Chronic Intermittent Hypoxia reveals role of the Postinspiratory Complex in swallow pattern generation

Abstract

Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that results in multiple bouts of intermittent hypoxia. OSA has many neurologic and systemic comorbidities including dysphagia, or disordered swallow and discoordination with breathing. However, the mechanism in which chronic intermittent hypoxia (CIH) causes dysphagia is unknown. Recently we showed the Postinspiratory complex (PiCo) acts as an interface between the swallow pattern generator (SPG) and the inspiratory rhythm generator, the preBötzinger Complex, to regulate proper swallow-breathing coordination (A. D. Huff et al., 2023). PiCo is characterized by interneurons co-expressing transporters for glutamate (Vglut2) and acetylcholine (ChAT). Here we show that optogenetic stimulation of ChATcre:Ai32, Vglut2cre:Ai32, and ChATcre:Vglut2FlpO:ChR2 mice exposed to CIH does not alter swallow-breathing coordination, but unexpectedly the generation of swallow motor pattern was significantly disturbed. This suggests, glutamatergic-cholinergic neurons in PiCo are not only critical for the gating of postinspiratory and swallow activity, but also play important roles in the generation of swallow motor pattern. Our study also suggests that swallow disruption, as seen in OSA involves central nervous mechanisms interfering with the generation of the swallow pattern and laryngeal activation. These findings are crucial for understanding the mechanisms underlying dysphagia in OSA and other breathing and neurological disorders.