Identification of the Mechanism Mediating Genioglossus Muscle Suppression in REM Sleep

Rationale: Inhibition of pharyngeal motoneurons accompanies REM sleep and is a cause of hypoventilation and obstructive sleep apnea in humans. One explanation posits that the neurotransmitters glycine and gamma-aminobutyric acid are responsible for REM sleep motor inhibition. However, blockade of that mechanism at cranial motor nuclei increases motor activity in all sleep wake states, and least of all in REM sleep; arguing against it as a major mechanism of REM sleep pharyngeal motor inhibition. Objectives: To identify the mechanism of REM sleep inhibition at the hypoglossal motor pool. Methods: Genioglossus and diaphragm activities were recorded in 34 rats across sleep wake states. Microdialysis probes were implanted into the hypoglossal motor pool. Measurements and Main Results: Here we show that muscarinic receptor antagonism at the hypoglossal motor pool prevents the inhibition of genioglossus activity throughout REM sleep; likewise, with G-protein-coupled inwardly rectifying potassium (G IRK) channel blockade. Importantly, the genioglossus activating effects of these interventions were largest in REM sleep and minimal or often absent in other sleep wake states. Finally, we showed that muscarinic inhibition of the genioglossus is functionally linked to GIRK channel activation. Conclusions: We identify a powerful cholinergic-GIRK channel mechanism operating at the hypoglossal motor pool that has its largest inhibitory influence in REM sleep and minimal or no effects in other sleep wake states. This mechanism is the major cause of REM sleep inhibition at a pharyngeal motor pool critical for effective breathing.