title: Activation of the Hypoglossal to Tongue Musculature Motor Pathway by Remote Control.
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.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, M5S 1A8, Canada.
authors.forename: Garret A
authors.initials: GA
authors.lastname: Horton
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, M5S 3G5, Canada.
authors.forename: Jimmy J
authors.initials: JJ
authors.lastname: Fraigne
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, M5S 3G5, Canada.
authors.forename: Zoltan A
authors.initials: ZA
authors.lastname: Torontali
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, M5S 3G5, Canada.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Snow
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, M5S 3G5, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Lapierre
authors.affiliation: Department of Medicine, University of Toronto, Toronto, M5S 1A8, Canada.
authors.forename: Hattie
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Toronto, Toronto, M5S 1A8, Canada.
authors.forename: Gaspard
authors.initials: G
authors.lastname: Montandon
authors.affiliation: Department of Physiology, University of Toronto, Toronto, M5S 1A8, Canada.|Department of Cell and Systems Biology, University of Toronto, Toronto, M5S 3G5, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: Peever
authors.affiliation: Department of Physiology, University of Toronto, Toronto, M5S 1A8, Canada.|Department of Medicine, University of Toronto, Toronto, M5S 1A8, Canada.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Horner
mesh_terms: D000818:Animals; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003964:Diaphragm / Q000294:innervation / Q000502:physiology; D004525:Efferent Pathways / Q000187:drug effects / Q000502:physiology; D004576:Electromyography; D005152:Facial Muscles / Q000294:innervation / Q000502:physiology; D007002:Hypoglossal Nerve / Q000502:physiology; D009046:Motor Neurons / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy / Q000503:physiopathology*; D014059:Tongue / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D012701:Serotonin; D003024:Clozapine; C079149:clozapine N-oxide