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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

Lack of effect of CNO in the mice in which the hypoglossal motor pool was transduced with the viral vector that lacked the DREADDs (hM3Dq) transgene, i.e., the inactive virus controls.Example (A) and group data (B) showing the lack of tongue muscle activation in response to systemic injection of CNO in a mouse with the inactive viral vector expressed at the hypoglossal motor pool. Values are mean + SEM. Abbreviations as for Fig. 2.
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f6: Lack of effect of CNO in the mice in which the hypoglossal motor pool was transduced with the viral vector that lacked the DREADDs (hM3Dq) transgene, i.e., the inactive virus controls.Example (A) and group data (B) showing the lack of tongue muscle activation in response to systemic injection of CNO in a mouse with the inactive viral vector expressed at the hypoglossal motor pool. Values are mean + SEM. Abbreviations as for Fig. 2.

Mentions: That the excitatory effect of CNO on tongue muscle activity is mediated by its effect on hM3Dq receptors at the hypoglossal motor pool is shown by the lack of effect of CNO in the mice in which the hypoglossal motor pool was transduced with the viral vector that lacked the DREADDs (hM3Dq) transgene, i.e., the inactive virus controls (Fig. 6).


Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control
Lack of effect of CNO in the mice in which the hypoglossal motor pool was transduced with the viral vector that lacked the DREADDs (hM3Dq) transgene, i.e., the inactive virus controls.Example (A) and group data (B) showing the lack of tongue muscle activation in response to systemic injection of CNO in a mouse with the inactive viral vector expressed at the hypoglossal motor pool. Values are mean + SEM. Abbreviations as for Fig. 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Lack of effect of CNO in the mice in which the hypoglossal motor pool was transduced with the viral vector that lacked the DREADDs (hM3Dq) transgene, i.e., the inactive virus controls.Example (A) and group data (B) showing the lack of tongue muscle activation in response to systemic injection of CNO in a mouse with the inactive viral vector expressed at the hypoglossal motor pool. Values are mean + SEM. Abbreviations as for Fig. 2.
Mentions: That the excitatory effect of CNO on tongue muscle activity is mediated by its effect on hM3Dq receptors at the hypoglossal motor pool is shown by the lack of effect of CNO in the mice in which the hypoglossal motor pool was transduced with the viral vector that lacked the DREADDs (hM3Dq) transgene, i.e., the inactive virus controls (Fig. 6).

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