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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

Persistent tongue muscle activation in response to systemic injection of CNO.Group data showing significant and sustained tongue muscle activation across sleep-wake states after systemic injection of CNO in the mice with hM3Dq receptors transduced at the hypoglossal motor pool. Data are shown in the baseline period pre-intervention and up to 10 hours post-intervention for each of the CNO, vehicle and sham conditions. For each of non-REM and REM sleep and quiet wakefulness (A–C), there was a significant effect of experimental condition on tongue muscle activity, with activity after CNO being significantly increased compared to both the vehicle and sham conditions. This effect of experimental condition just failed to reach statistical significance in active wakefulness (D, P = 0.052). The symbol ‘*’ indicates significant increases in tongue muscle activity after CNO, compared to the same time-bins in the vehicle and sham conditions from post-hoc analyses. The symbol ‘#’ indicates significant changes in tongue muscle activity over time after CNO (i.e., between time-bins) from post-hoc analyses. The symbol ‘‡’ in panel D indicates that tongue muscle activity during the 8th to 10th hour of recording post-intervention in active wakefulness (i.e., 17:00 to 19:00 hrs clock time) was significantly increased compared to earlier time points, independent of experimental condition. See text for further details.
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f9: Persistent tongue muscle activation in response to systemic injection of CNO.Group data showing significant and sustained tongue muscle activation across sleep-wake states after systemic injection of CNO in the mice with hM3Dq receptors transduced at the hypoglossal motor pool. Data are shown in the baseline period pre-intervention and up to 10 hours post-intervention for each of the CNO, vehicle and sham conditions. For each of non-REM and REM sleep and quiet wakefulness (A–C), there was a significant effect of experimental condition on tongue muscle activity, with activity after CNO being significantly increased compared to both the vehicle and sham conditions. This effect of experimental condition just failed to reach statistical significance in active wakefulness (D, P = 0.052). The symbol ‘*’ indicates significant increases in tongue muscle activity after CNO, compared to the same time-bins in the vehicle and sham conditions from post-hoc analyses. The symbol ‘#’ indicates significant changes in tongue muscle activity over time after CNO (i.e., between time-bins) from post-hoc analyses. The symbol ‘‡’ in panel D indicates that tongue muscle activity during the 8th to 10th hour of recording post-intervention in active wakefulness (i.e., 17:00 to 19:00 hrs clock time) was significantly increased compared to earlier time points, independent of experimental condition. See text for further details.

Mentions: Tongue muscle activity was analyzed up to 10 hours post-intervention in each of the CNO, vehicle and sham conditions and these data are shown in Fig. 9. Although there was significant tongue muscle activation that persisted for hours after CNO (Fig. 9, and analysed below), it is important to note that activity returned to similar baseline values each day before the interventions as measured in each sleep-wake state for each experimental condition, i.e., sham, vehicle or CNO (each F2,8 < 2.68, P > 0.128, one-way ANOVA-RM, Fig. 9).


Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control
Persistent tongue muscle activation in response to systemic injection of CNO.Group data showing significant and sustained tongue muscle activation across sleep-wake states after systemic injection of CNO in the mice with hM3Dq receptors transduced at the hypoglossal motor pool. Data are shown in the baseline period pre-intervention and up to 10 hours post-intervention for each of the CNO, vehicle and sham conditions. For each of non-REM and REM sleep and quiet wakefulness (A–C), there was a significant effect of experimental condition on tongue muscle activity, with activity after CNO being significantly increased compared to both the vehicle and sham conditions. This effect of experimental condition just failed to reach statistical significance in active wakefulness (D, P = 0.052). The symbol ‘*’ indicates significant increases in tongue muscle activity after CNO, compared to the same time-bins in the vehicle and sham conditions from post-hoc analyses. The symbol ‘#’ indicates significant changes in tongue muscle activity over time after CNO (i.e., between time-bins) from post-hoc analyses. The symbol ‘‡’ in panel D indicates that tongue muscle activity during the 8th to 10th hour of recording post-intervention in active wakefulness (i.e., 17:00 to 19:00 hrs clock time) was significantly increased compared to earlier time points, independent of experimental condition. See text for further details.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f9: Persistent tongue muscle activation in response to systemic injection of CNO.Group data showing significant and sustained tongue muscle activation across sleep-wake states after systemic injection of CNO in the mice with hM3Dq receptors transduced at the hypoglossal motor pool. Data are shown in the baseline period pre-intervention and up to 10 hours post-intervention for each of the CNO, vehicle and sham conditions. For each of non-REM and REM sleep and quiet wakefulness (A–C), there was a significant effect of experimental condition on tongue muscle activity, with activity after CNO being significantly increased compared to both the vehicle and sham conditions. This effect of experimental condition just failed to reach statistical significance in active wakefulness (D, P = 0.052). The symbol ‘*’ indicates significant increases in tongue muscle activity after CNO, compared to the same time-bins in the vehicle and sham conditions from post-hoc analyses. The symbol ‘#’ indicates significant changes in tongue muscle activity over time after CNO (i.e., between time-bins) from post-hoc analyses. The symbol ‘‡’ in panel D indicates that tongue muscle activity during the 8th to 10th hour of recording post-intervention in active wakefulness (i.e., 17:00 to 19:00 hrs clock time) was significantly increased compared to earlier time points, independent of experimental condition. See text for further details.
Mentions: Tongue muscle activity was analyzed up to 10 hours post-intervention in each of the CNO, vehicle and sham conditions and these data are shown in Fig. 9. Although there was significant tongue muscle activation that persisted for hours after CNO (Fig. 9, and analysed below), it is important to note that activity returned to similar baseline values each day before the interventions as measured in each sleep-wake state for each experimental condition, i.e., sham, vehicle or CNO (each F2,8 < 2.68, P > 0.128, one-way ANOVA-RM, Fig. 9).

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