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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

Group data showing tongue muscle activity varies across sleep-wake state pre-intervention.Tongue muscle activities recorded in the 2 hours of baseline recordings (i.e., before any interventions) were indistinguishable between the three experimental conditions (i.e., sham, pre-vehicle and pre-CNO). Tongue muscle activity varied across sleep-wake states, being higher in active wakefulness compared to quiet wakefulness, and higher in quiet wakefulness compared to sleep. Values are mean ± SEM.
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f3: Group data showing tongue muscle activity varies across sleep-wake state pre-intervention.Tongue muscle activities recorded in the 2 hours of baseline recordings (i.e., before any interventions) were indistinguishable between the three experimental conditions (i.e., sham, pre-vehicle and pre-CNO). Tongue muscle activity varied across sleep-wake states, being higher in active wakefulness compared to quiet wakefulness, and higher in quiet wakefulness compared to sleep. Values are mean ± SEM.

Mentions: The group data showed that tongue muscle activity recorded in the 2 hours of baseline recordings (i.e., before any interventions) were indistinguishable between the three experimental conditions (i.e., sham, before vehicle and before CNO, F2,14 = 1.34, P = 0.292, two-way ANOVA-RM). However, tongue muscle activity did vary significantly across sleep-wake states (F3,21 = 64.63, P < 0.001, two-way ANOVA-RM, Fig. 3). Further analyses confirmed that tongue muscle activity was higher in active wakefulness compared to quiet wakefulness (t7 = 7.68, P < 0.001, post-hoc paired t-test), higher in quiet wakefulness compared to non-REM sleep (t7 = 4.49, P = 0.001), but of similar magnitude between non-REM and REM sleep (t7 = 0.25, P = 1.00).


Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control
Group data showing tongue muscle activity varies across sleep-wake state pre-intervention.Tongue muscle activities recorded in the 2 hours of baseline recordings (i.e., before any interventions) were indistinguishable between the three experimental conditions (i.e., sham, pre-vehicle and pre-CNO). Tongue muscle activity varied across sleep-wake states, being higher in active wakefulness compared to quiet wakefulness, and higher in quiet wakefulness compared to sleep. Values are mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Group data showing tongue muscle activity varies across sleep-wake state pre-intervention.Tongue muscle activities recorded in the 2 hours of baseline recordings (i.e., before any interventions) were indistinguishable between the three experimental conditions (i.e., sham, pre-vehicle and pre-CNO). Tongue muscle activity varied across sleep-wake states, being higher in active wakefulness compared to quiet wakefulness, and higher in quiet wakefulness compared to sleep. Values are mean ± SEM.
Mentions: The group data showed that tongue muscle activity recorded in the 2 hours of baseline recordings (i.e., before any interventions) were indistinguishable between the three experimental conditions (i.e., sham, before vehicle and before CNO, F2,14 = 1.34, P = 0.292, two-way ANOVA-RM). However, tongue muscle activity did vary significantly across sleep-wake states (F3,21 = 64.63, P < 0.001, two-way ANOVA-RM, Fig. 3). Further analyses confirmed that tongue muscle activity was higher in active wakefulness compared to quiet wakefulness (t7 = 7.68, P < 0.001, post-hoc paired t-test), higher in quiet wakefulness compared to non-REM sleep (t7 = 4.49, P = 0.001), but of similar magnitude between non-REM and REM sleep (t7 = 0.25, P = 1.00).

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