Computational model of brainstem circuit for state dependent control of hypoglossal motoneurons

Abstract

In patients with obstructive sleep apnea (OSA) the pharyngeal muscles become relaxed during sleep, which leads to a partial or complete closure of upper airway. Empirical studies suggest that withdrawal of noradrenergic and serotonergic drives importantly contribute to depression of hypoglossal motoneurons during rapid eye-movement (REM) sleep and, therefore, may contribute to OSA pathophysiology; however, specific cellular and synaptic mechanisms remain unknown. It was recently suggested that, in order to explain experimental observations, the neuronal network for monoaminergic control of excitability of hypoglossal motoneurons has to include excitatory and inhibitory perihypoglossal interneurons that would mediate noradrenergic and serotonergic drives to the motoneurons. In this study, we applied a biophysical network model to validate the rationality of the proposed circuit and to investigate the dynamics of its neuronal populations during REM sleep-induced withdrawal of noradrenergic and serotonergic drives. The state-dependent activity of the model hypoglossal motoneurons during simulated REM sleep with or without a virtual application of noradrenergic and serotonergic drugs was in qualitative agreement with in vivo data. The study predicts the dynamics of the perihypoglossal interneurons during these conditions and corroborates the hypothesis that the excitatory interneurons may integrate both noradrenergic and serotonergic drives. The latter drive has to be mediated by the inhibitory interneurons. The study suggests that perihypoglossal interneurons may serve as novel potential targets for pharmacological treatment of OSA.