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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

Tongue muscle activity across sleep-wake states.Examples from one mouse showing the electroencephalogram (EEG) and the raw and/or integrated electromyograms (EMGs) of the tongue, neck and diaphragm muscles during non-REM and REM sleep, as well as during quiet and active wakefulness. The hypoglossal motor nucleus of this mouse was injected with the viral vector containing the DREADD transgene (rAVV8/hSyn-DIO-hM3Dq-mCherry) and the sample recordings are from the sham condition. Note the phasic tongue muscle activations during active wakefulness (grooming) but the lack of respiratory-related activity across sleep-wake states.
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f2: Tongue muscle activity across sleep-wake states.Examples from one mouse showing the electroencephalogram (EEG) and the raw and/or integrated electromyograms (EMGs) of the tongue, neck and diaphragm muscles during non-REM and REM sleep, as well as during quiet and active wakefulness. The hypoglossal motor nucleus of this mouse was injected with the viral vector containing the DREADD transgene (rAVV8/hSyn-DIO-hM3Dq-mCherry) and the sample recordings are from the sham condition. Note the phasic tongue muscle activations during active wakefulness (grooming) but the lack of respiratory-related activity across sleep-wake states.

Mentions: Stereotypical motor acts such as eating and grooming were associated with phasic activation of the tongue musculature in these freely behaving mice (Fig. 2). Periods of quiet wakefulness were mainly associated with tonic muscle activity interspersed with occasional phasic activations, but respiratory-related activity was not observed (Fig. 2). Tongue muscle activity was minimal in both non-REM and REM sleep, except for periods of transient tongue muscle activations during REM sleep that also occurred in the neck muscle (Fig. 2).


Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control
Tongue muscle activity across sleep-wake states.Examples from one mouse showing the electroencephalogram (EEG) and the raw and/or integrated electromyograms (EMGs) of the tongue, neck and diaphragm muscles during non-REM and REM sleep, as well as during quiet and active wakefulness. The hypoglossal motor nucleus of this mouse was injected with the viral vector containing the DREADD transgene (rAVV8/hSyn-DIO-hM3Dq-mCherry) and the sample recordings are from the sham condition. Note the phasic tongue muscle activations during active wakefulness (grooming) but the lack of respiratory-related activity across sleep-wake states.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Tongue muscle activity across sleep-wake states.Examples from one mouse showing the electroencephalogram (EEG) and the raw and/or integrated electromyograms (EMGs) of the tongue, neck and diaphragm muscles during non-REM and REM sleep, as well as during quiet and active wakefulness. The hypoglossal motor nucleus of this mouse was injected with the viral vector containing the DREADD transgene (rAVV8/hSyn-DIO-hM3Dq-mCherry) and the sample recordings are from the sham condition. Note the phasic tongue muscle activations during active wakefulness (grooming) but the lack of respiratory-related activity across sleep-wake states.
Mentions: Stereotypical motor acts such as eating and grooming were associated with phasic activation of the tongue musculature in these freely behaving mice (Fig. 2). Periods of quiet wakefulness were mainly associated with tonic muscle activity interspersed with occasional phasic activations, but respiratory-related activity was not observed (Fig. 2). Tongue muscle activity was minimal in both non-REM and REM sleep, except for periods of transient tongue muscle activations during REM sleep that also occurred in the neck muscle (Fig. 2).

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