ref. and republished with permission from Informa Healthcare, a member of the Taylor and Francis Group, obtained via the Copyright Clearance Center, Inc.)


Figure 2. Distribution of the major groups of respiratory neurons in the brainstem and upper spinal cord, as seen in a dorsal view. Brainstem respiratory neurons form longitudinal columns, of which the most prominent one is the VRG located in the ventrolateral medullary reticular formation. The rostralmost part of the VRG, the Bötzinger complex, contains mainly late expiratory neurons. Next region caudally, the pre‐Bötzinger complex, contains pacemaker neurons that, at least in neonatal animals, are capable of producing basic respiratory rhythm under in vitro conditions. Farther caudal is a large group of mainly inspiratory‐modulated neurons, of which many send axons to spinal motoneurons that innervate the diaphragm and external intercostal muscles. Nucleus ambiguus runs parallel to this part of VRG and contains cell bodies of laryngeal motoneurons. Caudal to the inspiratory part of the VRG is an expiratory region whose neurons send axons to spinal expiratory motoneurons that control internal intercostal and abdominal muscles. A spinal extension of the VRG, the C2 and C3 group, again contains inspiratory neurons whose function may be to reinforce the actions of the VRG. The dorsal respiratory group is located in the viscerosensory nucleus of the solitary tract. It contains mostly inspiratory‐modulated neurons, of which some have connections with spinal motoneurons and some receive input from pulmonary and laryngeal receptors. The pontine respiratory group located in the dorsolateral pons comprises cells with different patterns of respiratory modulation. These neurons integrate peripheral and central respiratory and nonrespiratory inputs and have descending projections to medullary respiratory neurons. (Modified from Fig. 2 in Ref. and republished with permission from the American Academy of Sleep Medicine.)


Figure 3. Major sources of pontomedullary afferent projections to the orofacial motor nuclei. (A) Schematic dorsal view of the most prominent afferent pathways common to all orofacial motor nuclei. The medullary IRt is the main source of bilateral projections to the trigeminal (V), facial (VII), hypoglossal (XII), and ambiguus (nA) motor nuclei (red arrows). The projections to these motor nuclei tend to exhibit a distinct rostro‐caudal pattern. The projections to orofacial motor nuclei that originate in the pontine reticular region surrounding the trigeminal motor nucleus (peri‐V), and the ventrolateral medullary gigantocellular region (GCv) tend to be unilateral (blue arrows). (Fig. 12 from Ref. colorized and republished with permission from John Wiley and Sons obtained via the Copyright Clearance Center, Inc.) (B) Major medullary sources of afferent projections to the XII nucleus in relation to the descending spinal collaterals of selected XII premotor neurons, as revealed by large retrograde tracer injections into the XII motor nucleus and ventral horns of the lumbar (L2) spinal cord. The two medullary levels illustrated are located rostral to the XII nucleus. Consistent with data in A, the IRt region contains the largest number of neurons retrogradely labeled with Diamidino Yellow (DY) tracer from the XII nucleus (red dots). Notably, no cells retrogradely labeled with Fast Blue (FB) tracer from the spinal cord (black dots) are located in this region. Additional medullary XII premotor neurons are located along the midline (enlarged images in the middle), the gigantocellular region pars α (GiA), and the lateral paragigantocellular (LPGi) region. A small fraction of cells in these medial and ventral locations has divergent projections to the XII nucleus and lumbar spinal cord (blue triangles). The key to anatomical regions is shown on the right. (Modified from Fig. 3B in Ref. and republished with permission from John Wiley and Sons obtained via the Copyright Clearance Center, Inc.) Additional abbreviations in A and B: Gi, gigantocellular reticular region; mlf, medial longitudinal fasiculus; MVe, medial vestibular nucleus; PCRtA, parvicellular reticular area; PrH, nucleus prepositus hypoglossi; py, pyramidal tract; RMg, Rob, Rpa, raphé magnus, pallidus, and obscurus nuclei; Sp5, spinal trigeminal sensory nucleus; SpVe, spinal vestibular nucleus.


Figure 4. Typical activity patterns during wakefulness and sleep states of selected neurochemically distinct groups of central neurons. Some groups have the highest activity during wakefulness (top/red); others have peaks during both wakefulness and REM sleep or during REM sleep only (middle/yellow), and still others during NREM or REM sleep (bottom/blue). These neuronal groups have direct and indirect connections with central respiratory neurons and upper airway motoneurons through which they impart state‐dependent changes onto the respiratory system.


Figure 5. Schematic representation of the four key neuroanatomically and neurochemically distinct inputs to the XII nucleus. NE afferents originate mainly in the pontine A7 and A5 groups and the SubC region, whereas the largest group of NE neurons, the LC, has negligible projections to the XII nucleus. For clarity, NE projections are shown on one side only; they are bilateral with a minor ipsilateral predominance. 5‐HT afferents come from the medullary raphé pallidus and obscurus nuclei, as well as the lateral wings of the medullary raphé. The medullary IRt contains glutamatergic and cholinergic XII premotor cells; the former provide inspiratory drive to XII motoneurons, and the latter may mediate pre‐ or postsynaptic modulatory influences that are either respiratory or state dependent. The LPGi and the adjacent areas contain cells that have been hypothesized to mediate active inhibitory effects of REM sleep to motoneurons. GABAergic, REM sleep‐active neurons with divergent projections ascending to the pons and descending to the spinal cord have been located in this area (). It is not known whether the same cells also have axonal projections to the XII nucleus. Abbreviations: A, nucleus ambiguus; IO, inferior olive, Po, nucleus pontis oralis; K‐F, Kölliker‐Fuse nucleus; NTS, nucleus of the solitary tract; py, pyramidal tract.


Figure 6. NE‐ and 5‐HT‐containing axon terminals are present throughout the XII nucleus. (A and B) Microscopic images of coronal cross‐sections through the XII nucleus on one side. The section in A was immunostained for dopamine‐ß‐hydroxylase (DBH), which in the XII nucleus labels noradrenergic fibers and terminals (black). The section in B was immunostained for 5‐HT fibers and terminals. In both panels, selected XII motoneurons that innervate the tongue also were labeled by retrograde transport from the base of the tongue (brown). Typical of motoneurons innervating the genioglossus, most labeled motoneurons are located in the ventromedial quadrant of the XII nucleus. Panels A1 and B1 show enlarged details framed in the corresponding panels on the left. The small dark‐brown and black particles in the enlarged images represent fine axonal ramifications and terminals containing NE (in A1) and 5‐HT (in B1). NE terminals are especially numerous in the ventromedial portion of the XII nucleus. CE, central canal. (Unpublished data from the study described in Ref. .)


Figure 7. Different firing rate outcomes resulting from different patterns of convergence of three functionally distinct excitatory inputs onto an upper airway motoneuron. The scheme shows three scenarios of how different combinations of inputs from functionally different sources may shape state‐dependent changes in motoneuronal activity. (A) The three distinct excitatory inputs considered—respiratory, state‐dependent, and reflex—are shown converging on an upper airway motoneuron. In B to D, the depolarizing actions contributed by each of these three inputs summate above the “baseline membrane potential” (black line at the bottom of each panel), which may result in the membrane potential crossing the firing threshold. Of the three distinct drives, the respiratory input is distinctly rhythmic (phasic), the central state‐dependent input is tonic, and the reflex input includes both a phasic respiratory and a tonic component. The respiratory input is assumed to increase during sleep (e.g., to make up for reduced ventilation during NREM sleep, or as a result of central activation during REM sleep). In the three scenarios shown in B to D, different relative magnitudes of the three drives during wakefulness and their different changes at sleep onset result in quantitatively and qualitatively different firing rate outcomes at the motoneuronal level. (B) A case with a moderate phasic respiratory, moderate reflex, and strong central tonic input during wakefulness. A large drop of the tonic input at the onset of sleep is compensated for by an increase in the respiratory input and the associated phasic component of the reflex input. As a result, the motoneuron's activity minimally changes on the transition from wakefulness to sleep. (C) A case with a strong phasic respiratory input and weak central and reflex inputs during wakefulness. The increase in respiratory input during sleep more than makes up for the loss of the reflex and tonic drives. As a result, the motoneuron is more active during sleep than during wakefulness. (D) A case with all three inputs having similar magnitudes during wakefulness and the state‐dependent input being profoundly reduced during sleep. In spite of a prominent increase in the respiratory input and a moderate increase in the reflex input during sleep, the motoneuron becomes silent. (Modified from Fig. 5 in Ref. and republished with permission from Informa Healthcare, a member of the Taylor and Francis Group, obtained via the Copyright Clearance Center, Inc.)


Figure 8. Time course of lingual muscle activity during transition from wakefulness (W) to NREM sleep in healthy humans and rats. (A) In healthy humans, peak firing rate of inspiratory phasic motor units recorded at the base of the tongue significantly declined in association with a transition from quiet wakefulness to NREM sleep (squares). Transitions were defined based on EEG power shift from α‐frequency to Θ‐frequency. Mean data from 29 inspiratory phasic motor units. In contrast, inspiratory tonic motor units (defined as those firing continuously throughout the respiratory cycle with firing rate increases during inspiration) either had minimal declines of firing rate in association with the onset of NREM sleep or were entirely silenced around the time of the transition. Filled circles show data for all 58 inspiratory tonic motor units studied, including those that became silent at NREM sleep onset. Open circles show data for the subset of inspiratory tonic motor units that were not silenced at the onset of NREM sleep; for this group (n = 29), there was only a very small and transient decrease of firing rate. Asterisks indicate significantly lower firing rate after NREM sleep onset when compared to the mean before the transition. (Fig. 2 in Ref. republished with permission from the American Academy of Sleep Medicine obtained via the Copyright Clearance Center, Inc.) (B) Lingual and nuchal EMGs averaged over multiple transitions from W to NREM sleep and from NREM sleep to W in rats. The top graphs show average levels of lingual EMG determined during successive 10 s intervals over 2‐min periods before and after the state transitions, as indicated above the panels. Root mean squares of muscle activity were normalized within each animal and recording session by its average level during W. The middle graphs show the corresponding changes in postural activity recorded from dorsal neck muscles. The bottom panels show the corresponding average changes in cortical delta power which characteristically increases during NREM sleep. Lingual activity is nearly abolished following entry into NREM sleep. Such a low level of activity is maintained throughout the duration of NREM sleep episodes and rapidly returns to the wakefulness level after arousal (right panels). (Modified from Fig. 5 in Ref. and republished with permission from Elsevier.)


Figure 9. Upper airway muscle activity during REM sleep in subjects with fully patent upper airway is dominated by nonrespiratory, phasic bursts that emerge from an otherwise atonic state. (A) Activity of the arytenoid (laryngeal) muscle during REM sleep in a healthy human subject. (Fig. 9 in Ref. republished with permission from the American Physiological Society.) (B) Average time course of lingual muscle activity during transitions from NREM to REM sleep in rats. Lingual and nuchal EMG levels were measured during successive 10 s intervals from 60 s before to 200 s after the state transition (time zero) and averaged over multiple transitions in multiple animals. Root mean squares of muscle activity were normalized within each animal by their average levels during wakefulness. The bottom graph shows the corresponding average time course of the ratio of EEG powers in β‐2 to Δ‐2 bands (the ratio characteristically increases during REM sleep). Lingual and nuchal EMGs follow a different time course during the transition. Whereas nuchal EMG declines prior to the onset of REM sleep and then maintains a low level (atonia), lingual EMG is nearly atonic prior to the onset of REM sleep (see Fig. 8B) and first gradually increases and then declines after REM sleep onset. The relatively smooth time course of the increase and then decline is a result of averaging of many short bursts of activity (twitches) across many NREM to REM sleep transitions. The resulting mean time course indicates that, after the onset of REM sleep, individual twitches first become gradually larger and more frequent and then gradually become smaller and less frequent when the duration of REM sleep episodes extends beyond its mean ( s in rats). (Modified from Fig. 6 in Ref. and republished with permission from Archives Italiennes de Biologie and the University of Pisa.)


Figure 10. REM sleep exerts a powerful excitatory effect on the activity of most brainstem respiratory neurons. In this example, cumulative activity of an augmenting medullary inspiratory neuron was recorded from a chronically instrumented cat over a period covering a transition from NREM to REM sleep and then from REM sleep to awakening. The period of REM sleep is marked by EEG desynchronization, appearance of PGO waves, and a slightly reduced and variable end‐expiratory CO2. The bottom panel shows that the neuron has a distinctly increased activity during REM sleep when compared to either the preceding period of NREM sleep or the period after awakening, as indicated by the slope of cumulative activity. (Fig. 1 in Ref. republished with permission from John Wiley and Sons obtained via the Copyright Clearance Center, Inc.)


Figure 11. REM sleep‐like episodes of depression of XII nerve activity accompanied by the characteristic cortical and hippocampal activation can be elicited by microinjections of a cholinergic agonist, carbachol, into the dorsal mesopontine tegmentum in urethane‐anesthetized, paralyzed, and artificially ventilated rats. (A) Typical REM sleep‐like episode. The moving average of XII nerve activity (top) shows inspiratory bursts of activity. The amplitude of the bursts is reduced and the central respiratory rate declines within less than 2 min following pontine carbachol injection (at arrow). Parallel to the depression of XII nerve activity, there is cortical and hippocampal activation. The second trace from top shows raw signal recorded from the hippocampus. The third trace from top shows the power of hippocampal activity in the 3 to 5 Hz frequency band, which represents theta‐like rhythm under urethane anesthesia. The increase in power of cortical EEG in the 6 to 9 Hz frequency band (bottom) indicates activation relative to the period prior to carbachol injection. The entire episode lasts about 5 min, after which all signals return to their precarbachol levels and patterns. The ability to repeatedly elicit such REM sleep‐like episodes allows one to investigate cellular, neurochemical, and network mechanisms of the interaction between REM sleep and the regulation of breathing and upper airway muscle activity. (Unpublished record from the study described in Ref. .) B: The sites at which carbachol microinjections elicit REM sleep‐like episodes in urethane‐anesthetized rats superimposed onto two standard cross sections of the brainstem from levels 8.3 mm and 8.72 mm caudal to bregma. Abbreviations: LDN, laterodorsal tegmental nucleus; PPN, pedunculopontine tegmental nucleus; scp, superior cerebellar peduncle; VT, ventral tegmental nucleus. (Modified from Fig. 2 in Ref. and republished with permission from Elsevier.)


Figure 12. Antagonism of glycinergic inhibition at the level of the XII motor nucleus did not prevent the REM sleep‐like depression of XII nerve activity elicited in decerebrate, paralyzed, vagotomized, and artificially ventilated cats by pontine microinjections of a cholinergic agonist, carbachol. Strychnine, a blocker of glycinergic receptors, was repeatedly microinjected into the right XII nucleus 3 to 16 min prior to the beginning of the record. The traces show moving averages of activities recorded from both XII nerves (upward deflections represent inspiratory bursts) and a cervical nerve branch that innervates dorsal neck muscles (a marker of postural activity). Pontine carbachol injection made at the marker initiated the REM sleep‐like suppression of activity in both XII nerves and the postural nerve. The activities of both XII nerves were similarly depressed despite the prior injection of strychnine into the right XII nucleus. (Modified from Fig. 2B in Ref. and republished with permission from Elsevier.)


Figure 13. Results from different laboratories and different animal models consistently indicate that antagonism of glycinergic inhibition at the motoneuronal level by strychnine does not abolish the REM sleep‐related depression of activity in orofacial motoneurons. (A) In chronically instrumented, behaving cats, microinjections of strychnine into the trigeminal motor nucleus only marginally diminished the REM sleep‐related depression of reflexly elicited activation of the masseter muscle. (Modified from Fig. 3 in Ref. and republished with permission from Elsevier.) (B) In unanesthetized, decerebrate cats, the REM sleep‐like depression of spontaneous activity of the XII nerve elicited by microinjection of a cholinergic agonist, carbachol, into the dorsomedal pontine tegmentum was well maintained despite microinjections of strychnine into the XII nucleus. (Modified from Fig. 5 in Ref. and republished with permission from Elsevier.) (C) REM sleep atonia of the masseter muscle was not reduced in naturally sleeping rats by continuous microperfusion of strychnine into the trigeminal motor nucleus. QW, quiet wakefulness. (Data extracted and replotted from Fig. 4D in Ref. with the authors' permission.) (C) In naturally sleeping rats, depression of activity of the genioglossus muscle (GG) measured in arbitrary units (A.U.) during the period of REM sleep without muscle twitches (“TONIC”) occurred with a similar magnitude during continuous microperfusion of the XII nucleus region with strychnine and when the nucleus was perfused with a vehicle (Control). (Data extracted and re‐plotted from Fig. 4 in Ref. with the authors' permission.)


Figure 14. Evidence that the REM sleep‐related depression of activity in XII motoneurons is caused by a concurrent withdrawal of endogenous activation mediated by NE and 5‐HT. When a cocktail containing the α1‐adrenergic receptor antagonist, prazosin, and a broad‐spectrum 5‐HT receptor antagonist, methysergide, is injected into the XII nucleus at multiple antero‐posterior levels, spontaneous XII nerve activity is depressed to 20% to 30% of its control level and remains depressed for several hours (line graph at the top). This indicates that XII motoneurons are under a strong endogenous excitatory drive mediated by NE and 5‐HT. The three sets of bar graphs at the bottom show XII nerve activity levels measured just before (B), during (D), and just after (A) REM sleep‐like episodes elicited by pontine microinjections of carbachol. The first set of bars characterizes typical REM sleep‐like depression elicited under the control conditions (before prazosin and methysergide injection into the XII nucleus; see Fig. 11A for a detailed time course and pattern of a typical REM sleep‐like episode). Under these control conditions, XII nerve activity is depressed to 20% to 30% of the control. The second set of bars represents XII nerve activity during REM sleep‐like episodes elicited 40 to 50 min after prazosin and methysergide microinjections, that is, when the antagonists exert maximal effect (cf. top graph). Under these conditions, there is no additional depression of XII nerve activity during the REM sleep‐like episode beyond that already caused by the antagonists. The third set of bars shows XII nerve activity during the REM sleep‐like episodes elicited when XII nerve activity partially recovered from the effect of the antagonists. At this time after the antagonist injections (about 170 min), XII nerve activity is again depressed during the REM sleep‐like episodes. Thus, when endogenous activation of XII motoneurons mediated by NE and 5‐HT is fully blocked (middle set of bars), no depression of XII nerve activity occurs during the REM sleep‐like episodes. This indicates an occlusion between the depression caused by the antagonists and the effect of REM sleep‐like state that takes place at the level of XII motoneurons. (Data from Ref. visualized as Fig. 3 in Ref. and republished with permission from Elsevier.)


Figure 15. Semiquantitative representation of afferent projections to the XII nucleus from distinct groups of pontomedulary NE neurons based on retrograde tracing studies. (A) When expressed relative to the total number of retrogradely labeled NE neurons found throughout the brainstem following tracer injections into the XII nucleus, projections from the A5 group are most prominent, followed by SubC region, and then A1/C1 and A7 groups. (B) When the numbers of NE cells retrogradely labeled from the XII nucleus found in each group are expressed relative to the total numbers of neurons present in this cell group, the A7 group contains the highest percentage of cells sending axons to the XII nucleus, followed by the A5 group and SubC. Regardless of the quantification method, projections from the LC are negligible. In both schemes, arrow thickness is proportional to the corresponding percentage of cells retrogradely labeled from the XII nucleus. (Data from Ref. modified from Fig. 4 in Ref. and republished with permission from Elsevier.)


Figure 16. Pathways transmitting activation from the hypothalamic wake‐active orexin neurons to orofacial motoneurons. Anatomical studies indicate that ACh, 5‐HT, and NE brainstem neurons as well as motoneurons, are among the major targets of axons descending from hypothalamic orexin‐containing neurons. However, physiological and pharmacological studies reveal that nonorexin cells located in the posterior hypothalamic orexinergic region also can significantly influence the respiratory output, including upper airway motoneurons. In particular, neither the combined antagonism of 5‐HT and NE‐mediated excitation at the XII nucleus level (), nor microinjections of a dual orexin receptor antagonist into the XII nucleus (), could significantly attenuate activation of XII motoneurons from the hypothalamic region containing orexin neurons. On the other hand, microinjections of a dual orexin receptor antagonist into the hypothalamic orexin cell field significantly attenuated activation of XII motoneurons from this hypothalamic region (). These results support the presence of an excitatory pathway that descends from the posterior hypothalamus parallel to the orexinergic pathway and targets different components of the respiratory system, including upper airway motoneurons. Additional connections may exist, such as nonorexinergic excitatory hypothalamo‐brainstem pathways to ACh, 5‐HT and NE neurons, and there may be additional orexinergic connections to central respiratory neurons, although specific details are not yet available. Cholinergic effects within the respiratory network may be excitatory or inhibitory (marked with yellow circles).


Figure 17. Effects of microdialysis perfusion of the XII nucleus region with different K+ channel blockers in chronically instrumented, behaving rats. (A) Perfusion with a solution containing barium ions, which primarily block the inwardly rectifying (Kir) channels, resulted in GG muscle activity being elevated in all sleep‐wake states and attaining the highest levels during wakefulness and REM sleep with muscle twitches (REM(+)). (B) During perfusion with an antagonist of the tandem pore domain (TASK) channels, methanandamide, activation was limited to wakefulness. (C) Perfusion with 4‐aminopyridine (4‐AP, a blocker of voltage‐dependent Kv4 channels) or TEA (a blocker of voltage‐dependent Kv2 channels) increased GG activity across all sleep‐wake states, with the strongest activation attained during REM sleep with twitches. Collectively, these experiments demonstrate that closure of certain K+ channels can elevate GG muscle activity during sleep to, or above, the levels seen during wakefulness. In all panels, integrated GG activity was measured during inspiration within different sleep‐wake states using arbitrary units while the XII nucleus region was perfused with a vehicle [artificial cerebrospinal fluid (ACSF) with or without an emulsificant] or with one of the blockers. Symbols in the graphs indicate statistically significant elevation of activity with the blocker when compared to vehicle. (Panels A‐C show Figs. 1E, 2B and 3C, respectively, from Ref. and are republished with permission from the American Academy of Sleep Medicine obtained via the Copyright Clearance Center, Inc.)


Figure 18. Summary of neurochemically distinct pathways that converge on upper airway motoneurons and determine the respiratory and sleep‐wake state‐dependent patterns of motoneuronal activity. Among the many excitatory pathways (shown on the left) the glutamatergic one mediates the respiratory drive, whereas the effects of all the remaining ones are likely to be wakefulness (or wakefulness and REM sleep) related. Among the inhibitory pathways (shown on the right), GABA, and glycine are especially important for shaping the reflex responses and rhythmic activities of orofacial motoneurons, whereas ACh may mediate pre‐ and postsynaptic, state‐dependent inhibitory effects through muscarinic (M) receptors [in addition to the excitatory effects of ACh mediated by nicotinic (N) receptors]. Additional state‐dependent and state‐independent presynaptic effects are exerted on the respiratory (glutamatergic) input to motoneurons by 5‐HT and GABA.


Figure 19. Upper airway muscle activity changes across sleep‐wake states have different patterns in healthy subjects and OSA subjects with anatomically compromised upper airway. The graph compares measurements obtained from recordings of sternohyoid muscle activity in English bulldogs, who present with OSA (especially during REM sleep), and in normal dogs (beagles). During wakefulness, sternohyoid EMG is higher in English bulldogs than in beagles. Furthermore, whereas in bulldogs sternohyoid EMG steadily declines from wakefulness to NREM sleep and then REM sleep, in beagles, there is a decline between wakefulness and NREM sleep and then an increase during REM sleep. The increase during REM sleep is similar to that in rats (), other healthy dogs (), cats (), and healthy humans (). (Graphical representation of numerical data in Ref. published as Fig. 3B in Ref. and republished with permission from Informa Healthcare, a member of the Taylor and Francis Group, obtained via the Copyright Clearance Center, Inc.)


Figure 20. Rats exposed to CIH have increased density of NE terminals in the ventromedial quadrant of the XII nucleus (top section) and increased endogenous excitatory drive to XII motoneurons mediated by α1‐adrenergic receptors (bottom section). (A1 and B1) Comparison of the appearance of NE‐containing terminals in 100 × 100 μm images of the ventromedial quadrant of the XII nucleus in a rat exposed to CIH for 35 days (A1) and a sham‐treated animal (B1). Also visible are several XII motoneurons retrogradely labeled from the base of the tongue (dark brown). (A2 and B2) Graphic renditions of all NE‐containing terminals found in the images shown in A1 and B1. Red dots indicate terminals that were closely apposed to the somatic membrane of retrogradely labeled XII motoneurons (gray), whereas black dots represent the remaining NE terminals. (C) Average numbers of NE terminals (immunostained for dopamine‐β‐hydroxylase) counted in 24 matched for the anteroposterior level pairs of brain sections from eight pairs of CIH/sham‐treated rats. (Panels A‐C modified from Fig. 2 and 3 in Ref. and republished with permission from the American Thoracic Society.) (D) Microinjections of the α1‐adrenergic receptor antagonist, prazosin (PZ), into the XII nucleus caused larger decrements of spontaneous XII nerve activity in anesthetized, paralyzed, and artificially ventilated rats that were earlier exposed to CIH for 35 days than in sham‐treated animals. (E) Prazosin injections did not cause any changes of the central respiratory rate. (Panels D and E modified from Fig. 3 in Ref. and republished with permission from the American Physiological Society.)
References
 1.Adachi M, Nonaka S, Katada A, Arakawa T, Ota R, Harada H, Takakusaki K, Harabuchi Y. Carbachol injection into the pontine reticular formation depresses laryngeal muscle activities and airway reflexes in decerebrate cats. Neurosci Res 67: 40‐50, 2010.
 2.Adachi T, Robinson DM, Miles GB, Funk GD. Noradrenergic modulation of XII motoneuron inspiratory activity does not involve α2‐receptor inhibition of the Ih current or presynaptic glutamate release. J Appl Physiol 98: 1297‐1308, 2005.
 3.Aghajanian GK, Sprouse JS, Sheldon P, Rasmussen K. Electrophysiology of the central serotonin system: Receptor subtypes and transducer mechanisms. Ann N Y Acad Sci 600: 93‐103, 1990.
 4.Agnati LF, Zoli M, Strömberg I, Fuxe K. Intercellular communication in the brain wiring versus volume transmission. Neuroscience 69: 711‐726, 1995.
 5.Ahmed WA, Tsutsumi M, Nakata S, Mori T, Nishimura Y, Fujisawa T, Kato I, Nakashima M, Kurahashi H, Suzuki K. A functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan. Laryngoscope 122: 925‐929, 2012.
 6.Al‐Zubaidy ZA, Erickson RL, Greer JJ. Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats. Pflügers Arch 431: 942‐949, 1996.
 7.Alam MN, McGinty D, Szymusiak R. Neuronal discharge of preoptic/anterior hypothalamic thermosensitive neurons: Relation to NREM sleep. Am J Physiol 269: R1240‐R1249, 1995.
 8.Alam MN, Kumar S, Bashir T, Suntsova N, Methippara MM, Szymusiak R, McGinty D. GABA‐mediated control of hypocretin‐ but not melanin‐concentrating hormone‐immunoreactive neurones during sleep in rats. J Physiol (Lond) 563: 569‐582, 2005.
 9.Aldes LD. Topographically organized projections from the nucleus subceruleus to the hypoglossal nucleus in the rat: A light and electron microscopic study with complementary axonal transport techniques. J Comp Neurol 302: 643‐656, 1990.
 10.Aldes LD, Chapman ME, Chronister RB, Haycock JW. Sources of noradrenergic afferents to the hypoglossal nucleus in the rat. Brain Res Bull 29: 931‐942, 1992.
 11.Aldes LD, Chronister RB, Shelton CI, Haycock JW, Marco LA, Wong DL. Catecholamine innervation of the rat hypoglossal nucleus. Brain Res Bull 21: 305‐312, 1988.
 12.Aldes LD, Chronister RC, Marco LA, Haycock JW, Thibault J. Differential distribution of biogenic amines in the hypoglossal nucleus of the rat. Exp Brain Res 73: 305‐314, 1988.
 13.Aldes LD, Marco LA, Chronister RB. Serotonin‐containing axon terminals in the hypoglossal nucleus of the rat. An immuno‐electronmicroscopic study. Brain Res Bull 23: 249‐256, 1989.
 14.Alheid GF, McCrimmon DR. The chemical neuroanatomy of breathing. Respir Physiol Neurobiol 164: 3‐11, 2008.
 15.Almendros I, Farre R, Planas AM, Torres M, Bonsignore MR, Navajas D, Montserrat JM. Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: Differential effect of obstructive apneas and intermittent hypoxia. Sleep 34: 1127‐1133, 2011.
 16.Altschuler SM, Bao X, Miselis RR. Dendritic architecture of hypoglossal motoneurons projecting to extrinsic tongue musculature in the rat. J Comp Neurol 342: 538‐550, 1994.
 17.Amis TC, O'Neill N, Wheatley JR, Van der Touw T, Di Somma E, Brancatisano A. Soft palate muscle response to negative upper airway pressure. J Appl Physiol 86: 523‐530, 1999.
 18.Anaclet C, Lin JS, Vetrivelan R, Krenzer M, Vong L, Fuller PM, Lu J. Identification and characterization of a sleep‐active cell group in the rostral medullary brainstem. J Neurosci 32: 17970‐17976, 2012.
 19.Anaclet C, Pedersen NP, Fuller PM, Lu J. Brainstem circuitry regulating phasic activation of trigeminal motoneurons during REM sleep. PLoS ONE 5: e8788, 2010. doi: 10.1371/journal.pone.0008788
 20.Anch AM, Remmers JE, Sauerland EK, DeGroot WJ. Oropharyngeal patency during waking and sleep in the Pickwickian syndrome: Electromyographic activity of the tensor veli palatini. EMG Clin Neurophysiol 21: 317‐330, 1981.
 21.Anderson CA, Dick TE, Orem J. Respiratory responses to tracheobronchial stimulation during sleep and wakefulness in the adult cat. Sleep 19: 472‐478, 1996.
 22.Arita H, Ochiishi M. Opposing effects of 5‐hydroxytryptamine on two types of medullary inspiratory neurons with distinct firing patterns. J Neurophysiol 66: 285‐292, 1991.
 23.Arita H, Sakamoto M, Hirokawa Y, Okado N. Serotonin innervation patterns differ among the various medullary motoneuronal groups involved in upper airway control. Exp Brain Res 95: 100‐110, 1993.
 24.Armstrong DM, Saper CB, Levey AI, Wainer BH, Terry RD. Distribution of cholinergic neurons in rat brain: Demonstrated by the immunocytochemical localization of choline acetyltransferase. J Comp Neurol 216: 53‐68, 1983.
 25.Arnulf I. The ‘scanning hypothesis’ of rapid eye movements during REM sleep: A review of the evidence. Arch Ital Biol 149: 367‐382, 2011.
 26.Aronson RM, Onal E, Carley DW, Lopata M. Upper airway and respiratory muscle responses to continuous negative airway pressure. J Appl Physiol 66: 1373‐1382, 1989.
 27.Arvidsson J, Cullheim S, Ulfhake B, Bennett GW, Fone KCF, Cuello AC, Verhofstad AAJ, Visser TJ, Hökfelt T. 5‐hydroxytryptamine, substance P, and thyrotropin‐releasing hormone in the adult cat spinal cord segment L7: Immunohistochemical and chemical studies. Synapse 6: 237‐270, 1990.
 28.Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 118: 273‐274, 1953.
 29.Aston‐Jones G, Bloom FE. Activity of norepinephrine‐containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep‐waking cycle. J Neurosci 1: 876‐886, 1981.
 30.Ayas NT, Hirsch AA, Laher I, Bradley TD, Malhotra A, Polotsky VY, Tasali E. New frontiers in obstructive sleep apnoea. Clin Sci 127: 209‐216, 2014.
 31.Badr MS, Kawak A, Skatrud JB, Morrell MJ, Zahn BR, Babcock MA. Effect of induced hypocapnic hypopnea on upper airway patency in humans during NREM sleep. Respir Physiol 110: 33‐45, 1997.
 32.Baghdoyan HA. Cholinergic mechanisms regulating REM sleep. In: Schwartz WJ, editor. Sleep Science: Integrating Basic Research and Clinical Practice. Basel: Karger, 1997.
 33.Baghdoyan HA. Location and quantification of muscarinic receptor subtypes in rat pons: Implications for REM sleep generation. Am J Physiol 273: R896‐R904, 1997.
 34.Bailey EF, Fregosi RF. Modulation of upper airway muscle activities by bronchopulmonary afferents. J Appl Physiol 101: 609‐617, 2006.
 35.Bailey EF, Fridel KW, Rice AD. Sleep/wake firing patterns of human genioglossus motor units. J Neurophysiol 98: 3284‐3291, 2007.
 36.Bailey TW, DiMicco JA. Chemical stimulation of the dorsomedial hypothalamus elevates plasma ACTH in conscious rats. Am J Physiol 280: R8‐R15, 2001.
 37.Barillot JC, Grèlot L, Reddad S, Bianchi AL. Discharge patterns of laryngeal motoneurones in the cat: An intracellular study. Brain Res 509: 99‐103, 1990.
 38.Bartlett D, Jr. Respiratory functions of the larynx. Physiol Rev 69: 33‐57, 1989.
 39.Bartlett D, Jr., Leiter JC. Coordination of breathing with nonrespiratory activities. Compr Physiol 2: 1387‐1415, 2012. doi: 10.1002/cphy.c110004
 40.Basner RC, Ringler J, Schwartzstein RM, Weinberger SE, Weiss JW. Phasic electromyographic activity of the genioglossus increases in normals during slow‐wave sleep. Respir Physiol 83: 189‐200, 1991.
 41.Bayliss DA, Viana F, Berger AJ. Mechanisms underlying excitatory effects of thyrotropin‐releasing hormone on rat hypoglossal motoneurons in vitro. J Neurophysiol 68: 1733‐1745, 1992.
 42.Bellemare F, Pecchiari M, Bandini M, Sawan M, D'Angelo E. Reversibility of airflow obstruction by hypoglossus nerve stimulation in anesthetized rabbits. Am J Respir Crit Care Med 172: 606‐612, 2005.
 43.Bellingham MC, Berger AJ. Presynaptic depression of excitatory synaptic inputs to rat hypoglossal motoneurons by muscarinic M2 receptors. J Neurophysiol 76: 3758‐3770, 1996.
 44.Berger AJ, Huynh P. Activation of 5HT1B receptors inhibits glycinergic synaptic inputs to mammalian motoneurons during postnatal development. Brain Res 956: 380‐384, 2002.
 45.Berry RB, Kouchi KG, Bower JL, Light RW. Effect of upper airway anesthesia on obstructive sleep apnea. Am J Respir Crit Care Med 151: 1857‐1861, 1995.
 46.Betschart C, Hintermann S, Behnke D, Cotesta S, Fendt M, Gee CE, Jacobson LH, Laue G, Ofner S, Chaudhari V, Badiger S, Pandit C, Wagner J, Hoyer D. Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia. J Med Chem 56: 7590‐7607, 2013.
 47.Bliwise DL, He L, Ansari FP, Rye DB. Quantification of electromyographic activity during sleep: A phasic electromyographic metric. J Clin Neurophysiol 23: 59‐67, 2006.
 48.Bochorishvili G, Nguyen T, Coates MB, Viar KE, Stornetta RL, Guyenet PG. The orexinergic neurons receive synaptic input from C1 cells in rats. J Comp Neurol 522: 3834‐38346, 2014. doi: 10.1002/cne.23643
 49.Böhmer G, Dinse HR, Fallert M, Sommer TJ. Microelectrophoretic application of antagonists of putative neurotransmitters onto various types of bulbar respiratory neurons. Arch Ital Biol 117: 13‐22, 1979.
 50.Boissard R, Fort P, Gervasoni D, Barbagli B, Luppi P‐H. Localization of the GABAergic and non‐GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset. Eur J Neurosci 18: 1627‐1639, 2003.
 51.Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, Luppi P‐H. The rat ponto‐medullary network responsible for paradoxical sleep onset and maintenance: A combined microinjection and functional neuroanatomical study. Eur J Neurosci 16: 1959‐1973, 2002.
 52.Bonora M, Bartlett D, Jr., Knuth SL. Changes in upper airway muscle activity related to head position in awake cats. Respir Physiol 60: 181‐192, 1985.
 53.Boucetta S, Cisse Y, Mainville L, Morales M, Jones BE. Discharge profiles across the sleep‐waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. J Neurosci 34: 4708‐4727, 2014.
 54.Bourgin P, Escourrou P, Gaultier C, Adrien J. Induction of rapid eye movement sleep by carbachol infusion into the pontine reticular formation in the rat. NeuroReport 6: 532‐536, 1995.
 55.Bourgin P, Huitrón‐Reséndiz S, Spier AD, Fabre V, Morte B, Criado JR, Sutcliffe JG, Henriksen SJ, de Lecea L. Hypocretin‐1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20: 7760‐7765, 2000.
 56.Bouryi VA, Lewis DI. The modulation by 5‐HT of glutamatergic inputs from the raphe pallidus to rat hypoglossal motoneurons in vitro. J Physiol (Lond) 553: 1019‐1031, 2003.
 57.Boyd JH, Petrof BJ, Hamid Q, Fraser R, Kimoff RJ. Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. Am J Respir Crit Care Med 170: 541‐546, 2004.
 58.Bradford A, McGuire M, O'Halloran KD. Does episodic hypoxia affect upper airway dilator muscle function? Implications for the pathophysiology of obstructive sleep apnoea. Respir Physiol Neurobiol 147: 223‐234, 2005.
 59.Bradley PB, Lucy AP. Cholinoceptive properties of respiratory neurones in the rat medulla. Neuropharmacology 22: 853‐858, 1983.
 60.Brandes IF, Stettner GM, Morschel M, Kubin L, Dutschmann M. REM sleep‐like episodes of motoneuronal depression and respiratory rate increase are triggered by pontine carbachol microinjections in in situ perfused rat brainstem preparation. Exp Physiol 96: 548‐555, 2011. doi: 10.1113/expphysiol.2010.056242
 61.Brennick MJ, Pack AI, Ko K, Kim E, Pickup S, Maislin G, Schwab RJ. Altered upper airway and soft tissue structures in the New Zealand obese mouse. Am J Respir Crit Care Med 179: 158‐169, 2009.
 62.Brisbare‐Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van GJ, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13: 150‐155, 2007.
 63.Brooks D, Horner RL, Kozar LF, Render‐Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension. J Clin Invest 99: 106‐109, 1997.
 64.Brooks PL, Peever JH. Glycinergic and GABAA‐mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J Neurosci 28: 3535‐3545, 2008.
 65.Brooks PL, Peever JH. Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis. J Neurosci 32: 9785‐9795, 2012.
 66.Brouillette RT, Thach BT. A neuromuscular mechanism maintaining extrathoracic airway patency. J Appl Physiol 46: 772‐779, 1979.
 67.Brown EC, Hudson AL, Butler JE, McKenzie DK, Bilston LE, Gandevia SC. Single motor unit recordings in human geniohyoid reveal minimal respiratory activity during quiet breathing. J Appl Physiol 110: 1054‐1059, 2011.
 68.Buckley NJ, Bonner TI, Brann MR. Localization of a family of muscarinic receptor mRNAs in rat brain. J Neurosci 8: 4646‐4652, 1988.
 69.Burgess C, Lai D, Siegel J, Peever J. An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep‐wake cycle. J Neurosci 28: 4649‐4660, 2008.
 70.Busquets X, Barbé F, Barceló A, de la Peña M, Sigritz N, Mayoralas LR, Ladaria A, Agustí A. Decreased plasma levels of orexin‐A in sleep apnea. Respiration 71: 575‐579, 2004.
 71.Cakirer B, Hans MG, Graham G, Aylor J, Tishler PV, Redline S. The relationship between craniofacial morphology and obstructive sleep apnea in whites and in African‐Americans. Am J Respir Crit Care Med 163: 947‐950, 2001.
 72.Campen MJ, Shimoda LA, O'Donnell CP. Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice. J Appl Physiol 99: 2028‐2035, 2005.
 73.Carberry JC, Hensen H, Fisher LP, Saboisky JP, Butler JE, Gandevia SC, Eckert DJ. Mechanisms contributing to the response of upper‐airway muscles to changes in airway pressure. J Appl Physiol 118: 1221‐1228, 2015.
 74.Carberry JC, Jordan AS, White DP, Wellman A, Eckert DJ. Upper airway collapsibility (Pcrit) and pharyngeal dilator muscle activity are sleep stage dependent. Sleep 39: 511‐521, 2016. doi: 10.5665/sleep.5516
 75.Cassell MD, Roberts L, Talman WT. Glycine‐containing terminals in the rat dorsal vagal complex. Neuroscience 50: 907‐920, 1992.
 76.Caulfield MP. Muscarinic receptors–characterization, coupling and function. Pharmacol Ther 58: 319‐379, 1993.
 77.Chaban R, Cole P, Hoffstein V. Site of upper airway obstruction in patients with idiopathic obstructive sleep apnea. Laryngoscope 98: 641‐647, 1988.
 78.Chadwick GA, Crowley P, Fitzgerald MX, O'Regan RG, McNicholas WT. Obstructive sleep apnea following topical oropharyngeal anesthesia in loud snorers. Am Rev Respir Dis 143: 810‐813, 1991.
 79.Chamberlin NL, Bocchiaro CM, Greene RW, Feldman JL. Nicotinic excitation of rat hypoglossal motoneurons. Neuroscience 115: 861‐870, 2002.
 80.Chamberlin NL, Eikermann M, Fassbender P, White DP, Malhotra A. Genioglossus premotoneurons and the negative pressure reflex in rats. J Physiol (Lond) 579: 515‐526, 2007.
 81.Champagnat J, Denavit‐Saubié M, Henry JL, Leviel V. Catecholaminergic depressant effects on bulbar respiratory mechanisms. Brain Res 160: 57‐68, 1979.
 82.Chan E, Steenland HW, Liu H, Horner RL. Endogenous excitatory drive modulating respiratory muscle activity across sleep‐wake states. Am J Respir Crit Care Med 174: 1264‐1273, 2006.
 83.Chandler SH, Chase MH, Nakamura Y. Intracellular analysis of synaptic mechanisms controlling trigeminal motoneuron activity during sleep and wakefulness. J Neurophysiol 44: 359‐371, 1980.
 84.Chang F.‐C.T. Modification of medullary respiratory‐related discharge patterns by behaviors and states of arousal. Brain Res 571: 281‐292, 1992.
 85.Chase MH, Morales F. The atonia and myoclonia of active (REM) sleep. Annu Rev Psychol 41: 557‐584, 1990.
 86.Chase MH, Soja PJ, Morales FR. Evidence that glycine mediates the postsynaptic potentials that inhibit lumbar motoneurons during the atonia of active sleep. J Neurosci 9: 743‐751, 1989.
 87.Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation. Cell 98: 437‐451, 1999.
 88.Chen H, Chatelain FC, Lesage F. Altered and dynamic ion selectivity of K+ channels in cell development and excitability. Trends Pharmacol Sci 35: 461‐469, 2014.
 89.Chen W, Ye J, Han D, Yin G, Wang B, Zhang Y. Association of prepro‐orexin polymorphism with obstructive sleep apnea/hypopnea syndrome. Am J Otolaryngol 33: 31‐36, 2012.
 90.Cheng S, Brown EC, Hatt A, Butler JE, Gandevia SC, Bilston LE. Healthy humans with a narrow upper airway maintain patency during quiet breathing by dilating the airway during inspiration. J Physiol (Lond) 592: 4763‐4774, 2014.
 91.Chokroverty S. Phasic tongue movements in human rapid‐eye‐movement sleep. Neurology 30: 665‐668, 1980.
 92.Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, Beuckmann CT, Chemelli RM, Sakurai T, Yanagisawa M, Saper CB, Scammell TE. Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21: RC168 (1-6), 2001.
 93.Clement O, Sapin E, Berod A, Fort P, Luppi P‐H. Evidence that neurons of the sublaterodorsal tegmental nucleus triggering paradoxical (REM) sleep are glutamatergic. Sleep 34: 419‐423, 2011.
 94.Corcoran A, Richerson G, Harris M. Modulation of respiratory activity by hypocretin‐1 (orexin A) in situ and in vitro. Adv Exp Med Biol 669: 109‐113, 2010.
 95.D'Adamo MC, Servettini I, Guglielmi L, Di MV, Di MR, Di GG, Pessia M. 5‐HT2 receptors‐mediated modulation of voltage‐gated K+ channels and neurophysiopathological correlates. Exp Brain Res 230: 453‐462, 2013.
 96.Davis EM, O'Donnell CP. Rodent models of sleep apnea. Respir Physiol Neurobiol 188: 355‐361, 2013.
 97.Day HEW, Campeau S, Watson SJ, Jr., Akil H. Distribution of α1a‐ α1b‐ and α1d‐adrenergic receptor mRNA in the rat brain and spinal cord. J Chem Neuroanat 13: 115‐139, 1997.
 98.Deegan PC, Mulloy E, McNicholas WT. Topical oropharyngeal anesthesia in patients with obstructive sleep apnea. Am J Respir Crit Care Med 151: 1108‐1112, 1995.
 99.Dematteis M, Godin‐Ribuot D, Arnaud C, Ribuot C, Stanke‐Labesque F, Pepin JL, Levy P. Cardiovascular consequences of sleep‐disordered breathing: Contribution of animal models to understanding the human disease. ILAR J 50: 262‐281, 2009.
 100.Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev 90: 47‐112, 2010.
 101.Deng BS, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T. Contribution of orexin in hypercapnic chemoreflex: Evidence from genetic and pharmacological disruption and supplementation studies in mice. J Appl Physiol 103: 1772‐1779, 2007.
 102.Deschenes M, Haidarliu S, Demers M, Moore J, Kleinfeld D, Ahissar E. Muscles involved in naris dilation and nose motion in rat. Anat Rec (Hoboken, N J) 298: 546‐553, 2015.
 103.Detari L, Rasmusson DD, Semba K. Phasic relationship between the activity of basal forebrain neurons and cortical EEG in urethane‐anesthetized rat. Brain Res 759: 112‐121, 1997.
 104.DeWeese EL, Sullivan TY. Effects of upper airway anesthesia on pharyngeal patency during sleep. J Appl Physiol 64: 1346‐1353, 1988.
 105.Dias MB, Li A, Nattie E. Focal CO2 dialysis in raphe obscurus does not stimulate ventilation but enhances the response to focal CO2 dialysis in the retrotrapezoid nucleus. J Appl Physiol 105: 83‐90, 2008.
 106.Dias MB, Li A, Nattie EE. Antagonism of orexin receptor‐1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness. J Physiol (Lond) 587: 2059‐2067, 2009.
 107.Dick TE, Bellingham MC, Richter DW. Pontine respiratory neurons in anesthetized cats. Brain Res 636: 259‐269, 1994.
 108.DiMicco JA, Abshire VM, Hankins KD, Sample RH, Wible JH, Jr. Microinjection of GABA antagonists into posterior hypothalamus elevates heart rate in anesthetized rats. Neuropharmacology 25: 1063‐1066, 1986.
 109.Dobbins EG, Feldman JL. Differential innervation of protruder and retractor muscles of the tongue in rat. J Comp Neurol 357: 376‐394, 1995.
 110.Doherty LS, Nolan P, McNicholas WT. Effects of topical anesthesia on upper airway resistance during wake‐sleep transitions. J Appl Physiol 99: 549‐555, 2005.
 111.Dotan Y, Pillar G, Schwartz AR, Oliven A. Asynchrony of lingual muscle recruitment during sleep in obstructive sleep apnea. J Appl Physiol 118: 1516‐1524, 2015.
 112.Douglas NJ, Jan MA, Yildirim N, Warren PM, Drummond GB. Effect of posture and breathing route on genioglossal electromyogram activity in normal subjects and in patients with the sleep apnea/hypopnea syndrome. Am Rev Respir Dis 148: 1341‐1345, 1993.
 113.Douse MA, White DP. Serotonergic effects on hypoglossal neural activity and reflex responses. Brain Res 726: 213‐222, 1996.
 114.Duffin J. Functional organization of respiratory neurones: A brief review of current questions and speculations. Exp Physiol 89: 517‐529, 2004.
 115.Dun NJ, Dun SL, Chen CT, Hwang LL, Kwok EH, Chang JK. Orexins: A role in medullary sympathetic outflow. Reg Pept 96: 65‐70, 2000.
 116.Duncan JR, Paterson DS, Hoffman JM, Mokler DJ, Borenstein NS, Belliveau RA, Krous HF, Haas EA, Stanley C, Nattie EE, Trachtenberg FL, Kinney HC. Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA 303: 430‐437, 2010.
 117.Dunin‐Barkowski WL, Orem JM. Suppression of diaphragmatic activity during spontaneous ponto‐geniculo‐occipital waves in cat. Sleep 21: 671‐675, 1998.
 118.Dutschmann M, Dick TE. Pontine mechanisms of respiratory control. Compr Physiol 2: 2443‐2469, 2012. doi: 10.1002/cphy.c100015
 119.Eastwood PR, Allison GT, Shepherd KL, Szollosi I, Hillman DR. Heterogeneous activity of the human genioglossus muscle assessed by multiple bipolar fine‐wire electrodes. J Appl Physiol 94: 1849‐1858, 2003.
 120.Eckert DJ, Malhotra A, Lo YL, White DP, Jordan AS. The influence of obstructive sleep apnea and gender on genioglossus activity during rapid eye movement sleep. Chest 135: 957‐964, 2009.
 121.Economo C von. Sleep as a problem of localization. J Nerv Ment Dis 71: 249‐259, 1930.
 122.Edge D, Bradford A, Jones JF, O'Halloran KD. Chronic intermittent hypoxia alters genioglossus motor unit discharge patterns in the anaesthetized rat. Adv Exp Med Biol 758: 295‐300, 2012.
 123.Edge D, McDonald FB, Jones JF, Bradford A, O'Halloran KD. Effect of chronic intermittent hypoxia on the reflex recruitment of the genioglossus during airway obstruction in the anesthetized rat. Progr Brain Res 209: 147‐168, 2014.
 124.Edstrom L, Larsson H, Larsson L. Neurogenic effects on the palatopharyngeal muscle in patients with obstructive sleep apnoea: A muscle biopsy study. J Neurol Neurosur Psych 55: 916‐920, 1992.
 125.Edwards E, Paton JFR. 5‐HT4 receptors in nucleus tractus solitarii attenuate cardiopulmonary reflex in anesthetized rats. Am J Physiol 277: H1914‐H1923, 1999.
 126.Edwards E, Paton JFR. Glutamate stimulation of raphe pallidus attenuates the cardiopulmonary reflex in anaesthetised rats. Auton Neurosci Bas Clin 82: 87‐96, 2000.
 127.El Mansari M, Sakai K, Jouvet M. Unitary characteristics of presumptive cholinergic tegmental neurons during the sleep‐waking cycle in freely moving cats. Exp Brain Res 76: 519‐529, 1989.
 128.Euler C von. Brain stem mechanisms for generation and control of breathing pattern. Compr Physiol 2011 (Suppl. 11): 1‐67.
 129.Ezure K. Reflections on respiratory rhythm generation. Progr Brain Res 143: 67‐74, 2004.
 130.Farre R, Nacher M, Serrano‐Mollar A, Galdiz JB, Alvarez FJ, Navajas D, Montserrat JM. Rat model of chronic recurrent airway obstructions to study the sleep apnea syndrome. Sleep 30: 930‐933, 2007.
 131.Fay R, Kubin L. Pontomedullary distribution of 5‐HT2A receptor‐like protein in the rat. J Comp Neurol 418: 323‐345, 2000.
 132.Fay RA, Norgren R. Identification of rat brainstem multisynaptic connections to the oral motor nuclei using pseudorabies virus III. Lingual muscle motor systems. Brain Res Rev 25: 291‐311, 1997.
 133.Feldman JL, Mitchell GS, Nattie EE. Breathing: Rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26: 239‐266, 2003.
 134.Fenik VB. Revisiting antagonist effects in hypoglossal nuleus: Brainstem circuit for the state‐dependent control of hypoglossal motoneurons: A hypothesis. Front Neurol 6: 254, 2015. doi: 10.3389/fneur.2015.00254
 135.Fenik P, Ogawa H, Veasey SC. Hypoglossal nerve response to 5‐HT3 drugs injected into the XII nucleus and vena cava in the rat. Sleep 24: 871‐878, 2001.
 136.Fenik P, Veasey SC. Pharmacological characterization of serotonergic receptor activity in the hypoglossal nucleus. Am J Respir Crit Care Med 167: 563‐569, 2003.
 137.Fenik V, Davies RO, Kubin L. Combined antagonism of aminergic excitatory and amino acid inhibitory receptors in the XII nucleus abolishes REM sleep‐like depression of hypoglossal motoneuronal activity. Arch Ital Biol 142: 237‐249, 2004.
 138.Fenik V, Davies RO, Pack AI, Kubin L. Differential suppression of upper airway motor activity during carbachol‐induced, REM sleep‐like atonia. J Appl Physiol 275: R1013‐R1024, 1998.
 139.Fenik V, Kubin L, Okabe S, Pack AI, Davies RO. Differential sensitivity of laryngeal and pharyngeal motoneurons to iontophoretic application of serotonin. Neuroscience 81: 873‐885, 1997.
 140.Fenik V, Marchenko V, Janssen P, Davies RO, Kubin L. A5 cells are silenced when REM sleep‐like signs are elicited by pontine carbachol. J Appl Physiol 93: 1448‐1456, 2002.
 141.Fenik VB, Davies RO, Kubin L. Noradrenergic, serotonergic and GABAergic antagonists injected together into the XII nucleus abolish the REM sleep‐like depression of hypoglossal motoneuronal activity. J Sleep Res 14: 419‐429, 2005.
 142.Fenik VB, Davies RO, Kubin L. REM sleep‐like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 172: 1322‐1330, 2005.
 143.Fenik VB, Kubin L. Differential localization of carbachol‐ and bicuculline‐sensitive pontine sites for eliciting REM sleep‐like effects in anesthetized rats. J Sleep Res 18: 99‐112, 2009.
 144.Fenik VB, Marchenko V, Davies RO, Kubin L. Inhibition of A5 neurons facilitates the occurrence of REM sleep‐like episodes in urethane‐anesthetized rats: A new role for noradrenergic A5 neurons? Front Neurol 3: 119, 2012. doi: 10.3389/fneur.2012.00119
 145.Fenik VB, Ogawa H, Davies RO, Kubin L. Carbachol injections into the ventral pontine reticular formation activate locus coeruleus cells in urethane‐anesthetized rats. Sleep 28: 551‐559, 2005.
 146.Fenik VB, Rukhadze I, Kubin L. Inhibition of pontine noradrenergic A7 cells reduces hypoglossal nerve activity in rats. Neuroscience 157: 473‐482, 2008.
 147.Fenik VB, Rukhadze I, Kubin L. Antagonism of α1‐adrenergic and serotonergic receptors in the hypoglossal motor nucleus does not prevent motoneuronal activation elicited from the posterior hypothalamus. Neurosci Lett 462: 80‐84, 2009.
 148.Fenik VB, Singletary T, Branconi JL, Davies RO, Kubin L. Glucoregulatory consequences and cardiorespiratory parameters in rats exposed to chronic‐intermittent hypoxia: Effects of the duration of exposure and losartan. Front Neurol 3: 51, 2012. doi: 10.3389/fneur.2012.00051
 149.Fletcher EC. Sympathetic activity and blood pressure in the sleep apnea syndrome. Respiration 64 (Suppl 1): 22‐28, 1997.
 150.Fletcher EC. Invited review. Physiological consequences of intermittent hypoxia: Systemic blood pressure. J Appl Physiol 90: 1600‐1605, 2001.
 151.Fletcher EC, Bao G, Li R. Renin activity and blood pressure in response to chronic episodic hypoxia. Hypertension 34: 309‐314, 1999.
 152.Fogel RB, Malhotra A, Pillar G, Edwards JK, Beauregard J, Shea SA, White DP. Genioglossal activation in patients with obstructive sleep apnea versus control subjects. Mechanisms of muscle control. Am J Respir Crit Care Med 164: 2025‐2030, 2001.
 153.Fogel RB, Trinder J, Malhotra A, Stanchina M, Edwards JK, Schory KE, White DP. Within‐breath control of genioglossal muscle activation in humans: Effect of sleep‐wake state. J Physiol (Lond) 550: 899‐910, 2003.
 154.Fort P, Luppi P‐H, Sakai K, Salvert D, Jouvet M. Nuclei of origin of monoaminergic, peptidergic, and cholinergic afferents to the cat trigeminal motor nucleus: A double‐labeling study with cholera‐toxin as a retrograde tracer. J Comp Neurol 301: 262‐275, 1990.
 155.Fort P, Sakai K, Luppi P‐H, Salvert D, Jouvet M. Monoaminergic, peptidergic, and cholinergic afferents to the cat facial nucleus as evidenced by a double immunostaining method with unconjugated cholera toxin as a retrograde tracer. J Comp Neurol 283: 285‐302, 1989.
 156.Foutz AS, Boudinot E, Morin‐Surun M‐P, Champagnat J, Gonsalves SF, Denavit‐Saubié M. Excitability of' “silent” respiratory neurons during sleep‐waking states: An iontophoretic study in undrugged chronic cats. Brain Res 404: 10‐20, 1987.
 157.Fraigne JJ, Orem JM. Phasic motor activity of respiratory and non‐respiratory muscles in REM sleep. Sleep 34: 425‐434, 2011.
 158.Friberg D, Ansved T, Borg K, Carlsson‐Norlander B, Larsson H, Svanborg E. Histological indications of a progressive snorers disease in the upper airway muscles. Am J Respir Crit Care Med 157: 586‐593, 1998.
 159.Fuller DD, Williams JS, Janssen PL, Fregosi RF. Effect of co‐activation of tongue protrudor and retractor muscles on tongue movements and pharyngeal airflow mechanics in the rat. J Physiol (Lond) 519: 601‐613, 1999.
 160.Fung SJ, Chase MH. Postsynaptic inhibition of hypoglossal motoneurons produces atonia of the genioglossal muscle during rapid eye movement sleep. Sleep 38: 139‐146, 2015.
 161.Fung SJ, Yamuy J, Sampogna S, Morales FR, Chase MH. Hypocretin (orexin) input to trigeminal and hypoglossal motoneurons in the cat: A double‐labeling immunohistochemical study. Brain Res 903: 257‐262, 2001.
 162.Fung SJ, Yamuy J, Xi MC, Engelhardt JK, Morales FR, Chase MH. Changes in electrophysiological properties of cat hypoglossal motoneurons during carbachol‐induced motor inhibition. Brain Res 885: 262‐272, 2000.
 163.Funk GD. Neuromodulation: Purinergic signaling in respiratory control. Compr Physiol 3: 331‐363, 2013. doi: 10.1002/cphy.c120004
 164.Funk GD, Smith JC, Feldman JL. Generation and transmission of respiratory oscillations in medullary slices: Role of excitatory amino acids. J Neurophysiol 70: 1497‐1515, 1993.
 165.Funk GD, Smith JC, Feldman JL. Development of thyrotropin‐releasing hormone and norepinephrine potentiation of inspiratory‐related hypoglossal motoneuron discharge in neonatal and juvenile mice in vitro. J Neurophysiol 72: 2538‐2541, 1994.
 166.Gallego J. Genetic diseases: Congenital central hypoventilation, Rett, and Prader‐Willi syndromes. Compr Physiol 2: 2255‐2279, 2012. doi: 10.1002/cphy.c100037
 167.Gatti PJ, Llewellyn‐Smith IJ, Sun QJ, Chalmers D, Pilowsky P. Substance P‐immunoreactive boutons closely appose inspiratory protruder hypoglossal motoneurons in the cat. Brain Res 834: 155‐159, 1999.
 168.Glenn LL, Dement WC. Membrane potential, synaptic activity, and excitability of hindlimb motoneurons during wakefulness and sleep. J Neurophysiol 46: 839‐854, 1981.
 169.Goutagny R, Luppi P‐H, Salvert D, Lapray D, Gervasoni D, Fort P. Role of the dorsal paragigantocellular reticular nucleus in paradoxical (rapid eye movement) sleep generation: A combined electrophysiological and anatomical study in the rat. Neuroscience 152: 849‐857, 2008.
 170.Grace KP, Hughes SW, Horner RL. Identification of the mechanism mediating genioglossus muscle suppression in REM sleep. Am J Respir Crit Care Med 187: 311‐319, 2013.
 171.Grace KP, Hughes SW, Horner RL. Identification of a pharmacological target for genioglossus reactivation throughout sleep. Sleep 37: 41‐50, 2014.
 172.Grace KP, Hughes SW, Shahabi S, Horner RL. K+ channel modulation causes genioglossus inhibition in REM sleep and is a strategy for reactivation. Respir Physiol Neurobiol 188: 277‐288, 2013.
 173.Grahn DA, Radeke CM, Heller HC. Arousal state vs. temperature effects on neuronal activity in subcoeruleus area. Am J Physiol 256: R840‐R849, 1989.
 174.Greenberg HE, Sica AL, Scharf SM, Ruggiero DA. Expression of c‐fos in the rat brainstem after chronic intermittent hypoxia. Brain Res 816: 638‐645, 1999.
 175.Guilleminault C, Akhtar F. Pediatric sleep‐disordered breathing: New evidence on its development. Sleep Med Rev 24: 46‐56, 2015.
 176.Guyenet PG. Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 4: 1511‐1562, 2014. doi: 10.1002/cphy.c140004
 177.Guyenet PG, Abbott SB, Stornetta RL. The respiratory chemoreception conundrum: Light at the end of the tunnel? Brain Res 1511: 126‐137, 2013.
 178.Guyenet PG, Stornetta RL, Bayliss DA. Retrotrapezoid nucleus and central chemoreception. J Physiol (Lond) 586: 2043‐2048, 2008.
 179.Haji A, Furuichi S, Takeda R. Effects on iontophoretically applied acetylcholine on membrane potential and synaptic activity of bulbar respiratory neurones in decerebrate cats. Neuropharmacology 35: 195‐203, 1996.
 180.Haji A, Takeda R, Okazaki M. Neuropharmacology of control of respiratory rhythm and pattern in mature mammals. Pharmacol Ther 86: 277‐304, 2000.
 181.Hajnik T, Lai YY, Siegel JM. Atonia‐related regions in the rodent pons and medulla. J Neurophysiol 84: 1942‐1948, 2000.
 182.Hamrahi H, Chan B, Horner RL. On‐line detection of sleep‐wake states and application to produce intermittent hypoxia only in sleep in rats. J Appl Physiol 90: 2130‐2140, 2001.
 183.Hamrahi H, Stephenson R, Mahamed S, Liao KS, Horner RL. Regulation of sleep‐wake states in response to intermittent hypoxic stimuli applied only in sleep. J Appl Physiol 90: 2490‐2501, 2001.
 184.Han F, Mignot E, Wei YC, Dong SX, Li J, Lin L, An P, Wang LH, Wang JS, He MZ, Gao HY, Li M, Gao ZC, Strohl KP. Ventilatory chemoresponsiveness, narcolepsy‐cataplexy and human leukocyte antigen DQB1*0602 status. Eur Respir J 36: 577‐583, 2010.
 185.Harasawa Y, Inoue M, Ariyasinghe S, Yamamura K, Yamada Y. Changes in reflex responses of the genioglossus muscle during sleep in rabbits. Brain Res 1065: 79‐85, 2005.
 186.Harms CA, Zeng Y‐J, Smith CA, Vidruk EH, Dempsey JA. Negative pressure‐induced deformation of the upper airway causes central apnea in awake and sleeping dogs. J Appl Physiol 80: 1528‐1539, 1996.
 187.Harper RM, Sieck GC. Discharge correlations between neurons in the nucleus parabrachialis medialis during sleep‐waking states. Brain Res 199: 343‐358, 1980.
 188.Haxhiu MA, van Lunteren E, Mitra J, Cherniack NS. Comparison of the response of diaphragm and upper airway dilating muscle activity in sleeping cats. Respir Physiol 70: 183‐193, 1987.
 189.Helke CJ, Shults CW, Chase TN, O'Donohue TL. Autoradiographic localization of substance P receptors in rat medulla: Effect of vagotomy and nodose ganglionectomy. Neuroscience 12: 215‐223, 1984.
 190.Hendricks JC, Kline LR, Kovalski RJ, O'Brien JA, Morrison AR, Pack AI. The English bulldog: A natural model of sleep‐disordered breathing. J Appl Physiol 63: 1344‐1350, 1987.
 191.Hendricks JC, Petrof BJ, Panckeri K, Pack AI. Upper airway dilating muscle hyperactivity during non‐rapid eye movement sleep in English bulldogs. Am Rev Respir Dis 148: 185‐194, 1993.
 192.Henke KG. Upper airway muscle activity and upper airway resistance in young adults during sleep. J Appl Physiol 84: 486‐491, 1998.
 193.Henke KG, Badr MS, Skatrud JB, Dempsey JA. Load compensation and respiratory muscle function during sleep. J Appl Physiol 72: 1221‐1234, 1992.
 194.Henke KG, Sullivan CE. Effects of high‐frequency oscillating pressures on upper airway muscles in humans. J Appl Physiol 75: 856‐862, 1993.
 195.Henry JN, Manaker S. Colocalization of substance P or enkephalin in serotonergic neuronal afferents to the hypoglossal nucleus in the rat. J Comp Neurol 391: 491‐505, 1998.
 196.Hieble JP, Bylund DB, Clarke DE, Eikenburg DC, Langer SZ, Lefkowitz RJ, Minneman KP, RuffoloRR, Jr. International union of pharmacology. X. Recommendation for nomenclature of a1‐adrenoceptors: Consensus update. Pharmacol Rev 47: 267‐270, 1995.
 197.Hinrichsen CFL, Weston S. Substance P in the hypoglossal nucleus of the rat. Arch Oral Biol 44: 683‐691, 1999.
 198.Hlavac MC, Catcheside PG, Adams A, Eckert DJ, McEvoy RD. The effects of hypoxia on load compensation during sustained incremental resistive loading in patients with obstructive sleep apnea. J Appl Physiol 103: 234‐239, 2007.
 199.Hodges MR, Tattersall GJ, Harris MB, McEvoy SD, Richerson DN, Deneris ES, Johnson RL, Chen ZF, Richerson GB. Defects in breathing and thermoregulation in mice with near‐complete absence of central serotonin neurons. J Neurosci 28: 2495‐2505, 2008.
 200.Hökfelt T, Fuxe K, Johansson O, Jeffcoate S, White N. Distribution of thyrotropin‐releasing hormone (TRH) in the central nervous system as revealed with immunohistochemistry. Eur J Pharmacol 34: 389‐392, 1975.
 201.Hökfelt T, Johansson O, Goldstein M. Chemical anatomy of the brain. Science 225: 1326‐1334, 1984.
 202.Holmes CJ, Jones BE. Importance of cholinergic, GABAergic, serotonergic and other neurons in the medial medullary reticular formation for sleep‐wake states studied by cytotoxic lesions in the cat. Neuroscience 62: 1179‐1200, 1994.
 203.Holmes CJ, Mainville LS, Jones BE. Distribution of cholinergic, GABAergic and serotonergic neurons in the medial medullary reticular formation and their projections studied by cytotoxic lesions in the cat. Neuroscience 62: 1155‐1178, 1994.
 204.Holtman JR, Jr. Immunohistochemical localization of serotonin‐ and substance P‐containing fibers around respiratory muscle motoneurons in the nucleus ambiguus of the cat. Neuroscience 26: 169‐178, 1988.
 205.Holtman JR, Jr., Marion LJ, Speck DF. Origin of serotonin‐containing projections to the ventral respiratory group in the rat. Neuroscience 37: 541‐552, 1990.
 206.Horner RL. Neural control of the upper airway: Integrative physiological mechanisms and relevance for sleep disordered breathing. Compr Physiol 2: 2012, 2012. doi: 10.1002/cphy.c110023
 207.Horner RL, Hughes SW, Malhotra A. State‐dependent and reflex drives to the upper airway: Basic physiology with clinical implications. J Appl Physiol 116: 325‐336, 2014. doi: 10.1152/japplphysiol.00531.2013
 208.Horner RL, Innes JA, Holden HB, Guz A. Afferent pathwyas for pharynyeal dilator reflex to negative pressure in man: A study using upper airway anaesthesia. J Physiol (Lond) 436: 31‐44, 1991.
 209.Horner RL, Innes JA, Morrell MJ, Shea SA, Guz A. The effect of sleep on reflex genioglossus muscle activation by stimuli of negative airway pressure in humans. J Physiol (Lond) 476: 141‐151, 1994.
 210.Horner RL, Kozar LF, Kimoff RJ, Phillipson EA. Effects of sleep on the tonic drive to respiratory muscle and the threshold for rhythm generation in the dog. J Physiol (Lond) 474: 525‐537, 1994.
 211.Horner RL, Liu X, Gill H, Nolan P, Liu H, Sood S. Effects of sleep‐wake state on the genioglossus vs. diaphragm muscle response to CO2 in rats. J Appl Physiol 92: 878‐887, 2002.
 212.Horvath TL, Peyron C, Diano S, Ivanov A, Aston‐Jones G, Kilduff TS, van den Pol AN. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415: 145‐159, 1999.
 213.Hoyer D, Martin G. 5‐HT receptor classification and nomenclature: Towards a harmonization with the human genome. Neuropharmacology 36: 419‐428, 1997.
 214.Huangfu D, Guyenet PG. Alpha 2‐adrenergic autoreceptors in A5 and A6 neurons of neonate rats. Am J Physiol 273: H2290‐H2295, 1997.
 215.Huangfu D, Koshiya N, Guyenet PG. Central respiratory modulation of facial motoneurons in rats. Neurosci Lett 151: 224‐228, 1993.
 216.Hudgel DW. Variable site of airway narrowing among obstructive sleep apnea patients. J Appl Physiol 61: 1403‐1409, 1986.
 217.Hudgel DW, Harasick T. Fluctuation in timing of upper airway and chest wall inspiratory muscle activity in obstructive sleep apnea. J Appl Physiol 69: 443‐450, 1990.
 218.Hunter JD, Milsom WK. Cortical activation states in sleep and anesthesia. I. Cardio‐respiratory effects. Respir Physiol 112: 71‐81, 1998.
 219.Hwang J‐C, St. John WM, Bartlett D, Jr. Afferent pathways for hypoglossal and phrenic responses to changes in upper airway pressure. Respir Physiol 55: 341‐354, 1984.
 220.Iigaya K, Horiuchi J, McDowall LM, Lam AC, Sediqi Y, Polson JW, Carrive P, Dampney RA. Blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro‐ or chemoreceptor reflex responses. Am J Physiol 303: R1011‐R1022, 2012.
 221.Ireland MF, Funk GD, Bellingham MC. Muscarinic acetylcholine receptors enhance neonatal mouse hypoglossal motoneuron excitability in vitro. J Appl Physiol 113: 1024‐1039, 2012.
 222.Ireland MF, Lenal FC, Lorier AR, Loomes DE, Adachi T, Alvares TS, Greer JJ, Funk GD. Distinct receptors underlie glutamatergic signalling in inspiratory rhythm‐generating networks and motor output pathways in neonatal rat. J Physiol (Lond) 586: 2357‐2370, 2008.
 223.Iscoe SD. Central control of the upper airway. In: Mathew OP, Sant'Ambrogio G, editors. Respiratory Function of the Upper Airway. New York, Marcel Dekker, 1988.
 224.Issa FG, Bitner S. Effect of route of breathing on the ventilatory and arousal responses to hypercapnia in awake and sleeping dogs. J Physiol (Lond) 465: 615‐628, 1993.
 225.Issa FG, Edwards P, Szeto E, Lauff D, Sullivan C. Genioglossus and breathing responses to airway occlusion: Effect of sleep and route of occlusion. J Appl Physiol 64: 543‐549, 1988.
 226.Issa FG, Sullivan CE. Upper airway closing pressures in obstructive sleep apnea. J Appl Physiol 57: 520‐527, 1984.
 227.Itier V, Bertrand D. Neuronal nicotinic receptors: From protein structure to function. FEBS Lett 504: 118‐125, 2001.
 228.Ivanov A, Aston‐Jones G. Hypocretin/orexin depolarizes and decreases potassium conductance in locus coeruleus neurons. NeuroReport 11: 1755‐1758, 2000.
 229.Iverfeldt K, Serfözö P, Diaz Arnesto L, Bartfai T. Differential release of coexisting neurotransmitters: Frequency dependence of the efflux of substance P, thyrotropin releasing hormone and [3H]serotonin from tissue slices of rat ventral spinal cord. Acta Physiol Scand 137: 63‐71, 1989.
 230.Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev 72: 165‐229, 1992.
 231.Janczewski WA, Feldman JL. Distinct rhythm generators for inspiration and expiration in the juvenile rat. J Physiol (Lond) 570: 407‐420, 2006.
 232.Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol 3: 141‐163, 2013. doi: 10.1002/cphy.c110057
 233.Jelev A, Sood S, Liu H, Nolan P, Horner RL. Microdialysis perfusion of 5‐HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep‐wake states in rats. J Physiol (Lond) 532: 467‐481, 2001.
 234.John J, Wu MF, Boehmer LN, Siegel JM. Cataplexy‐active neurons in the hypothalamus: Implications for the role of histamine in sleep and waking behavior. Neuron 42: 619‐634, 2004.
 235.Johnson H, Ulfhake B, Dagerlind A, Bennett GW, Fone KC. The serotoninergic bulbospinal system and brainstem‐spinal cord content of serotonin‐, TRH, and substance P‐like immunoreactivity in the aged rat with special reference to the spinal cord motor nucleus. Synapse 15: 63‐89, 1993.
 236.Johnson SM, Smith JC, Feldman JL. Modulation of respiratory rhythm in vitro: Role of Gi/o protein‐mediated mechanisms. J Appl Physiol 80: 2120‐2133, 1996.
 237.Jones BE, Beaudet A. Distribution of acetylcholine and catecholamine neurons in the cat brainstem: A choline acetyltransferase and tyrosine hydroxylase immunohistochemical study. J Comp Neurol 261: 15‐32, 1987.
 238.Kachidian P, Poulat P, Marlier L, Privat A. Immunohistochemical evidence for the coexistence of substance P, thyrotropin‐releasing hormone, GABA, methionin‐enkephalin, and leucin‐enkephalin in the serotonergic neurons of the caudal raphe nuclei: A dual labeling in the rat. J Neurosci Res 30: 521‐530, 1991.
 239.Kalia M, Fuxe K, Goldstein M. Rat medulla oblongata. II. Dopaminergic, noradrenergic (A1 and A2) and adrenergic neurons, nerve fibers, and presumptive terminal processes. J Comp Neurol 233: 308‐332, 1985.
 240.Kalia M, Fuxe K, Goldstein M. Rat medulla oblongata. III. Adrenergic (C1 and C2) neurons, nerve fibers and presumptive terminal processes. J Comp Neurol 233: 333‐349, 1985.
 241.Kam K, Worrell JW, Janczewski WA, Cui Y, Feldman JL. Distinct inspiratory rhythm and pattern generating mechanisms in the pre‐Bötzinger complex. J Neurosci 33: 9235‐9245, 2013.
 242.Kanamori N, Sakai K, Jouvet M. Neuronal activity specific to paradoxical sleep in the ventromedial medullary reticular formation of unrestrained cats. Brain Res 189: 251‐255, 1980.
 243.Karlsson KA, Blumberg MS. Active medullary control of atonia in week‐old rats. Neuroscience 130: 275‐283, 2005.
 244.Katakura N, Chandler SH. An iontophoretic analysis of the pharmacologic mechanisms responsible for trigeminal motoneuronal discharge during masticatory‐like activity in the guinea pig. J Neurophysiol 63: 356‐369, 1990.
 245.Kato T, Masuda Y, Morimoto T. Patterns of masseter muscle activities during sleep in guinea pigs. Arch Oral Biol 52: 385‐386, 2007.
 246.Katz ES, White DP. Genioglossus activity in children with obstructive sleep apnea during wakefulness and sleep onset. Am J Respir Crit Care Med 168: 664‐670, 2003.
 247.Katz ES, White DP. Genioglossus activity during sleep in normal control subjects and children with obstructive sleep apnea. Am J Respir Crit Care Med 170: 553‐560, 2004.
 248.Kay A, Trinder J, Bowes G, Kim Y. Changes in airway resistance during sleep onset. J Appl Physiol 76: 1600‐1607, 1994.
 249.Kayama Y, Ohta M, Jodo E. Firing of ‘possibly’ cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness. Brain Res 569: 210‐220, 1992.
 250.Kezirian EJ, Goding GS, Jr., Malhotra A, O'Donoghue FJ, Zammit G, Wheatley JR, Catcheside PG, Smith PL, Schwartz AR, Walsh JH, Maddison KJ, Claman DM, Huntley T, Park SY, Campbell MC, Palme CE, Iber C, Eastwood PR, Hillman DR, Barnes M. Hypoglossal nerve stimulation improves obstructive sleep apnea: 12‐month outcomes. J Sleep Res 23: 77‐83, 2014.
 251.Kheirandish‐Gozal L, Gozal D. Genotype‐phenotype interactions in pediatric obstructive sleep apnea. Respir Physiol Neurobiol 189: 338‐343, 2013.
 252.Kia HK, Miquel M‐C, Brisorgueil M‐J, Davel G, Riad M, Mestikawy SE, Hamon M, Verge D. Immunocytochemical localization of serotonin1A receptors in the rat central nervous system. J Comp Neurol 365: 289‐305, 1996.
 253.Kianicka I, Praud J‐P. Influence of sleep states on laryngeal and abdominal muscle response to upper airway occlusion in lambs. Ped Res 41: 862‐871, 1997.
 254.Kimoff JR, Makino H, Horner RL, Kozar LF, Lue F, Slutsky AS, Phillipson EA. Canine model of obstructive sleep apnea: Model description and preliminary application. J Appl Physiol 76: 1810‐1816, 1994.
 255.Kimura H, Kubin L, Davies RO, Pack AI. Cholinergic stimulation of the pons depresses respiration in decerebrate cats. J Appl Physiol 69: 2280‐2289, 1990.
 256.King ED, O'Donnell CP, Smith PL, Schwartz AR. A model of obstructive sleep apnea in normal humans. Role of the upper airway. Am J Respir Crit Care Med 161: 1979‐1984, 2000.
 257.Knight WD, Little JT, Carreno FR, Toney GM, Mifflin SW, Cunningham JT. Chronic intermittent hypoxia increases blood pressure and expression of FosB/DeltaFosB in central autonomic regions. Am J Physiol 301: R131‐R139, 2011.
 258.Ko EM, Estabrooke IV, McCarthy M, Scammell TE. Wake‐related activity of tuberomammillary neurons in rats. Brain Res 992: 220‐226, 2003.
 259.Kodama T, Lai YY, Siegel JM. Changes in inhibitory amino acid release linked to pontine‐induced atonia: An in vivo microdialysis study. J Neurosci 23: 1548‐1554, 2003.
 260.Kodama T, Takahashi Y, Honda Y. Enhancement of acetylcholine release during paradoxical sleep in the dorsal tegmental field of the cat brain stem. Neurosci Lett 114: 277‐282, 1990.
 261.Kohlmeier KA, Burns J, Reiner PB, Semba K. Substance P in the descending cholinergic projection to REM sleep‐induction regions of the rat pontine reticular formation: Anatomical and electrophysiological analyses. Eur J Neurosci 15: 176‐196, 2002.
 262.Koizumi H, Wilson CG, Wong S, Yamanishi T, Koshiya N, Smith JC. Functional imaging, spatial reconstruction, and biophysical analysis of a respiratory motor circuit isolated in vitro. J Neurosci 28: 2353‐2365, 2008.
 263.Kolta A, Dubuct R, Lund JP. An immunocytochemical and autoradiographic investigation of the serotoninergic innervation of trigeminal mesencephalic and motor nuclei in the rabbit. Neuroscience 53: 1113‐1126, 1993.
 264.Krolo M, Stuth EA, Tonkovic‐Capin M, Hopp FA, McCrimmon DR, Zuperku EJ. Relative magnitude of tonic and phasic synaptic excitation of medullary inspiratory neurons in dogs. Am J Physiol 279: R639‐R649, 2000.
 265.Kubin L. Carbachol models of REM sleep: Recent developments and new directions. Arch Ital Biol 139: 147‐168, 2001.
 266.Kubin L. Respiratory physiology: CNS ventilatory control. In: Amlaner CJ, Fuller PM, editors. Basics of Sleep Guide (2nd ed). Westchester, Il: Sleep Research Society, 2009.
 267.Kubin L. Sleep‐wake control of the upper airway by noradrenergic neurons, with and without intermittent hypoxia. In: Holstege G, Beers CM, Subramanian HH, editors. The Central Nervous System Control of Respiration. Amsterdam: Elsevier, 2014. doi: 10.1016/B978‐0‐444‐63274‐6.00013‐8
 268.Kubin L, Alheid GF, Zuperku EJ, McCrimmon DR. Central pathways of pulmonary and lower airway vagal afferents. J Appl Physiol 101: 618‐627, 2006. doi: 10.1152/japplphysiol.00252.2006
 269.Kubin L, Davies RO. Central pathways of pulmonary and airway vagal afferents. In: Dempsey JA, Pack AI, editors. Regulation of Breathing. New York: Marcel Dekker, 1995.
 270.Kubin L, Davies RO. Mechanisms of upper airway hypotonia. In: Pack AI, editor. Sleep Apnea: Pathogenesis, Diagnosis and Treatment (2nd ed). St. Heliers: Informa Healthcare, 2011.
 271.Kubin L, Davies RO, Pack AI. Control of upper airway motoneurons during REM sleep. News Physiol Sci 13: 91‐97, 1998.
 272.Kubin L, Fenik V. Pontine cholinergic mechanisms and their impact on respiratory regulation. Respir Physiol Neurobiol 143: 235‐249, 2004. doi: 10.1016/j.resp.2004.04.017
 273.Kubin L, Kimura H, Tojima H, Davies RO, Pack AI. Suppression of hypoglossal motoneurons during the carbachol‐induced atonia of REM sleep is not caused by fast synaptic inhibition. Brain Res 611: 300‐312, 1993.
 274.Kubin L, Kimura H, Tojima H, Pack AI, Davies RO. Behavior of VRG neurons during the atonia of REM sleep induced by pontine carbachol in decerebrate cats. Brain Res 592: 91‐100, 1992.
 275.Kubin L, Reignier C, Tojima H, Taguchi O, Pack AI, Davies RO. Changes in serotonin level in the hypoglossal nucleus region during the carbachol‐induced atonia. Brain Res 645: 291‐302, 1994.
 276.Kubin L, Tojima H, Davies RO, Pack AI. Serotonergic excitatory drive to hypoglossal motoneurons in the decerebrate cat. Neurosci Lett 139: 243‐248, 1992.
 277.Kubin L, Tojima H, Reignier C, Pack AI, Davies RO. Interaction of serotonergic excitatory drive to hypoglossal motoneurons with carbachol‐induced, REM sleep‐like atonia. Sleep 19: 187‐195, 1996.
 278.Kuna ST, Insalaco G, Villeponteaux RD. Arytenoideus muscle activity in normal adult humans during wakefulness and sleep. J Appl Physiol 70: 1655‐1664, 1991.
 279.Kuna ST, Insalaco G, Woodson GE. Thyroarytenoid muscle activity during wakefulness and sleep in normal adults. J Appl Physiol 65: 1332‐1339, 1988.
 280.Kuna ST, Smickley J. Response of genioglosus muscle activity to nasal airway occlusion in normal sleeping adults. J Appl Physiol 64: 347‐353, 1988.
 281.Kuna ST, Smickley JS. Superior pharyngeal constrictor activation in obstructive sleep apnea. Am J Respir Crit Care Med 156: 874‐880, 1997.
 282.Kuna ST, Smickley JS, Insalaco G. Posterior cricoarytenoid muscle activity during wakefulness and sleep in normal adults. J Appl Physiol 68: 1746‐1754, 1990.
 283.Kuna ST, Smickley JS, Vanoye CR. Respiratory‐related pharyngeal constrictor muscle activity in normal human adults. Am J Respir Crit Care Med 155: 1991‐1999, 1997.
 284.Kuna ST, Smickley JS, Vanoye CR, McMillan TH. Cricothyroid muscle activity during sleep in normal adult humans. J Appl Physiol 76: 2326‐2332, 1994.
 285.Kurasawa I, Toda K, Nakamura Y. Non‐reciprocal facilitation of trigeminal motoneurons innervating jaw‐closing and jaw‐opening muscles induced by iontophoretic application of serotonin in the guinea pig. Brain Res 515: 126‐134, 1990.
 286.Lai J, Shao XM, Pan RW, Dy E, Huang CH, Feldman JL. RT‐PCR reveals muscarinic acetylcholine receptor mRNA in the pre‐Bötzinger complex. Am J Physiol 281: L1420‐L1424, 2001.
 287.Lai YY, Clements JR, Wu XY, Shalita T, Wu J‐P, Kuo JS, Siegel JM. Brainstem projections to the ventromedial medulla in cat: Retrograde transport horseradish peroxidase and immunohistochemical studies. J Comp Neurol 408: 419‐436, 1999.
 288.Lai YY, Kodama T, Siegel J. Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: An in vivo microdialysis study. J Neurosci 21: 7384‐7391, 2001.
 289.Lalley PM. The excitability and rhythm of medullary respiratory neurons in the cat are altered by the serotonin receptor agonist 5‐methoxy‐N, N, dimethyltryptamine. Brain Res 648: 87‐98, 1994.
 290.Lalley PM, Bischoff AM, Richter DW. 5‐HT1A receptor‐mediated modulation of medullary expiratory neurons in the cat. J Physiol (Lond) 476: 117‐130, 1994.
 291.Langmead CJ, Watson J, Reavill C. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther 117: 232‐243, 2008.
 292.Larkin EK, Patel SR, Goodloe RJ, Li Y, Zhu X, Gray‐McGuire C, Adams MD, Redline S. A candidate gene study of obstructive sleep apnea in European Americans and African Americans. Am J Respir Crit Care Med 182: 947‐953, 2010.
 293.Larkman PM, Kelly JS. Ionic mechanisms mediating 5‐hydroxytryptamine‐ and noradrenaline‐evoked depolarization of adult rat facial motoneurones. J Physiol (Lond) 456: 473‐490, 1992.
 294.Launois C, Attali V, Georges M, Raux M, Morawiec E, Rivals I, Arnulf I, Similowski T. Cortical drive to breathe during wakefulness in patients with obstructive sleep apnea syndrome. Sleep 38: 1743‐1749, 2015.
 295.Lazarenko RM, Stornetta RL, Bayliss DA, Guyenet PG. Orexin A activates retrotrapezoid neurons in mice. Respir Physiol Neurobiol 175: 283‐287, 2011.
 296.Le Novere N, Corringer PJ, Changeux JP. The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol 53: 447‐456, 2002.
 297.Lee LY, Yu J. Sensory nerves in lung and airways. Compr Physiol 4: 287‐324, 2014. doi: 10.1002/cphy.c130020
 298.Lee MC, Lee CH, Hong SL, Kim SW, Lee WH, Lim JY, Joe S, Yoon IY, Kim JW. Establishment of a rabbit model of obstructive sleep apnea by paralyzing the genioglossus. JAMA Otolaryngol Head Neck Surg 139: 834‐840, 2013.
 299.Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep‐waking cycle. J Neurosci 25: 6716‐6720, 2005.
 300.Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype‐specific antibodies. J Neurosci 11: 3218‐3226, 1991.
 301.Levy P, Tamisier R, Arnaud C, Monneret D, Baguet JP, Stanke‐Labesque F, Dematteis M, Godin‐Ribuot D, Ribuot C, Pepin JL. Sleep deprivation, sleep apnea and cardiovascular diseases. Front Biosci 4: 2007‐2021, 2012.
 302.Li J, Grigoryev DN, Ye SQ, Thorne L, Schwartz AR, Smith PL, O'Donnell CP, Polotsky VY. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol 99: 1643‐1648, 2005.
 303.Li R, Bao G, El‐Mallakh RS, Fletcher EC. Effects of chronic episodic hypoxia on monoamine metabolism and motor activity. Physiol Behav 60: 1071‐1076, 1996.
 304.Li Y‐Q, Takada M, Kaneko T, Mizuno M. Distribution of GABAergic and glycinergic premotor neurons projecting to facial and hypoglossal nuclei in the rat. J Comp Neurol 378: 283‐294, 1997.
 305.Li YQ, Takada M, Mizuno N. Premotor neurons projecting simultaneously to two orofacial motor nuclei by sending their branched axons. A study with a fluorescent retrograde double‐labeling technique in the rat. Neurosci Lett 152: 29‐32, 1993.
 306.Li Y‐Q, Takada M, Mizuno N. The sites of origin of serotoninergic afferent fibers in the trigeminal motor, facial, and hypoglossal nuclei in the rat. Neurosci Res 17: 307‐313, 1993.
 307.Lin CM, Huang YS, Guilleminault C. Pharmacotherapy of obstructive sleep apnea. Exp Opin Pharmacother 13: 841‐857, 2012.
 308.Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98: 365‐376, 1999.
 309.Lipski J, Zhang X, Kruszewska B, Kanjhan R. Morphological study of long axonal projections of ventral medullary inspiratory neurons in the rat. Brain Res 640: 171‐184, 1994.
 310.Liu X, Sood S, Liu H, Horner RL. Opposing muscarinic and nicotinic modulation of hypoglossal motor output to genioglossus muscle in rats in vivo. J Physiol (Lond) 565: 965‐980, 2005.
 311.Lonergan RP, III, Ware JC, Atkinson RL, Winter WC, Suratt PM. Sleep apnea in obese miniature pigs. J Appl Physiol 84: 531‐536, 1998.
 312.Lopes JM, Tabachnik E, Muller NL, Levison H, Bryan AC. Total airway resistance and respiratory muscle activity during sleep. J Appl Physiol 54: 773‐777, 1983.
 313.Lowe AA. The neural regulation of tongue‐movements. Progr Neurobiol 15: 295‐344, 1981.
 314.Lu JW, Fenik VB, Branconi JL, Mann GL, Rukhadze I, Kubin L. Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol‐induced REM sleep‐like episodes in rats. J Physiol (Lond) 582: 52‐67, 2007.
 315.Lu JW, Kubin L. Electromyographic activity at the base and tip of the tongue across sleep‐wake states in rats. Respir Physiol Neurobiol 167: 307‐315, 2009. doi: 10.1016/j.resp.2009.06.004
 316.Lu JW, Mann GL, Ross RJ, Morrison AR, Kubin L. Differential effect of sleep‐wake states on lingual and dorsal neck muscle activity in rats. Respir Physiol Neurobiol 147: 191‐203, 2005.
 317.Lujan R, Marron FV, Aguado C, Wickman K. New insights into the therapeutic potential of Girk channels. Trends Neurosci 37: 20‐29, 2014.
 318.Malhotra A, Trinder J, Fogel R, Stanchina M, Patel SR, Schory K, Kleverlaan D, White DP. Postural effects on pharyngeal protective reflex mechanisms. Sleep 27: 1105‐1112, 2004.
 319.Maljevic S, Lerche H. Potassium channels: A review of broadening therapeutic possibilities for neurological diseases. J Neurol 260: 2201‐2211, 2013.
 320.Mallios VJ, Lydic R, Baghdoyan HA. Muscarinic receptor subtypes are differentially distributed across brain stem respiratory nuclei. Am J Physiol 268: L941‐L949, 1995.
 321.Manaker S, Rizio G. Autoradiographic localization of thyrotropin‐releasing hormone and substance P receptors in the rat dorsal vagal complex. J Comp Neurol 290: 516‐526, 1989.
 322.Manaker S, Tischler LJ. Origin of serotonergic afferents to the hypoglossal nucleus in the rat. J Comp Neurol 334: 466‐476, 1993.
 323.Manaker S, Tischler LJ, Morrison AR. Raphespinal and reticulospinal axon collaterals to the hypoglossal nucleus in the rat. J Comp Neurol 322: 68‐78, 1992.
 324.Manaker S, Verderame HM. Organization of serotonin 1A and 1B receptors in the nucleus of the solitary tract. J Comp Neurol 301: 535‐553, 1990.
 325.Manaker S, Zucchi PC. Autoradiographic localization of neurotransmitter binding sites in the hypoglossal and motor trigeminal nuclei of the rat. Synapse 28: 44‐59, 1998.
 326.Manns ID, Alonso A, Jones BE. Discharge properties of juxtacellularly labeled and immunohistochemically identified cholinergic basal forebrain neurons recorded in association with the electroencephalogram in anesthetized rats. J Neurosci 20: 1505‐1518, 2000.
 327.Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435: 6‐25, 2001.
 328.Mateika JH, Syed Z. Intermittent hypoxia, respiratory plasticity and sleep apnea in humans: Present knowledge and future investigations. Respir Physiol Neurobiol 188: 289‐300, 2013.
 329.Mathew OP, Abu‐Osba YK, Thach BT. Genioglossus muscle responses to upper airway pressure changes: Afferent pathways. J Appl Physiol 52: 445‐450, 1982.
 330.Mathew OP, Abu‐Osba YK, Thach BT. Influence of upper airway pressure changes on genioglossus muscle respiratory activity. J Appl Physiol 52: 438‐444, 1982.
 331.McCall RB, Aghajanian GK. Serotonergic facilitation of facial motoneuron excitation. Brain Res 169: 11‐27, 1979.
 332.McCarter SJ, St Louis EK, Duwell EJ, Timm PC, Sandness DJ, Boeve BF, Silber MH. Diagnostic thresholds for quantitative REM sleep phasic burst duration, phasic and tonic muscle activity, and REM atonia index in REM sleep behavior disorder with and without comorbid obstructive sleep apnea. Sleep 37: 1649‐1662, 2014.
 333.McClung JR, Goldberg SJ. Functional anatomy of the hypoglossal innervated muscles of the rat tongue: A model for elongation and protrusion of the mammalian tongue. Anat Rec 260: 378‐386, 2000.
 334.McGinley BM, Schwartz AR, Schneider H, Kirkness JP, Smith PL, Patil SP. Upper airway neuromuscular compensation during sleep is defective in obstructive sleep apnea. J Appl Physiol 105: 197‐205, 2008.
 335.McGinty DJ, Harper RM. Dorsal raphe neurons: Depression of firing during sleep in cats. Brain Res 101: 569‐575, 1976.
 336.McGuire M, Zhang Y, White DP, Ling L. Effect of hypoxic episode number and severity on ventilatory long‐term facilitation in awake rats. J Appl Physiol 93: 2155‐2161, 2002.
 337.McKay LC, Janczewski WA, Feldman JL. Sleep‐disordered breathing after targeted ablation of preBotzinger complex neurons. Nat Neurosci 8: 1142‐1144, 2005.
 338.McSharry DG, Saboisky JP, Deyoung P, Jordan AS, Trinder J, Smales E, Hess L, Chamberlin NL, Malhotra A. Physiological mechanisms of upper airway hypotonia during REM sleep. Sleep 37: 561‐569, 2014.
 339.McSharry DG, Saboisky JP, DeYoung P, Matteis P, Jordan AS, Trinder J, Smales E, Hess L, Guo M, Malhotra A. A mechanism for upper airway stability during slow wave sleep. Sleep 36: 555‐563, 2013.
 340.Megirian D, Cespuglio R, Jouvet M. Rhythmical activity of the rats's tongue in sleep and wakefulness. EEG Clin Neurophysiol 44: 8‐13, 1978.
 341.Megirian D, Hinrichsen CFL, Sherrey JH. Respiratory roles of genioglossus, sternothyroid, and sternohyoid muscles during sleep. Exp Neurol 90: 118‐128, 1985.
 342.Megirian D, Sherrey JH. Respiratory functions of the laryngeal muscles during sleep. Sleep 3: 289‐298, 1980.
 343.Mengod G, Pompeiano M, Martínez‐Mir MI, Palacios JM. Localization of the mRNA for the 5‐HT2 receptor by in situ hybridization histochemistry. Correlation with the distribution of receptor sites. Brain Res 524: 139‐143, 1990.
 344.Mesulam MM, Mufson EJ, Wainer BH, Levey AI. Central cholinergic pathways in the rat: An overview based on an alternative nomenclature (Ch1‐Ch6). Neuroscience 10: 1185‐1201, 1983.
 345.Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 89: 1571‐1579, 1992.
 346.Mezzanotte WS, Tangel DJ, White DP. Influence of sleep onset on upper‐airway muscle activity in apnea patients versus normal controls. Am J Respir Crit Care Med 153: 1880‐1887, 1996.
 347.Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46: 787‐798, 2005.
 348.Millhorn DE, Hökfelt T, Szymeczek CL, Bayliss DA, Seroogy KB. Cellular, molecular and developmental aspects of chemical synaptic transmission. In: Haddad GG, Farber JP, editors. Developmental Neurobiology of Breathing. New York: Dekker, 1991.
 349.Mody P, Rukhadze I, Kubin L. Rats subjected to chronic‐intermittent hypoxia have increased density of noradrenergic terminals in the trigeminal sensory and motor nuclei. Neurosci Lett 505: 176‐179, 2011. doi: 10.1016/j.neulet.2011.10.015
 350.Moore MW, Akladious A, Hu Y, Azzam S, Feng P, Strohl KP. Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse. Respir Physiol Neurobiol 200: 118‐125, 2014.
 351.Morales FR, Boxer P, Chase MH. Behavioral state‐specific inhibitory postsynaptic potentials impinge on cat lumbar motoneurons during active sleep. Exp Neurol 98: 418‐435, 1987.
 352.Morales FR, Chase MH. Postsynaptic control of lumbar motoneuron excitability during active sleep in the chronic cat. Brain Res 225: 279‐295, 1981.
 353.Morales FR, Chase MH. Repetitive synaptic potentials responsible for inhibition of spinal cord motoneurons during active sleep. Exp Neurol 78: 471‐476, 1982.
 354.Morales FR, Engelhardt JK, Soja PJ, Pereda AE, Chase MH. Motoneuron properties during motor inhibition produced by microinjection of carbachol into the pontine reticular formation of the decerebrate cat. J Neurophysiol 57: 1118‐1129, 1987.
 355.Morales M, Battenberg E, de Lecea L, Sanna PP, Bloom FE. Cellular and subcellular immunolocalization of the type 3 serotonin receptor in the rat central nervous system. Mol Brain Res 36: 251‐260, 1996.
 356.Morin‐Surun MP, Champagnat J, Denavit‐Saubié M, Moyanova S. The effects of acetylcholine on bulbar respiratory related neurones. Consequences of anaesthesia by pentobarbital. Naunyn‐Schmiedebergs Arch Pharmacol 325: 205‐208, 1984.
 357.Morrison DL, Launois SH, Isono S, Feroah TR, Whitelaw WA, Remmers JE. Pharyngeal narrowing and closing pressures in patients with obstructive sleep apnea. Am Rev Respir Dis 148: 606‐611, 1993.
 358.Morrison JL, Sood S, Liu H, Park E, Liu X, Nolan P, Horner RL. Role of inhibitory amino acids in control of hypoglossal motor outflow to genioglossus muscle in naturally sleeping rats. J Physiol (Lond) 552: 975‐991, 2003.
 359.Morrison JL, Sood S, Liu X, Liu H, Park E, Nolan P, Horner RL. Glycine at hypoglossal motor nucleus: Genioglossus activity, CO2 responses, and the additive effects of GABA. J Appl Physiol 93: 1786‐1796, 2002.
 360.Morrison JL, Sood S, Liu H, Park E, Nolan P, Horner RL. GABAA receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM but not REM sleep. J Physiol (Lond) 548: 569‐583, 2003.
 361.Mortimore IL, Douglas NJ. Palatopharyngeus has respiratory activity and responds to negative pressure in sleep apnoeics. Eur Respir J 9: 773‐778, 1996.
 362.Mortimore IL, Douglas NJ. Palatal muscle EMG response to negative pressure in awake sleep apneic and control subjects. Am J Respir Crit Care Med 156: 867‐873, 1997.
 363.Mukai T, Nagao Y, Nishioka S, Hayashi T, Shimizu S, Ono A, Sakagami Y, Watanabe S, Ueda Y, Hara M, Tokudome K, Kato R, Matsumura Y, Ohno Y. Preferential suppression of limbic Fos expression by intermittent hypoxia in obese diabetic mice. Neurosci Res 77: 202‐207, 2013.
 364.Mutoh T, Bonham AC, Joad JP. Substance P in the nucleus of the solitary tract augments bronchopulmonary C fiber reflex output. Am J Physiol 279: R1215‐R1223, 2000.
 365.Nakamura Y, Goldberg LJ, Chandler SH, Chase MH. Intracellular analysis of trigeminal motoneuron activity during sleep in the cat. Science 199: 204‐207, 1978.
 366.Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T. Vigilance state‐dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 102: 241‐248, 2007.
 367.Nakaya Y, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J Comp Neurol 347: 249‐274, 1994.
 368.Nasse J, Travers JB. Adrenoceptor modulation of oromotor pathways in the rat medulla. J Neurophysiol 112: 580‐593, 2014. doi: 10.1152/jn.00091.2014
 369.Netick A, Orem J, Dement W. Neuronal activity specific to REM sleep and its relationship to breathing. Brain Res 120: 197‐207, 1977.
 370.Neuzeret PC, Gormand F, Reix P, Parrot S, Sastre JP, Buda C, Guidon G, Sakai K, Lin JS. A new animal model of obstructive sleep apnea responding to continuous positive airway pressure. Sleep 34: 541‐548, 2011.
 371.Neuzeret P‐C, Sakai K, Gormand F, Petitjean T, Buda C, Sastre J‐P, Parrot S, Guidon G, Lin J‐S. Application of histamine and serotonin to the hypoglossal nucleus increases genioglossus activity across the wake‐sleep cycle. J Sleep Res 18: 113‐121, 2009.
 372.Nguyen AT, Jobin V, Payne R, Beauregard J, Naor N, Kimoff RJ. Laryngeal and velopharyngeal sensory impairment in obstructive sleep apnea. Sleep 28: 585‐593, 2005.
 373.Nicholas AP, Pieribone VA, Arvidsson U, Hökfelt T. Serotonin‐, substance P‐ and glutamate/aspartate‐like immunoreactivities in medullo‐spinal pathways of rat and primate. Neuroscience 48: 545‐559, 1992.
 374.Nicholas CL, Bei B, Worsnop C, Malhotra A, Jordan AS, Saboisky JP, Chan JK, Duckworth E, White DP, Trinder J. Motor unit recruitment in human genioglossus muscle in response to hypercapnia. Sleep 33: 1529‐1538, 2010.
 375.Nicholas CL, Jordan AS, Heckel L, Worsnop C, Bei B, Saboisky JP, Eckert DJ, White DP, Malhotra A, Trinder J. Discharge patterns of human tensor palatini motor units during sleep onset. Sleep 35: 699‐707, 2012.
 376.Nishijima T, Sakurai S, Arihara Z, Takahashi K. Plasma orexin‐A‐like immunoreactivity in patients with sleep apnea hypopnea syndrome. Peptides 24: 407‐411, 2003.
 377.Oh JD, Woolf NJ, Roghani A, Edwards RH, Butcher LL. Cholinergic neurons in the rat central nervous system demonstrated by in situ hybridization of choline acetyltransferase mRNA. Neuroscience 47: 807‐822, 1992.
 378.Okabe S, Hida W, Kikuchi Y, Taguchi O, Takishima T, Shirato K. Upper airway muscle activity during REM and non‐REM sleep of patients with obstructive apnea. Chest 106: 767‐773, 1994.
 379.Okabe S, Kubin L. Role of 5HT1 receptors in the control of hypoglossal motoneurons in vivo. Sleep 19: S150‐S153, 1996.
 380.Okabe S, Mackiewicz M, Kubin L. Serotonin receptor mRNA expression in the hypoglossal motor nucleus. Respir Physiol 110: 151‐160, 1997.
 381.Okabe S, Woch G, Kubin L. Role of GABAB receptors in the control of hypoglossal motoneurons in vivo. NeuroReport 5: 2573‐2576, 1994.
 382.Oliven A, O'Hearn DJ, Boudewyns A, Odeh M, De BW, van de HP, Smith PL, Eisele DW, Allan L, Schneider H, Testerman R, Schwartz AR. Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea. J Appl Physiol 95: 2023‐2029, 2003.
 383.Onimaru H, Homma I. A novel functional neuron group for respiratory rhythm generation in the ventral medulla. J Neurosci 23: 1478‐1486, 2003.
 384.Ono T, Ishiwata Y, Inaba N, Kuroda T, Nakamura Y. Hypoglossal premotor neurons with rhythmical inspiratory‐related activity in the cat: Localization and projection to the phrenic nucleus. Exp Brain Res 98: 1‐12, 1994.
 385.Orem J. Medullary respiratory neuron activity: Relationship to tonic and phasic REM sleep. J Appl Physiol 48: 54‐65, 1980.
 386.Orem J. Neuronal mechanisms of respiration in REM sleep. Sleep 3: 251‐267, 1980.
 387.Orem J. The nature of the wakefulness stimulus for breathing. In: Suratt P, Remmers JE, editors. Sleep and Respiration. New York: Wiley‐Liss, 1990.
 388.Orem J. Central respiratory activity in rapid eye movement sleep: Augmenting and late inspiratory cells. Sleep 17: 665‐673, 1994.
 389.Orem J. Excitatory drive to the respiratory system in REM sleep. Sleep 19: S154‐S156, 1996.
 390.Orem J, Anderson CA. Diaphragmatic activity during REM sleep in the adult cat. J Appl Physiol 73: 751‐760, 1996.
 391.Orem J, Kubin L. Respiratory physiology: Central neural control. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine (4th ed). Philadelphia: Elsevier‐Saunders, 2005.
 392.Orem J, Lovering AT, Dunin‐Barkowski W, Vidruk EH. Endogenous excitatory drive in the respiratory system in rapid eye movement sleep in cats. J Physiol (Lond) 527: 365‐376, 2000.
 393.Orem J, Montplaisir J, Dement WC. Changes in the activity of respiratory neurons during sleep. Brain Res 82: 309‐315, 1974.
 394.Orem J, Osorio I, Brooks E, Dick TE. Activity of respiratory neurons during NREM sleep. J Neurophysiol 54: 1144‐1156, 1985.
 395.Orem JM. Respiratory neuronal activity in sleep. In: Edelman NH, Santiago TV, editors. Breathing Disorders of Sleep. New York: Churchill Livingstone, 1986.
 396.Orem JM, Lovering AT, Vidruk EH. Excitation of medullary respiratory neurons in REM sleep. Sleep 28: 801‐807, 2005.
 397.Pagliardini S, Gosgnach S, Dickson CT. Spontaneous sleep‐like brain state alternations and breathing characteristics in urethane anesthetized mice. PLoS ONE 8: e70411, 2013.
 398.Pagliardini S, Greer JJ, Funk GD, Dickson CT. State‐dependent modulation of breathing in urethane‐anesthetized rats. J Neurosci 32: 11259‐11270, 2012.
 399.Parisi RA, Edelman NH, Santiago TV. Central respiratory carbon dioxide chemosensitivity does not decrease during sleep. Am Rev Respir Dis 145: 832‐836, 1992.
 400.Parisi RA, Neubauer JA, Frank MM, Edelman NH, Santiago TV. Correlation between genioglossal and diaphragmatic responses to hypercapnia during sleep. Am Rev Respir Dis 135: 378‐382, 1987.
 401.Parisi RA, Santiago TV, Edelman NH. Genioglossal and diaphragmatic EMG responses to hypoxia during sleep. Am Rev Respir Dis 138: 610‐616, 1988.
 402.Parkis MA, Bayliss DA, Berger AJ. Actions of norepinephrine on rat hypoglossal motoneurons. J Neurophysiol 74: 1911‐1919, 1995.
 403.Parkis MA, Berger AJ. Clonidine reduces hyperpolarization‐activated inward current (Ih) in rat hypoglossal motoneurons. Brain Res 769: 108‐118, 1997.
 404.Patel SR, Goodloe R, De G, Kowgier M, Weng J, Buxbaum SG, Cade B, Fulop T, Gharib SA, Gottlieb DJ, Hillman D, Larkin EK, Lauderdale DS, Li L, Mukherjee S, Palmer L, Zee P, Zhu X, Redline S. Association of genetic loci with sleep apnea in European Americans and African‐Americans: The Candidate Gene Association Resource (CARe). PLoS ONE 7: e48836, 2012.
 405.Patil SP, Schneider H, Marx JJ, Gladmon E, Schwartz AR, Smith PL. Neuromechanical control of upper airway patency during sleep. J Appl Physiol 102: 547‐556, 2007.
 406.Pazos A, Probst A, Palacios JM. Serotonin receptors in the human brain. IV. Autoradiographic mapping of serotonin‐2 receptors. Neuroscience 21: 123‐139, 1987.
 407.Pedroarena C, Castillo P, Chase MH, Morales FR. The control of jaw‐opener motoneurons during active sleep. Brain Res 653: 31‐38, 1994.
 408.Peever JH, Shen L, Duffin J. Respiratory pre‐motor control of hypoglossal motoneurons in the rat. Neuroscience 110: 711‐722, 2002.
 409.Petrof BJ, Pack AI, Kelly AM. Pharyngeal myopathy of loaded upper airway in dogs with sleep apnea. J Appl Physiol 76: 1746‐1752, 1994.
 410.Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff T. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18: 9996‐10015, 1998.
 411.Philip P, Gross CE, Taillard J, Bioulac B, Guilleminault C. An animal model of a spontaneously reversible obstructive sleep apnea syndrome in the monkey. Neurobiol Dis 20: 428‐431, 2005.
 412.Pilowsky PM, Lipski J, Prestidge R, Jiang C. Dual fluorescence combined with a two‐color immunoperoxidase technique: A new way of visualizing diverse neuronal elements. J Neurosci Meth 36: 185‐193, 1991.
 413.Piper AJ, Yee BJ. Hypoventilation syndromes. Compr Physiol 4: 1639‐1676, 2014. doi: 10.1002/cphy.c140008
 414.Plowman L, Lauff DC, Berthon‐Jones M, Sullivan CE. Waking and genioglossal muscle responses to upper airway pressure oscillation in sleeping dogs. J Appl Physiol 68: 2564‐2573, 1990.
 415.Polotsky M, Elsayed‐Ahmed AS, Pichard L, Harris CC, Smith PL, Schneider H, Kirkness JP, Polotsky V, Schwartz AR. Effects of leptin and obesity on the upper airway function. J Appl Physiol 112: 1637‐1643, 2012.
 416.Polotsky M, Elsayed‐Ahmed AS, Pichard L, Richardson RA, Smith PL, Schneider H, Kirkness JP, Polotsky V, Schwartz AR. Effect of age and weight on upper airway function in a mouse model. J Appl Physiol 111: 696‐703, 2011.
 417.Pompeiano O. The neurophysiological mechanisms of the postrual and motor events during desynchronized sleep. Res Publ Assoc Res Nerv Ment Dis 45: 351‐423, 1967.
 418.Powell GL, Rice A, Bennett‐Cross SJ, Fregosi RF. Respiration‐related dischange of hyoglossus muscle motor units in the rat. J Neurophysiol 111: 361‐368, 2014. doi: 10.1152/jn.00670.2013
 419.Proctor DF. The upper airways. I. Nasal physiology and defense of the lungs. Am Rev Respir Dis 115: 97‐129, 1977.
 420.Puizillout J‐J, Ternaux J‐P. Variations d'activités toniques, phasiques et respiratoires, au niveau bulbaire pendant l'endormement de la préparation encéphale isolé. Brain Res 66: 67‐83, 1974.
 421.Punjabi NM, Caffo BS, Goodwin JL, Gottlieb DJ, Newman AB, O'Connor GT, Rapoport DM, Redline S, Resnick HE, Robbins JA, Shahar E, Unruh ML, Samet JM. Sleep‐disordered breathing and mortality: A prospective cohort study. PLoS Med 6: e1000132, 2009.
 422.Quirion R, Araujo D, Regenold W, Boksa P. Characterization and quantitative autoradiographic distribution of [3H]acetylcholine muscarinic receptors in mammalian brain. Apparent labelling of an M2‐like receptor sub‐type. Neuroscience 29: 271‐289, 1989.
 423.Quitadamo C, Fabbretti E, Lamanauskas N, Nistri A. Activation and desensitization of neuronal nicotinic receptors modulate glutamatergic transmission on neonatal rat hypoglossal motoneurons. Eur J Neurosci 22: 2723‐2734, 2005.
 424.Rainbow TC, Parsons B, Wolfe BB. Quantitative autoradiography of b1‐ and b2‐adrenergic receptors in rat brain. Proc Natl Acad Sci USA 81: 1585‐1589, 1984.
 425.Ramirez JM, Doi A, Garcia AJ, III, Elsen FP, Koch H, Wei AD. The cellular building blocks of breathing. Compr Physiol 2: 2683‐2731, 2012. doi: 10.1002/cphy.c110033
 426.Ramirez JM, Richter DW. The neuronal mechanisms of respiratory rhythm generation. Curr Op Neurobiol 6: 817‐825, 1996.
 427.Rampin O, Pierrefiche O, Denavit‐Saubié M. Effects of serotonin and substance P on bulbar respiratory neurons in vivo. Brain Res 622: 185‐193, 1993.
 428.Rampon C, Luppi P‐H, Fort P, Peyron C, Jouvet M. Distribution of glycine‐immunoreactive cell bodies and fibers in the rat brain. Neuroscience 75: 737‐755, 1996.
 429.Ratnavadivel R, Chau N, Stadler D, Yeo A, McEvoy RD, Catcheside PG. Marked reduction in obstructive sleep apnea severity in slow wave sleep. J Clin Sleep Med 5: 519‐524, 2009.
 430.Ray AD, Magalang UJ, Michlin CP, Ogasa T, Krasney JA, Gosselin LE, Farkas GA. Intermittent hypoxia reduces upper airway stability in lean but not obese Zucker rats. Am J Physiol 293: R372‐R378, 2007.
 431.Reiner PB. Clonidine inhibits central noradrenergic neurons in unanesthetized cats. Eur J Pharmacol 115: 249‐257, 1985.
 432.Reiner PB. Correlational analysis of central noradrenergic neuronal activity and sympathetic tone in behaving cats. Brain Res 378: 86‐96, 1986.
 433.Reinke C, Bevans‐Fonti S, Drager LF, Shin MK, Polotsky VY. Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes. J Appl Physiol 111: 881‐890, 2011.
 434.Rekling JC. Excitatory effects of thyrotropin‐releasing hormone (TRH) in hypoglossal motoneurons. Brain Res 510: 175‐179, 1990.
 435.Remmers JE, DeGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 44: 931‐938, 1978.
 436.Ribeiro‐do‐Valle LE, Metzler CW, Jacobs BL. Facilitation of masseter EMG and masseteric (jaw‐closure) reflex by serotonin in behaving cats. Brain Res 550: 197‐204, 1991.
 437.Richard CA, Harper RM. Respiratory‐related activity in hypoglossal neurons across sleep‐waking states in cats. Brain Res 542: 167‐170, 1991.
 438.Richerson GB, Wang W, Tiwari J, Bradley SR. Chemosensitivity of serotonergic neurons in the rostral ventral medulla. Respir Physiol 129: 175‐189, 2001.
 439.Rivera‐Garcia AP, Ramirez‐Salado I, Corsi‐Cabrera M, Calvo JM. Facial muscle activation during sleep and its relation to the rapid eye movements of REM sleep. J Sleep Res 20: 82‐91, 2011.
 440.Roberts JL, Reed WR, Thach BT. Pharyngeal airway‐stabilizing function of sternohyoid and sternothyroid muscles in the rabbit. J Appl Physiol 57: 1790‐1795, 1984.
 441.Rosin DL, Talley EM, Lee A, Stornetta RL, Gaylinn BD, Guyenet PG, Lynch KR. Distribution of a2C‐adrenergic receptor‐like immunoreactivity in the rat central nervous system. J Comp Neurol 372: 135‐165, 1996.
 442.Rowley JA, Permutt S, Willey S, Smith PL, Schwartz AR. Effect of tracheal and tongue displacement on upper airway airflow dynamics. J Appl Physiol 80: 2171‐2178, 1996.
 443.Rukhadze I, Fenik VB, Benincasa KE, Price A, Kubin L. Chronic intermittent hypoxia alters density of aminergic terminals and receptors in the hypoglossal motor nucleus. Am J Respir Crit Care Med 182: 1321‐1329, 2010. doi: 10.1164/rccm.200912‐1884OC
 444.Rukhadze I, Fenik VB, Branconi JL, Kubin L. Fos expression in pontomedullary catecholaminergic cells following REM sleep‐like episodes elicited by pontine carbachol in urethane‐anesthetized rats. Neuroscience 152: 208‐222, 2008.
 445.Rukhadze I, Kalter J, Stettner GM, Kubin L. Lingual muscle activity across sleep‐wake states in rats with surgically altered upper airway. Front Neurol 5: 61, 2014. doi: 10.3389/fneur.2014.00061
 446.Rukhadze I, Kamani H, Kubin L. Quantitative differences among EMG activities of muscles innervated by subpopulations of hypoglossal and upper spinal motoneurons during non‐REM sleep ‐ REM sleep transitions: A window on neural processes in the sleeping brain. Arch Ital Biol 149: 499‐515, 2011.
 447.Rukhadze I, Kubin L. Differential pontomedullary catecholaminergic projections to hypoglossal motor nucleus and viscerosensory nucleus of the solitary tract. J Chem Neuroanat 33: 23‐33, 2007.
 448.Rukhadze I, Kubin L. Mesopontine cholinergic projections to the hypoglossal motor nucleus. Neurosci Lett 413: 121‐125, 2007.
 449.Ryan S, Nolan P. Superior laryngeal and hypoglossal afferents tonically influence upper airway motor excitability in anesthetized rats. J Appl Physiol 99: 1019‐1028, 2005.
 450.Rye DB. Contributions of the pedunculopontine region to normal and altered REM sleep. Sleep 20: 757‐788, 1997.
 451.Rye DB, Lee HJ, Saper CB, Wainer BH. Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat. J Comp Neurol 269: 315‐341, 1988.
 452.Saboisky JP, Butler JE, Fogel RB, Taylor JL, Trinder JA, White DP, Gandevia SC. Tonic and phasic respiratory drives to human genioglossus motoneurons during breathing. J Neurophysiol 95: 2213‐2221, 2006.
 453.Saboisky JP, Jordan AS, Eckert DJ, White DP, Trinder JA, Nicholas CL, Gautam S, Malhotra A. Recruitment and rate‐coding strategies of the human genioglossus muscle. J Appl Physiol 109: 1939‐1949, 2010.
 454.Saha S, Appenteng K, Batten TFC. Light and electron microscopical localisation of 5‐HT‐immunoreactive boutons in the rat trigeminal motor nucleus. Brain Res 559: 145‐148, 1991.
 455.Sahin M, Durand DM, Haxhiu MA. Chronic recordings of hypoglossal nerve activity in a dog model of upper airway obstruction. J Appl Physiol 87: 2197‐2206, 1999.
 456.Sakai K. Discharge properties of presumed cholinergic and noncholinergic laterodorsal tegmental neurons related to cortical activation in non‐anesthetized mice. Neuroscience 224: 172‐190, 2012.
 457.Sakai K, Sastre J‐P, Kanamori N, Jouvet M. State‐specific neurons in the ponto‐medullary reticular formation with special reference to the postural atonia during paradoxical sleep in the cat. In: Pompeiano O, Ajmone Marsan C, editors. Brain Mechanisms of Perceptual Awareness and Purposeful Behavior. New York: Raven, 1981.
 458.Sakai K, Takada T, Nakayama H, Kubota Y, Nakamata M, Satoh M, Suzuki E, Akazawa K, Gejyo F. Serotonin‐2A and 2C receptor gene polymorphisms in Japanese patients with obstructive sleep apnea. Int Med 44: 928‐933, 2005.
 459.Sakurai S, Nishijima T, Takahashi S, Yamauchi K, Arihara Z, Takahashi K. Low plasma orexin‐A levels were improved by continuous positive airway pressure treatment in patients with severe obstructive sleep apnea‐hypopnea syndrome. Chest 127: 731‐737, 2005.
 460.Sakurai T. Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 9: 231‐241, 2005.
 461.Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein‐coupled receptors that regulate feeding behavior. Cell 92: 573‐585, 1998.
 462.Sant'Ambrogio G, Tsubone H, Sant'Ambrogio FB. Sensory information from the upper airway: Role in the control of breathing. Respir Physiol 102: 1‐16, 1995.
 463.Sapin E, Lapray D, rod A, Goutagny R, ger L, Ravassard P, ment O, Hanriot L, Fort P, Luppi P‐H. Localization of the brainstem GABAergic neurons controlling paradoxical (REM) sleep. PLoS ONE 4: e4272, 2009.
 464.Sauerland EK, Harper RM. The human tongue during sleep: Electromyographic activity of the genioglossus muscle. Exp Neurol 51: 160‐170, 1976.
 465.Sauerland EK, Orr WC, Hairston LE. EMG patterns of oropharyngeal muscles during respiration in wakefulness and sleep. EMG Clin Neurophysiol 21: 307‐316, 1981.
 466.Scammell TE, Winrow CJ. Orexin receptors: Pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51: 243‐266, 2011.
 467.Scheinin M, Lomasney JW, Hayden‐Hixson DM, Schambra UB, Caron MG, Lefkowitz RJ, Fremeau RT, Jr. Distribution of α2‐adrenergic receptor subtype gene expression in rat brain. Mol Brain Res 21: 133‐149, 1994.
 468.Schmid K, Böhmer G, Gebauer K. GABAB receptor mediated effects on central respiratory system and their antagonism by phaclofen. Neurosci Lett 99: 305‐310, 1989.
 469.Schwab RJ, Gefter WB, Hoffman EA, Gupta KB, Pack AI. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis 148: 1385‐1400, 1993.
 470.Schwab RJ, Kim C, Bagchi S, Keenan BT, Comyn FL, Wang S, Tapia IE, Huang S, Traylor J, Torigian DA, Bradford RM, Marcus CL. Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents. Am J Respir Crit Care Med 191: 1295‐1309, 2015.
 471.Schwartz AR, Eisele DW, Hari A, Testerman R, Erickson D, Smith PL. Electrical stimulation of the lingual musculature in obstructive sleep apnea. J Appl Physiol 81: 643‐652, 1996.
 472.Schwartz AR, Smith PL, Oliven A. Electrical stimulation of the hypoglossal nerve: A potential therapy. J Appl Physiol 116: 337‐344, 2014.
 473.Schwarz PB, Peever JH. Noradrenergic control of trigeminal motoneurons in sleep: Relevance to sleep apnea. Adv Exp Med Biol 669: 281‐284, 2010.
 474.Schwarz PB, Yee N, Mir S, Peever JH. Noradrenaline triggers muscle tone by amplifying glutamate‐driven excitation of somatic motoneurones in anaesthetized rats. J Physiol (Lond) 586: 5787‐5802, 2008.
 475.Segizbaeva MO, Pogodin MA, Aleksandrova NP. Effects of body positions on respiratory muscle activation during maximal inspiratory maneuvers. Adv Exp Med Biol 756: 355‐363, 2013.
 476.Sekizawa S, Joad JP, Bonham AC. Substance P presynaptically depresses the transmission of sensory input to bronchopulmonary neurons in the guinea pig nucleus tractus solitarii. J Physiol (Lond) 552: 547‐559, 2003.
 477.Selvaratnam SR, Parkis MA, Funk GD. Devalopmental modulation of mouse hypoglossal nerve inspiratory output in vitro by noradrenergic receptor agonists. Brain Res 805: 104‐115, 1998.
 478.Semba K, Fibiger HC. Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: A retro‐ and antero‐grade transport and immunohistochemical study. J Comp Neurol 323: 387‐410, 1992.
 479.Sériès F, Cormier Y, Desmeules M, La Forge J. Effects of respiratory drive on upper airways in sleep apnea patients and normal subjects. J Appl Physiol 67: 973‐979, 1989.
 480.Series F, Simoneau J‐A, St. Pierre S, Marc I. Characteristics of the genioglossus and musculus uvulae in sleep apnea hypopnea syndrome and in snorers. Am J Respir Crit Care Med 153: 1870‐1874, 1996.
 481.Shah NH, Aizenman E. Voltage‐gated potassium channels at the crossroads of neuronal function, ischemic tolerance, and neurodegeneration. Transl Stroke Res 5: 38‐58, 2014.
 482.Shao XM, Feldman JL. Acetylcholine modulates respiratory pattern: Effects mediated by M3‐like receptors in pre‐Bötzinger complex inspiratory neurons. J Neurophysiol 83: 1243‐1252, 2000.
 483.Shao XM, Feldman JL. Mechanisms underlying regulation of respiratory pattern by nicotine in pre‐Bötzinger complex. J Neurophysiol 85: 2461‐2467, 2001.
 484.Shao XM, Feldman JL. Pharmacology of nicotinic receptors in pre‐Bötzinger complex that mediate modulation of respiratory pattern. J Neurophysiol 88: 1851‐1858, 2002.
 485.Shao Y, Sutin J. Noradrenergic facilitation of motor neurons: Localization of adrenergic receptors in neurons and nonneuronal cells in the trigeminal motor nucleus. J Neurosci 6: 30‐37, 1986.
 486.Shao Y, Sutin J. Expression of adrenergic receptors in individual astrocytes and motor neurons isolated from the adult rat brain. Glia 6: 108‐117, 1992.
 487.Sharma A, Punhani T, Fone KCF. Distribution of the 5‐hydroxytryptamine2c receptor protein in adult rat brain and spinal cord determined using a receptor‐directed antibody: Effect of 5,7‐dihydroxytryptamine. Synapse 27: 45‐56, 1997.
 488.Shaw C‐F, Cohen MI, Barnhardt R. Inspiratory‐modulated neurons of the rostrolateral pons: Effects of pulmonary afferent input. Brain Res 485: 179‐184, 1989.
 489.Shepard JW, Jr, Thawley SE. Localization of upper airway collapse during sleep in patients with obstructive sleep apnea. Am Rev Respir Dis 141: 1350‐1355, 1990.
 490.Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Activation of ventrolateral preoptic neurons during sleep. Science 271: 216‐219, 1996.
 491.Sherrey JH, Megirian D. State dependence of upper airway respiratory motoneurons: Functions of the cricothyroid and nasolabial muscles of the unanesthetized rat. EEG Clin Neurophysiol 43: 218‐228, 1977.
 492.Sherrey JH, Megirian D. Respiratory EMG activity of the posterior cricoarytenoid, cricothyroid and diaphragm muscles during sleep. Respir Physiol 39: 355‐365, 1980.
 493.Sherrey JH, Pollard MJ, Megirian D. Respiratory functions of the inferior pharyngeal constrictor and sternohyoid muscles during sleep. Exp Neurol 92: 267‐277, 1986.
 494.Shiromani PJ, Lai YY, Siegel JM. Descending projections from the dorsolateral pontine tegmentum to the paramedian reticular nucleus of the caudal medulla in the cat. Brain Res 517: 224‐228, 1990.
 495.Sica AL, Greenberg HE, Ruggiero DA, Scharf SM. Chronic‐intermittent hypoxia: A model of sympathetic activation in the rat. Respir Physiol 121: 173‐184, 2000.
 496.Sieck GC, Harper RM. Pneumotaxic area neuronal discharge during sleep‐waking states in the cat. Exp Neurol 67: 79‐102, 1980.
 497.Sieck GC, Trelease RB, Harper RM. Sleep influences on diaphragmatic motor unit discharge. Exp Neurol 85: 316‐335, 1984.
 498.Siegel JM. Narcolepsy. Scient Amer 282: 58‐63, 2000.
 499.Siegel JM, Wheeler RL, McGinty D. Activity of medullary reticular formation neurons in the unrestrained cat during waking and sleep. Brain Res 179: 49‐60, 1999.
 500.Silvani A, Bastianini S, Berteotti C, Franzini C, Lenzi P, Lo Martire V, Zoccoli G. Dysregulation of heart rhythm during sleep in leptin‐deficient obese mice. Sleep 33: 355‐361, 2010.
 501.Singer JH, Bellingham MC, Berger AJ. Presynaptic inhibition of glutamatergic synaptic transmission to rat motoneurons by serotonin. J Neurophysiol 76: 799‐807, 1996.
 502.Sirieix C, Gervasoni D, Luppi P‐H, Leger L. Role of the lateral paragigantocellular nucleus in the network of paradoxical (REM) sleep: An electrophysiological and anatomical study in the rat. PLoS One 7: e28724, 2012.
 503.Smith CA, Henderson KS, Xi L, Chow CM, Eastwood PR, Dempsey JA. Neural‐mechanical coupling of breathing in REM sleep. J Appl Physiol 83: 1923‐1932, 1997.
 504.Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL. Pre‐Bötzinger complex: A brainstem region that may generate respiratory rhythm in mammals. Science 254: 726‐729, 1991.
 505.Soja PJ, Finch DM, Chase MH. Effect of inhibitory amino acid antagonists on masseteric reflex suppression during active sleep. Exp Neurol 96: 178‐193, 1987.
 506.Soja PJ, López‐Rodríguez F, Morales FR, Chase MH. The postsynaptic inhibitory control of lumbar motoneurons during the atonia of active sleep: Effect of strychnine on motoneuron properties. J Neurosci 11: 2804‐2811, 1991.
 507.Sood S, Liu X, Liu H, Horner RL. Genioglossus muscle activity and serotonergic modulation of hypoglossal motor output in obese Zucker rats. J Appl Physiol 102: 2240‐2250, 2007.
 508.Sood S, Liu X, Liu H, Nolan P, Horner RL. 5‐HT at hypoglossal motor nucleus and respiratory control of genioglossus muscle in anesthetized rats. Respir Physiol Neurobiol 138: 205‐221, 2003.
 509.Sood S, Morrison JL, Liu H, Horner RL. Role of endogenous serotonin in modulating genioglossus muscle activity in awake and sleeping rats. Am J Respir Crit Care Med 172: 1338‐1347, 2005.
 510.Stanchina ML, Malhotra A, Fogel RB, Ayas N, Edwards JK, Schory K, White DP. Genioglossus muscle responsiveness to chemical and mechanical stimuli during non‐rapid eye movement sleep. Am J Respir Crit Care Med 165: 945‐949, 2002.
 511.Stanchina ML, Malhotra A, Fogel RB, Trinder J, Edwards JK, Schory K, White DP. The influence of lung volume on pharyngeal mechanics, collapsibility, and genioglossus muscle activation during sleep. Sleep 26: 851‐856, 2003.
 512.Stanek E, Cheng S, Takatoh J, Han BX, Wang F. Monosynaptic premotor circuit tracing reveals neural substrates for oro‐motor coordination. eLife 3: e02511, 2014.
 513.Steenland HW, Liu H, Horner RL. Endogenous glutamatergic control of rhythmically active mammalian respiratory motoneurons in vivo. J Neurosci 28: 6826‐6835, 2008.
 514.Steenland HW, Liu H, Sood S, Liu X, Horner RL. Respiratory activation of the genioglossus muscle involves both non‐NMDA and NMDA glutamate receptors at the hypoglossal motor nucleus in vivo. Neuroscience 138: 1407‐1424, 2006.
 515.Steinbusch HWM. Distribution of serotonin‐immunoreactivity in the central nervous system of the rat‐cell bodies and terminals. Neuroscience 6: 557‐618, 1981.
 516.Steriade M, Datta S, Paré D, Oakson G, Curró Dossi R. Neuronal activities in brain‐stem cholinergic nuclei related to tonic activation processes in thalamocortical systems. J Neurosci 10: 2541‐2559, 1990.
 517.Stettner GM, Fenik VB, Kubin L. Effect of chronic intermittent hypoxia on noradrenergic activation of hypoglossal motoneurons. J Appl Physiol 112: 305‐312, 2012. doi: 10.1152/japplphysiol.00697.2011
 518.Stettner GM, Kubin L. Antagonism of orexin receptors in the posterior hypothalamus reduces hypoglossal and cardiorespiratory excitation from the perifornical hypothalamus. J Appl Physiol 114: 119‐130, 2013. doi: 10.1152/japplphysiol.00965.2012
 519.Stettner GM, Lei Y, Benincasa HK, Kubin L. Evidence that adrenergic ventrolateral medullary cells are activated whereas precerebellar lateral reticular nucleus neurons are suppressed during REM sleep. PLoS One 8: e62410, 2013. doi: 10.1371/journal.pone.0062410
 520.Stettner GM, Rukhadze I, Mann GL, Lei Y, Kubin L. Respiratory modulation of lingual muscle activity across sleep‐wake states in rats. Respir Physiol Neurobiol 188: 308‐317, 2013. doi: 10.1016/j.resp.2013.05.033
 521.Strohl KP, Olson LG. Concerning the importance of pharyngeal muscles in the maintenance of upper airway patency during sleep. Chest 92: 918‐920, 1987.
 522.Strollo PJ, Gillespie MB, Soose RJ, Maurer JT, de Vries N, Cornelius J, Hanson RD, Padhya TA, Steward DL, Woodson BT, Verbraecken J, Vanderveken OM, Goetting MG, Feldman N, Chabolle F, Badr MS, Randerath W, Strohl KP, Stimulation Therapy for Apnea Reduction (STAR) Trial Group. Upper airway stimulation for obstructive sleep apnea: Durability of the treatment effect at 18 months. Sleep 38: 1593‐1598, 2015.
 523.Sullivan CE, Murphy E, Kozar LF, Phillipson EA. Waking and ventilatory responses to laryngeal stimulation in sleeping dogs. J Appl Physiol 45: 681‐689, 1978.
 524.Sun QJ, Berkowitz RG, Goodchild AK, Pilowsky PM. Serotonin inputs to inspiratory laryngeal motoneurons in the rat. J Comp Neurol 451: 91‐98, 2002.
 525.Sun QJ, Pilowsky P, Llewellyn‐Smith IJ. Thyrotropin‐releasing hormone inputs are preferentially directed towards respiratory motoneurons in rat nucleus ambiguus. J Comp Neurol 362: 320‐330, 1995.
 526.Sunanaga J, Deng BS, Zhang W, Kanmura Y, Kuwaki T. CO2 activates orexin‐containing neurons in mice. Respir Physiol Neurobiol 166: 184‐186, 2009.
 527.Svanborg E. Impact of obstructive apnea syndrome on upper airway respiratory muscles. Respir Physiol Neurobiol 147: 263‐272, 2005.
 528.Swale DR, Kharade SV, Denton JS. Cardiac and renal inward rectifier potassium channel pharmacology: Emerging tools for integrative physiology and therapeutics. Cur Op Pharmacol 15: 7‐15, 2014.
 529.Tago H, McGeer PL, McGeer EG, Akiyama H, Hersh LB. Distribution of choline acetyltransferase immunopositive structures in the rat brainstem. Brain Res 495: 271‐297, 1989.
 530.Taguchi O, Kubin L, Pack AI. Evocation of postural atonia and respiratory depression by pontine carbachol in the decerebrate rat. Brain Res 595: 107‐115, 1992.
 531.Takahash K, Lin J‐S, Sakai K. Neuronal activity of orexin and non‐orexin waking‐active neurons during wake‐sleep states in the mouse. Neuroscience 153: 860‐870, 2008.
 532.Takahashi K, Kayama Y, Lin JS, Sakai K. Locus coeruleus neuronal activity during the sleep‐waking cycle in mice. Neuroscience 169: 1115‐1126, 2010.
 533.Takahashi K, Lin JS, Sakai K. Neuronal activity of histaminergic tuberomammillary neurons during wake‐sleep states in the mouse. J Neurosci 26: 10292‐10298, 2006.
 534.Takakusaki K, Ohta Y, Mori S. Single medullary reticulospinal neurons exert postsynaptic inhibitory effects via inhibitory interneurons upon alpha‐motoneurons innervating cat hindlimb muscles. Exp Brain Res 74: 11‐23, 1989.
 535.Takata M. Two types of inhibitory postsynaptic potentials in the hypoglossal motoneurons. Progr Neurobiol 40: 385‐411, 1993.
 536.Tallaksen‐Greene SJ, Elde R, Wessendorf MW. Regional distribution of serotonin and substance P co‐existing in nerve fibers and terminals in the brainstem of the rat. Neuroscience 53: 1127‐1142, 1993.
 537.Talley EM, Rosin DL, Lee A, Guyenet PG, Lynch KR. Distribution of α2A‐adrenergic receptor‐like immunoreactivity in the rat central nervous system. J Comp Neurol 372: 111‐134, 1996.
 538.Talley EM, Sadr NN, Bayliss DA. Postnatal development of serotonergic innervation, 5‐HT1A receptor expression, and 5‐HT responses in rat motoneurons. J Neurosci 17: 4473‐4485, 1997.
 539.Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas R, Levy P, Weiss JW. A new model of chronic intermittent hypoxia in humans: Effect on ventilation, sleep, and blood pressure. J Appl Physiol 107: 17‐24, 2009.
 540.Tan W, Janczewski WA, Yang P, Shao XM, Callaway EM, Feldman JL. Silencing pre‐Bötzinger complex somatostatin‐expressing neurons induces persistent apnea in awake rat. Nat Neurosci 11: 538‐540, 2008.
 541.Tangel DJ, Mezzanotte WS, Sandberg EJ, White DP. Influences of NREM sleep on the activity of tonic vs. inspiratory phasic muscles in normal men. J Appl Physiol 73: 1058‐1066, 1992.
 542.Tangel DJ, Mezzanotte WS, White DP. Influences of NREM sleep on activity of palatoglossus and levator palatini muscles in normal men. J Appl Physiol 78: 689‐695, 1995.
 543.Tantucci C, Mehiri S, Duguet A, Similowski T, Arnulf I, Zelter M, Derenne J‐P, Milic‐Emili J. Application of negative expiratory pressure during expiration and activity of genioglossus in humans. J Appl Physiol 84: 1076‐1082, 1998.
 544.Tasali E, Ip MS. Obstructive sleep apnea and metabolic syndrome: Alterations in glucose metabolism and inflammation. Proc Am Thor Soc 5: 207‐217, 2008.
 545.Thach BT. Potential central nervous cystem involvement in sudden unexpected infant deaths and the sudden infant death syndrome. Compr Physiol 5: 1061‐1068, 2015. doi: 10.1002/cphy.c130052
 546.Thor KB, Blitz‐Siebert A, Helke CJ. Autoradiographic localization of 5HT1 binding sites in autonomic areas of the rat dorsomedial medulla oblongata. Synapse 10: 217‐227, 1992.
 547.Thor KB, Helke CJ. Serotonin‐ and substance p‐containing projections to the nucleus tractus solitarii of the rat. J Comp Neurol 265: 275‐293, 1987.
 548.Tian C, Zhu R, Zhu L, Qiu T, Cao Z, Kang T. Potassium channels: Structures, diseases, and modulators. Chem Biol Drug Des 83: 1‐26, 2014.
 549.Tojima H, Kubin L, Kimura H, Davies RO. Spontaneous ventilation and respiratory motor output during carbachol‐induced atonia of REM sleep in the decerebrate cat. Sleep 15: 404‐414, 1992.
 550.Torterolo P, Chase MH. The hypocretins (orexins) mediate the “phasic” components of REM sleep: A new hypothesis. Sleep Sci 7: 19‐29, 2014.
 551.Travers JB, Norgren R. Afferent projections to the oral motor nuclei in the rat. J Comp Neurol 220: 280‐298, 1983.
 552.Travers JB, Rinaman L. Identification of lingual motor control circuits using two strains of preudorabies virus. Neuroscience 115: 1139‐1151, 2002.
 553.Travers JB, Yoo JE, Chandran R, Herman K, Travers SP. Neurotransmitter phenotypes of intermediate zone reticular formation projections to the motor trigeminal and hypoglossal nuclei in the rat. J Comp Neurol 488: 28‐47, 2005.
 554.Trimmer JS. Subcellular localization of K+ channels in mammalian brain neurons: Remarkable precision in the midst of extraordinary complexity. Neuron 85: 238‐256, 2015.
 555.Trinder J, Jordan AS, Nicholas CL. Discharge properties of upper airway motor units during wakefulness and sleep. Progr Brain Res 212: 59‐75, 2014.
 556.Trinder J, Woods M, Nicholas CL, Chan JK, Jordan AS, Semmler JG. Motor unit activity in upper airway muscles genioglossus and tensor palatini. Respir Physiol Neurobiol 188: 362‐369, 2013.
 557.Ugolini G. Specificity of rabies virus as a transneuronal tracer of motor networks: Transfer from hypoglossal motoneurons to connected second‐order and higher order central nervous system cell groups. J Comp Neurol 356: 457‐480, 1995.
 558.Umemiya M, Berger AJ. Presynaptic inhibition by serotonin of glycinergic inhibitory synaptic currents in the rat brain stem. J Neurophysiol 73: 1192‐1200, 1995.
 559.Vander Maelen CP, Aghajanian GK. Serotonin‐induced depolarization of rat facial motoneurons in vivo: Comparison with amino acid transmitters. Brain Res 239: 139‐152, 1982.
 560.Vanni‐Mercier G, Sakai K, Lin JS, Jouvet M. Mapping of cholinoceptive brainstem structures responsible for the generation of paradoxical sleep in the cat. Arch Ital Biol 127: 133‐164, 1989.
 561.Veasey SC. Serotonin agonists and antagonists in obstructive sleep apnea: Therapeutic potential. Am J Respir Med 2: 21‐29, 2003.
 562.Veasey SC, Davis CW, Fenik P, Zhan G, Hsu YJ, Pratico D, Gow A. Long‐term intermittent hypoxia in mice: Protracted hypersomnolence with oxidative injury to sleep‐wake brain regions Sleep 27: 194‐201, 2004.
 563.Veasey SC, Fornal CA, Metzler CW, Jacobs BL. Response of serotonergic caudal raphe neurons in relation to specific motor activities in freely moving cats. J Neurosci 15: 5346‐5359, 1995.
 564.Veasey SC, Panckeri KA, Hoffman EA, Pack AI, Hendricks JC. The effects of serotonin antagonists in an animal model of sleep‐disordered breathing. Am J Respir Crit Care Med 153: 776‐786, 1996.
 565.Veasey SC, Zhan G, Fenik P, Pratico D. Long‐term intermittent hypoxia: Reduced excitatory hypoglossal nerve output. Am J Respir Crit Care Med 170: 665‐672, 2004.
 566.Vibert JF, Foutz AS, Caille D, Hugelin A. Respiratory rhythm multistability during sleep‐wake states. Brain Res 448: 403‐405, 1988.
 567.Vilaro MT, Palacios JM, Mengod G. Multiplicity of muscarinic autoreceptor subtypes? Comparison of the distribution of cholinergic cells and cells containing mRNA for five subtypes of muscarinic receptors in the rat brain. Mol Brain Res 21: 30‐46, 1994.
 568.Vincent SR, Kimura H. Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46: 755‐784, 1992.
 569.Volgin DV, Fay R, Kubin L. Postnatal development of serotonin 1B, 2A and 2C receptors in brainstem motoneurons. Eur J Neurosci 17: 1179‐1188, 2003.
 570.Volgin DV, Lu JW, Stettner GM, Mann GL, Ross RJ, Morrison AR, Kubin L. Time‐ and behavioral state‐dependent changes in posterior hypothalamic GABAA receptors contribute to the regulation of sleep. PLoS ONE 9: e86545, 2014. doi: 10.1371/journal.pone.0086545
 571.Volgin DV, Mackiewicz M, Kubin L. α1B receptors are the main postsynaptic mediators of adrenergic excitation in brainstem motoneurons, a single‐cell RT‐PCR study. J Chem Neuroanat 22: 157‐166, 2001.
 572.Volgin DV, Rukhadze I, Kubin L. Hypoglossal premotor neurons of the intermediate medullary reticular region express cholinergic markers. J Appl Physiol 105: 1576‐1584, 2008.
 573.Volgin DV, Saghir M, Kubin L. Developmental changes in the orexin 2 receptor mRNA in hypoglossal motoneurons. NeuroReport 13: 433‐436, 2002.
 574.Volgin DV, Stettner GM, Kubin L. Circadian dependence of receptors that mediate wake‐related excitatory drive to hypoglossal motoneurons. Respir Physiol Neurobiol 188: 301‐307, 2013. doi: 10.1016/j.resp.2013.04.024
 575.Voss MD, de Castro D, Lipski J, Pilowsky PM, Jiang C. Serotonin immunoreactive boutons form close appositions with respiratory neurons of the dorsal respiratory group in the cat. J Comp Neurol 295: 208‐218, 1990.
 576.Vranish JR, Bailey EF. A comprehensive assessment of genioglossus electromyographic activity in healthy adults. J Neurophysiol 113: 2692‐2699, 2015.
 577.Wang S, Benamer N, Zanella S, Kumar NN, Shi Y, Bevengut M, Penton D, Guyenet PG, Lesage F, Gestreau C, Barhanin J, Bayliss DA. TASK‐2 channels contribute to pH sensitivity of retrotrapezoid nucleus chemoreceptor neurons. J Neurosci 33: 16033‐16044, 2013.
 578.Wang S, Shi Y, Shu S, Guyenet PG, Bayliss DA. Phox2b‐expressing retrotrapezoid neurons are intrinsically responsive to H+ and CO2. J Neurosci 33: 7756‐7761, 2013.
 579.Weber F, Chung S, Beier KT, Xu M, Luo L, Dan Y. Control of REM sleep by ventral medulla GABAergic neurons. Nature 526: 435‐438, 2015.
 580.Wess J, Blin N, Yun J, Schoneberg T, Liu J. Molecular aspects of muscarinic receptor assembly and function. Progr Brain Res 109: 153‐162, 1996.
 581.Wheatley JR, Mezzanotte WS, Tangel DJ, White DP. Influence of sleep on genioglossus muscle activation by negative pressure in normal men. Am Rev Respir Dis 148: 597‐605, 1993.
 582.Wheatley JR, Tangel DJ, Mezzanotte WS, White DP. Influence of sleep on alae nasi EMG and nasal resistance in normal men. J Appl Physiol 75: 626‐632, 1993.
 583.Wheatley JR, Tangel DJ, Mezzanotte WS, White DP. Influence of sleep on response to negative airway pressure of tensor palatini muscle and retropalatal airway. J Appl Physiol 75: 2117‐2124, 1993.
 584.White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 172: 1363‐1370, 2005.
 585.White DP. The pathogenesis of obstructive sleep apnea: Advances in the past 100 years. Am J Respir Cell Mol Biol 34: 1‐6, 2006.
 586.White DP, Younes MK. Obstructive sleep apnea. Compr Physiol 2: 2541‐2594, 2012. doi: 10.1002/cphy.c110064
 587.White SR, Fung SJ, Jackson DA, Imel KM. Serotonin, norepinephrine and associated neuropeptides: Effects on somatic motoneuron excitability. Progr Brain Res 107: 183‐199, 1996.
 588.Widdicombe JG. Reflexes from the upper respiratory tract. Compr Physiol 2011 (Suppl. 11): 363‐394.
 589.Wiegand DA, Latz B, Zwillich CW, Wiegand L. Geniohyoid muscle activity in normal men during wakefulness and sleep. J Appl Physiol 69: 1262‐1269, 1990.
 590.Wiegand DA, Latz B, Zwillich CW, Wiegand L. Upper airway resistance and geniohyoid muscle activity in normal men during wakefulness and sleep. J Appl Physiol 69: 1252‐1261, 1990.
 591.Wiegand L, Zwillich CW, Wiegand D, White DP. Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men. J Appl Physiol 71: 488‐497, 1991.
 592.Wilkinson V, Malhotra A, Nicholas CL, Worsnop C, Jordan AS, Butler JE, Saboisky JP, Gandevia SC, White DP, Trinder J. Discharge patterns of human genioglossus motor units during sleep onset. Sleep 31: 525‐533, 2008.
 593.Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D. Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci U S A 104: 10685‐10690, 2007.
 594.Winter WC, Gampper T, Gay SB, Suratt PM. Enlargement of the lateral pharyngeal fat pad space in pigs increases upper airway resistance. J Appl Physiol 79: 726‐731, 1995.
 595.Winzer‐Serhan UH, Raymon HK, Broide RS, Chen Y, Leslie FM. Expression of a2 adrenoceptors during rat brain development ‐ I. α2A messenger RNA expression. Neuroscience 76: 241‐260, 1997.
 596.Wirth KJ, Steinmeyer K, Ruetten H. Sensitization of upper airway mechanoreceptors as a new pharmacologic principle to treat obstructive sleep apnea: Investigations with AVE0118 in anesthetized pigs. Sleep 36: 699‐708, 2013.
 597.Withington‐Wray DJ, Mifflin SW, Spyer KM. Intracellular analysis of respiratory‐modulated hypoglossal motoneurons in the cat. Neuroscience 25: 1041‐1051, 1988.
 598.Woch G, Davies RO, Pack AI, Kubin L. Behavior of raphe cells projecting to the dorsomedial medulla during carbachol‐induced atonia in the cat. J Physiol (Lond) 490: 745‐758, 1996.
 599.Woch G, Kubin L. Non‐reciprocal control of rhythmic activity in respiratory‐modulated XII motoneurons. NeuroReport 6: 2085‐2088, 1995.
 600.Woch G, Ogawa H, Davies RO, Kubin L. Behavior of hypoglossal inspiratory premotor neurons during the carbachol‐induced, REM sleep‐like suppression of upper airway motoneurons. Exp Brain Res 130: 508‐520, 2000.
 601.Worsnop C, Kay A, Pierce R, Kim Y, Trinder J. Activity of respiratory pump and upper airway muscles during sleep onset. J Appl Physiol 85: 908‐920, 1998.
 602.Wright DE, Seroogy KB, Lundgren KH, Davis BM, Jennes L. Comparative localization of serotonin1A, 1C, and 2 receptor subtype mRNAs in rat brain. J Comp Neurol 351: 357‐373, 1995.
 603.Wu MF, John J, Boehmer LN, Yau D, Nguyen GB, Siegel JM. Activity of dorsal raphe cells across the sleep‐waking cycle and during cataplexy in narcoleptic dogs. J Physiol (Lond) 554: 202‐215, 2004.
 604.Yamada Y, Yamamura K, Inoue M. Coordination of cranial motoneurons during mastication. Respir Physiol Neurobiol 147: 177‐189, 2005.
 605.Yamuy J, Fung SJ, Xi M, Morales FR, Chase MH. Hypoglossal motoneurons are postsynaptically inhibited during carbachol‐induced rapid eye movement sleep. Neuroscience 94: 11‐15, 1999.
 606.Yasuda K, Robinson DM, Selvaratnam SR, Walsh CW, McMorland AJ, Funk GD. Modulation of hypoglossal motoneuron excitability by NK1 receptor activation in neonatal mice in vitro. J Physiol (Lond) 534: 447‐464, 2001.
 607.Yoo PB, Durand DM. Effects of selective hypoglossal nerve stimulation on canine upper airway mechanics. J Appl Physiol 99: 937‐943, 2005.
 608.Younes M. Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea. Am J Respir Crit Care Med 168: 645‐658, 2003.
 609.Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med 169: 623‐633, 2004.
 610.Young T, Finn L, Peppard PE, Szklo‐Coxe M, Austin D, Nieto FJ, Stubbs R, Hla KM. Sleep disordered breathing and mortality: Eighteen‐year follow‐up of the Wisconsin sleep cohort. Sleep 31: 1071‐1078, 2008.
 611.Yu MS, Jung NR, Choi KH, Choi K, Lee BJ, Chung YS. An animal model of obstructive sleep apnea in rabbit. Laryngoscope 124: 789‐796, 2014.
 612.Zanella S, Viemari JC, Hilaire G. Muscarinic receptors and α2‐adrenoceptors interact to modulate the respiratory rhythm in mouse neonates. Respir Physiol Neurobiol 157: 215‐225, 2007.
 613.Zaninetti M, Tribollet E, Bertrand D, Raggenbass M. Presence of functional neuronal nicotinic acetylcholine receptors in brainstem motoneurons of the rat. Eur J Neurosci 11: 2737‐2748, 1999.
 614.Zhan G, Shaheen F, Mackiewicz M, Fenik P, Veasey SC. Single cell laser dissection with molecular beacon polymerase chain reaction identifies 2A as the predominant serotonin receptor subtype in hypoglossal motoneurons. Neuroscience 113: 145‐154, 2002.
 615.Zhang GH, Liu ZL, Zhang BJ, Geng WY, Song NN, Zhou W, Cao YX, Li SQ, Huang ZL, Shen LL. Orexin A activates hypoglossal motoneurons and enhances genioglossus muscle activity in rats. Br J Pharmacol 171: 4233‐4246, 2014.
 616.Zhang H, Ye JY, Hua L, Chen ZH, Ling L, Zhu Q, Wang LM, Zheng L, Zhang YH. Inhomogeneous neuromuscular injury of the genioglossus muscle in subjects with obstructive sleep apnea. Sleep Breath 19: 539‐545, 2015.
 617.Zhang SX, Wang Y, Gozal D. Pathological consequences of intermittent hypoxia in the central nervous system. Compr Physiol 2: 1767‐1777, 2012. doi: 10.1002/cphy.c100060.
 618.Zhu Y, Fenik P, Zhan G, Mazza E, Kelz M, Aston‐Jones G, Veasey SC. Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model. J Neurosci 27: 10060‐10071, 2007.
 619.Zifa E, Fillion G. 5‐hydroxytryptamine receptors. Pharmacol Rev 44: 401‐458, 1992.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Leszek Kubin. Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms. Compr Physiol 2016, 6: 1801-1850. doi: 10.1002/cphy.c160002