Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency

Curado, Thomaz Fleury; Fishbein, Kenneth W.; Pho, Huy; Brennick, Michael J.; Dergacheva, Olga; Sennes, Luiz Ubirajara; Pham, Luu V.; Ladenheim, Ellen E.; Spencer, Richard G.; Mendelowitz, David; Schwartz, Alan R.; Polotsky, Vsevolod Y.

doi:10.1038/srep44392

Cited by 43 publications

(43 citation statements)

References 38 publications

(27 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Two previous studies used cre-dependent viral vectors to transduce hypoglossal motoneurons of ChAT-Cre+ mice with hM3Dq receptors 21,22 . Those studies identified that systemic administration of clozapine-N-oxide led to increased tongue muscle activity that enlarged the pharyngeal airspace in anesthetized mice 21 , and caused sustained tongue muscle activation across sleep-wake states in behaving mice 22 . However, a key limitation of such 'chemogenetic' studies 21,22 is the inability to impose acute, precise and direct control over hypoglossal motor activity using an intervention that can be transiently turned on and off, as well as graded in intensity, in order to interrogate properties of net motor excitability and responsivity.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the identified properties are relevant to understanding and manipulating tongue motor control, in particular hypoglossal motor excitability and responsivity, that are key pathophysiological and phenotypic traits related to human OSA 5-8 . Such key properties of hypoglossal motor excitability and responsivity are not are amenable to systematic quantification using previous 'chemogenetic' approaches 21,22 given the inability to impose acute, precise and direct control over hypoglossal motor output using an intervention that can be transiently turned on and off, and graded in intensity, as is possible with photostimulation.The rationale for Study 1 in anesthetized mice was to interrogate the properties of hypoglossal motor output from the evoked motor responses using different protocols under stable conditions throughout the experiment (i.e., in the absence of spontaneous behaviors). The results from that study then led to the selection of one protocol to address properties of hypoglossal motor excitability and responsivity across naturally occurring sleep-wake states.…”

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confidence: 99%

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Manipulation of certain potassium channels at the hypoglossal motor pool can activate the tongue musculature throughout sleep to waking levels 40, 42 . Importantly, it has been recently shown that introducing a “designer” receptor into the hypoglossal motor pool, and selectively modulating it with a “designer” drug, led to significant and sustained increases in tongue muscle activity and increases in upper airway size in pre-clinical rodent models 60, 61 . Moreover, the increases in tongue muscle activity during sleep persisted for 8–10 hours, were of physiological pattern and magnitude, and were specific and selective for the tongue with no effects on diaphragm or postural muscle activities, or sleep-wake states 60 .…”

Section: Mapping Potential Drug Targets In the Circuitry Controllimentioning

confidence: 99%

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

2017

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There is currently no pharmacotherapy for OSA, but there is no principled a-priori reason why there shouldn’t be one. This review identifies a rational decision-making strategy with the necessary logical underpinnings that any reasonable approach would be expected to navigate to develop a viable pharmacotherapy for OSA. The process first involves phenotyping an individual to quantify and characterize the critical predisposing factor(s) to their OSA pathogenesis and identify, a-priori, if the patient is likely to benefit from a pharmacotherapy that targets those factors. We then identify rational strategies to manipulate those critical predisposing factor(s), and the barriers that have to be overcome for success of any OSA pharmacotherapy. A new analysis then identifies candidate drug targets to manipulate the upper airway motor circuitry for OSA pharmacotherapy. The first conclusion is that there are two general pharmacological approaches for OSA treatment that are of most potential benefit and are practically realistic, one being fairly intuitive but the second perhaps less so. The second conclusion is that after identifying the critical physiological obstacles to OSA pharmacotherapy, there are current therapeutic targets of high interest for future development. The final analysis provides a tabulated resource of “druggable” targets that are relatively restricted to the circuitry controlling the upper airway musculature, with these candidate targets being of high priority for screening and further study. We also emphasize that a pharmacotherapy may not cure OSA per se, but may still be a useful adjunct to improve the effectiveness of, and adherence to, other treatment mainstays.

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Neuropsychiatric Quinism: Chronic Encephalopathy Caused by Poisoning by Mefloquine and Related Quinoline Drugs

Nevin¹

2019

Veteran Psychiatry in the US

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Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency

Cited by 43 publications

References 38 publications

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

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

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

Neuropsychiatric Quinism: Chronic Encephalopathy Caused by Poisoning by Mefloquine and Related Quinoline Drugs

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