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Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control

View Article: PubMed Central - PubMed

ABSTRACT

Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a “designer” receptor into the HMN and selectively modulated it with a “designer” drug. We used cre-dependent viral vectors (AAV8-hSyn-DIO-hM3Dq-mCherry) to transduce hypoglossal motoneurons of ChAT-Cre+ mice with hM3Dq (activating) receptors. We measured sleep and breathing in three conditions: (i) sham, (ii) after systemic administration of clozapine-N-oxide (CNO; 1 mg/kg) or (iii) vehicle. CNO activates hM3Dq receptors but is otherwise biologically inert. Systemic administration of CNO caused significant and sustained increases in tongue muscle activity in non-REM (261 ± 33% for 10 hrs) and REM sleep (217 ± 21% for 8 hrs), both P < 0.01 versus controls. Responses were specific and selective for the tongue with no effects on diaphragm or postural muscle activities, or sleep-wake states. These results support targeting a selective and restricted “druggable” target at the HMN (e.g., Kir2.4) to activate tongue motor activity during sleep.

No MeSH data available.


Related in: MedlinePlus

Responses to systemic injection of CNO were specific to the tongue musculature as there were no effects on other physiological variables.There were no significant differences between the three experimental conditions (i.e., sham, and responses to vehicle or CNO) on respiratory rate (A), diaphragm amplitude (B), neck muscle activity (C), the percent time spent in each sleep-wake state (D), the number of sleep-wake bouts (E) or their duration (F). Values are mean + SEM.
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f8: Responses to systemic injection of CNO were specific to the tongue musculature as there were no effects on other physiological variables.There were no significant differences between the three experimental conditions (i.e., sham, and responses to vehicle or CNO) on respiratory rate (A), diaphragm amplitude (B), neck muscle activity (C), the percent time spent in each sleep-wake state (D), the number of sleep-wake bouts (E) or their duration (F). Values are mean + SEM.

Mentions: There was no effect of experimental condition (i.e., sham, vehicle or CNO) on respiratory rate (F2,14 = 2.22, P = 0.142, two-way ANOVA-RM, Fig. 8A). There was a significant effect of sleep-wake state on respiratory rate (F2,14 = 15.30, P < 0.001), with rate being lower in REM sleep than non-REM sleep (t7 = 5.36, P < 0.001, post-hoc paired t-test). The effect of sleep-wake state on respiratory rate did not depend on experimental condition (F4,20 = 0.39, P = 0.814). Respiratory rates were only analyzed in periods of quiet waking, non-REM and REM sleep due to artefacts and non-respiratory activity present during behaviors in active waking.


Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control
Responses to systemic injection of CNO were specific to the tongue musculature as there were no effects on other physiological variables.There were no significant differences between the three experimental conditions (i.e., sham, and responses to vehicle or CNO) on respiratory rate (A), diaphragm amplitude (B), neck muscle activity (C), the percent time spent in each sleep-wake state (D), the number of sleep-wake bouts (E) or their duration (F). Values are mean + SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382915&req=5

f8: Responses to systemic injection of CNO were specific to the tongue musculature as there were no effects on other physiological variables.There were no significant differences between the three experimental conditions (i.e., sham, and responses to vehicle or CNO) on respiratory rate (A), diaphragm amplitude (B), neck muscle activity (C), the percent time spent in each sleep-wake state (D), the number of sleep-wake bouts (E) or their duration (F). Values are mean + SEM.
Mentions: There was no effect of experimental condition (i.e., sham, vehicle or CNO) on respiratory rate (F2,14 = 2.22, P = 0.142, two-way ANOVA-RM, Fig. 8A). There was a significant effect of sleep-wake state on respiratory rate (F2,14 = 15.30, P < 0.001), with rate being lower in REM sleep than non-REM sleep (t7 = 5.36, P < 0.001, post-hoc paired t-test). The effect of sleep-wake state on respiratory rate did not depend on experimental condition (F4,20 = 0.39, P = 0.814). Respiratory rates were only analyzed in periods of quiet waking, non-REM and REM sleep due to artefacts and non-respiratory activity present during behaviors in active waking.

View Article: PubMed Central - PubMed

ABSTRACT

Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a &ldquo;designer&rdquo; receptor into the HMN and selectively modulated it with a &ldquo;designer&rdquo; drug. We used cre-dependent viral vectors (AAV8-hSyn-DIO-hM3Dq-mCherry) to transduce hypoglossal motoneurons of ChAT-Cre+ mice with hM3Dq (activating) receptors. We measured sleep and breathing in three conditions: (i) sham, (ii) after systemic administration of clozapine-N-oxide (CNO; 1&thinsp;mg/kg) or (iii) vehicle. CNO activates hM3Dq receptors but is otherwise biologically inert. Systemic administration of CNO caused significant and sustained increases in tongue muscle activity in non-REM (261&thinsp;&plusmn;&thinsp;33% for 10&thinsp;hrs) and REM sleep (217&thinsp;&plusmn;&thinsp;21% for 8&thinsp;hrs), both P&thinsp;&lt;&thinsp;0.01 versus controls. Responses were specific and selective for the tongue with no effects on diaphragm or postural muscle activities, or sleep-wake states. These results support targeting a selective and restricted &ldquo;druggable&rdquo; target at the HMN (e.g., Kir2.4) to activate tongue motor activity during sleep.

No MeSH data available.


Related in: MedlinePlus