Cholinergic modulation of upper airway control: maturational changes and mechanisms at cellular and synaptic levels

Respiration is governed by a central rhythm and pattern generator, which has the pre-Bötzinger complex as the inspiratory oscillator initiating the coordinated activity of several respiratory muscles, including the diaphragm, intercostals, and upper airway muscles. The diaphragm is the main inspiratory pump muscle driving inflow, whereas dilator upper airway muscles, such as tongue muscles, reduce airway resistance during inspiration. Breathing exhibits a marked state-dependent pattern attributed to changes in neuromodulatory tone in respiratory-related brain regions, including decreases in noradrenaline and serotonin and increases in acetylcholine levels during rapid eye movement (REM) sleep. Here, we discuss respiratory modulation by acetylcholine acting on its metabotropic muscarinic receptors, focusing on the regulation of upper airway muscle activity during sleep and wakefulness and its changing effects with postnatal maturation. We focus on experimental data examining muscarinic receptor distribution patterns, the ion channels they modulate, and how these distribution patterns change with postnatal maturation. We also consider experimental data highlighting cholinergic cellular and synaptic effects on hypoglossal motoneurons and pre-Bötzinger complex neurons and how they might explain changes in the effects of cholinergic modulation with development. Overall, this discussion is critical to comprehending the postnatal maturation in the cholinergic modulation of the respiratory control system leading to opposing effects of muscarinic receptors on upper airway muscle activity in neonate (excitatory) and adult (inhibitory) preparations. The changes in cholinergic pathways associated with dysfunctional upper airway patency control are also discussed in the context of pathologies such as sleep-disordered breathing.