Muscarinic Inhibition of Hypoglossal Motoneurons: Possible Implications for Upper Airway Muscle Hypotonia during REM Sleep

Zhu, Lin; Chamberlin, Nancy L.; Arrigoni, Elda

doi:10.1523/jneurosci.0461-19.2019

Cited by 16 publications

(11 citation statements)

References 72 publications

(113 reference statements)

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“…In addition, the KEGG enrichment analysis of the differentially expressed mRNAs showed that most of the enriched pathways had been linked to OSA ( Figure 3D ). Among them, the transforming growth factor-β (TGF-β) pathway ( 20 ), glutamatergic synapse ( 21 ), and ERBB pathway ( 22 ) have been reported to be closely relevant to OSA.…”

Section: Resultsmentioning

confidence: 99%

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Screening of plasma exosomal lncRNAs to identify potential biomarkers for obstructive sleep apnea

Chen¹,

Liu²,

Huang³

et al. 2022

Ann Transl Med

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Background Obstructive sleep apnea (OSA) is highly prevalent, but frequently undiagnosed. The existing biomarkers of OSA are relatively insensitive and inaccurate. Long non-coding RNAs (lncRNAs) have no protein-coding ability but have a role in regulating gene expression. They are stably expressed in exosomes, easily and rapidly measurable. Changes in expression of exosomal lncRNAs can be useful for disease diagnoses. However, there are few reports on the association of exosomal lncRNAs with OSA. We aimed to investigate the exosomal lncRNA profiles to establish the differences between non-OSA, OSA with or without hypertension (HTN) and serve as a potential diagnostic biomarker. Methods This diagnostic test included 63 participants: [normal control (NC) =25], (OSA =23), and (HTN-OSA =15). Expression profiling of lncRNAs in isolated exosomes was performed through high-throughput sequencing in 9 participants. Subsequently, OSA/HTN-OSA related lncRNAs were selected for validation by droplet digital polymerase chain reaction (ddPCR), receiver operating characteristic (ROC) curves were used to determine the diagnostic value. The reliabilities of the screened gene were further validated in another independent cohort: (NC =10), (OSA mild =10), (OSA moderate =11), and (OSA severe =10), the correlation between clinical features and its expression was analyzed. The MiRanda software was used to predict the binding sites of interaction between microRNA (miRNA) and target genes regulated by screened lncRNA. Results We identified the differentially expressed lncRNAs and mRNAs in plasma exosomes of the NC, OSA, HTN-OSA groups. Most pathways enriched in differentially expressed lncRNAs and mRNAs had previously been linked to OSA. Among them, ENST00000592016 enables discrimination between NC and OSA individuals [area under curve (AUC) =0.846, 95% confidence interval (CI): 0.72–0.97]. The severity of OSA was associated with changes in the ENST00000592016 expression. Furthermore, ENST00000592016 affected the PI3K-Akt, MAPK, and TNF pathways by regulating miRNA expressions. Conclusions This is the first report about differential expression of lncRNA in OSA and HTN-OSA exosomes. ENST00000592016 enables discrimination between NC and OSA individuals. This work enabled characterization of OSA and provided the preliminary work for the study of biomarker of OSA.

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Section: Resultsmentioning

confidence: 99%

“…Figure 4 shows the KEGG enrichment analysis of the 15 most differentially expressed lncRNAs. Most of the enriched pathways had been linked to OSA, including the mammalian target of rapamycin (mTOR) pathway ( 23 ), the WNT signaling pathway ( 24 ), and the glutamatergic synapse pathway ( 21 ), among others.…”

Section: Resultsmentioning

confidence: 99%

Screening of plasma exosomal lncRNAs to identify potential biomarkers for obstructive sleep apnea

Chen¹,

Liu²,

Huang³

et al. 2022

Ann Transl Med

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“…This includes, for example, hypoglossal pre-motor neurons of the intermediate medullary reticular region that are cholinergic 46 . Many of the neurons in this region have increased activity during REM sleep 47 , although it is unknown if these specific REM sleep-active neurons are cholinergic and if they are also the source of the motor inhibition of the hypoglossal motor pool in REM sleep [48][49][50] . It is also possible that a local increase in acetylcholine release at the hypoglossal motoneuron pool via activation of cholinergic pre-motor neurons could be excitatory or inhibitory [50][51][52][53] and modulate the direct light-induced activation of the motoneurons per se.…”

Section: Discussionmentioning

confidence: 99%

“…Many of the neurons in this region have increased activity during REM sleep 47 , although it is unknown if these specific REM sleep-active neurons are cholinergic and if they are also the source of the motor inhibition of the hypoglossal motor pool in REM sleep [48][49][50] . It is also possible that a local increase in acetylcholine release at the hypoglossal motoneuron pool via activation of cholinergic pre-motor neurons could be excitatory or inhibitory [50][51][52][53] and modulate the direct light-induced activation of the motoneurons per se. Since an increase in tongue motor activity is consistently elicited by each photostimulation pulse in each behavioral state including general anesthesia, the potential for any light-induced activation of inhibitory inputs (which would also be elicited in each behavioral state) must be overwhelmed by the post-synaptic excitation mediated by direct cation influx in stimulated cholinergic neurons, including hypoglossal motoneurons following the ChR2(H134R) activation.…”

Section: Discussionmentioning

confidence: 99%

Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo

Aggarwal

Liu

Montandon

et al. 2020

Sci Rep

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Motoneurons are the final output pathway for the brain's influence on behavior. Here we identify properties of hypoglossal motor output to the tongue musculature. tongue motor control is critical to the pathogenesis of obstructive sleep apnea, a common and serious sleep-related breathing disorder. Studies were performed on mice expressing a light sensitive cation channel exclusively on cholinergic neurons (ChAT-ChR2(H134R)-EYFP). Discrete photostimulations under isoflurane-induced anesthesia from an optical probe positioned above the medullary surface and hypoglossal motor nucleus elicited discrete increases in tongue motor output, with the magnitude of responses dependent on stimulation power (p < 0.001, n = 7) and frequency (P = 0.002, n = 8, with responses to 10 Hz stimulation greater than for 15-25 Hz, P < 0.022). Stimulations during REM sleep elicited significantly reduced responses at powers 3-20 mW compared to non-rapid eye movement (non-REM) sleep and wakefulness (each p < 0.05, n = 7). Response thresholds were also greater in REM sleep (10 mW) compared to non-REM and waking (3 to 5 mW, P < 0.05), and the slopes of the regressions between input photostimulation powers and output motor responses were specifically reduced in REM sleep (P < 0.001). This study identifies that variations in photostimulation input produce tunable changes in hypoglossal motor output in-vivo and identifies REM sleep specific suppression of net motor excitability and responsivity.Obstructive sleep apnea (OSA) is a common and serious breathing disorder with significant clinical, social and economic consequences 1 . OSA is characterized by repeated episodes of upper airway obstruction that occur only during sleep, with the airway obstructions leading to futile breathing efforts, asphyxia, sleep disturbance and other physiological sequalae of medical relevance 2,3 . The root cause of the upper airway obstruction is reduced activity and reflex compensatory responses of the pharyngeal muscles during sleep, whereas in wakefulness the motor activity and responsivity are sufficient to keep the airspace open 4 . Ultimately, state-dependent pharyngeal muscle activity and responsivity of the brainstem motor pools driving these muscles are pivotal to OSA pathophysiology and the phenotypic traits of OSA patients 5-8 .Such state-dependent activity of the pharyngeal musculature is central to OSA pathogenesis, and the hypoglossal motoneuron pool is the source of motor output to the largest of the pharyngeal muscles, the tongue 2,4 . Single unit recordings of tongue motor activity are an experimentally powerful indicator of the discharge patterns and recruitment characteristics of single hypoglossal motoneurons in the medulla that are otherwise inaccessible for investigation [9][10][11][12][13][14][15][16][17][18][19] . One limitation of such single-unit studies, however, is the inability to impose acute, precise and direct control over hypoglossal motor output to interrogate physiological properties relevant to tongue motor control.In the present...

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“…Several groups have also used chemo-and optogenetic methods to stimulate excitatory or inhibitory presynaptic neural pathways to better understand the neural regulation of XII motoneuron activity [90][91][92][93]. For example, medullary A1/C1 neurons were demonstrated to have an excitatory impact on XII motoneurons using a DREADD approach.…”

Section: Tongue Activation Using Chemogenetic and Optogenetic Approachesmentioning

confidence: 99%

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

et al. 2021

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Dysfunction and/or reduced activity in the tongue muscles contributes to conditions such as dysphagia, dysarthria, and sleep disordered breathing. Current treatments are often inadequate, and the tongue is a readily accessible target for therapeutic gene delivery. In this regard, gene therapy specifically targeting the tongue motor system offers two general strategies for treating lingual disorders. First, correcting tongue myofiber and/or hypoglossal (XII) motoneuron pathology in genetic neuromuscular disorders may be readily achieved by intralingual delivery of viral vectors. The retrograde movement of viral vectors such as adeno-associated virus (AAV) enables targeted distribution to XII motoneurons via intralingual viral delivery. Second, conditions with impaired or reduced tongue muscle activation can potentially be treated using viral-driven chemo- or optogenetic approaches to activate or inhibit XII motoneurons and/or tongue myofibers. Further considerations that are highly relevant to lingual gene therapy include (1) the diversity of the motoneurons which control the tongue, (2) the patterns of XII nerve branching, and (3) the complexity of tongue muscle anatomy and biomechanics. Preclinical studies show considerable promise for lingual directed gene therapy in neuromuscular disease, but the potential of such approaches is largely untapped.

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Muscarinic Inhibition of Hypoglossal Motoneurons: Possible Implications for Upper Airway Muscle Hypotonia during REM Sleep

Cited by 16 publications

References 72 publications

Screening of plasma exosomal lncRNAs to identify potential biomarkers for obstructive sleep apnea

Screening of plasma exosomal lncRNAs to identify potential biomarkers for obstructive sleep apnea

Measurement and State-Dependent Modulation of Hypoglossal Motor Excitability and Responsivity In-Vivo

Gene delivery to the hypoglossal motor system: preclinical studies and translational potential

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