Cholinergic modulation of the parafacial respiratory group

Abstract

Active inspiration and expiration are opposing respiratory phases generated by two separate oscillators in the brainstem: inspiration driven by a neuronal network located in the preBötzinger complex (preBötC) and expiration driven by a neuronal network located in the parafacial respiratory group (pFRG). While continuous activity of the preBötC is necessary for maintaining ventilation, the pFRG behaves as a conditional expiratory oscillator, being silent in resting conditions and becoming rhythmically active in the presence of increased respiratory drive (e.g. hypoxia, hypercapnia, exercise and through release of inhibition). Recent evidence from our laboratory suggests that expiratory activity in the principal expiratory pump muscles, the abdominals, is modulated in a state-dependent fashion, frequently occurring during periods of REM sleep. We hypothesized that acetylcholine, a neurotransmitter released in wakefulness and REM sleep by mesopontine structures, contributes to the activation of pFRG neurons and thus acts to promote the recruitment of expiratory abdominal muscle activity. We investigated the stimulatory effect of cholinergic neurotransmission on pFRG activity and recruitment of active expiration in vivo under anaesthesia. We demonstrate that local application of the acetylcholinesterase inhibitor physostigmine into the pFRG potentiated expiratory activity. Furthermore, local application of the cholinomimetic carbachol into the pFRG activated late expiratory neurons and induced long lasting rhythmic active expiration. This effect was completely abolished by pre-application of the muscarinic antagonist scopolamine, and more selective M3 antagonists 4DAMP and J104129. We conclude that cholinergic muscarinic transmission contributes to excitation of pFRG neurons and promotes both active recruitment of abdominal muscles and active expiratory flow.

Hypercapnia‐induced active expiration increases in sleep and enhances ventilation in unanaesthetized rats

“…) and cholinergic (Boutin et al . ) neurotransmission in the RTN/pFRG have now been reported to induce active expiration in anaesthetized rats. Disinhibition of these neurons has been shown to underlie the recruitment of active expiration (Pagliardini et al .…”

Release of ATP by pre‐Bötzinger complex astrocytes contributes to the hypoxic ventilatory response via a Ca2+‐dependent P2Y1 receptor mechanism

“…V T was obtained by integration of the airflow recording and converted to millilitres of air using a five‐point calibration curve (range 0.5–5 ml) (Boutin et al . ). Parameters during drug application were compared with the average value during a 2 min control period preceding drug application.…”

Brainstem mechanisms underlying the cough reflex and its regulation

“…In more detail, expiratory muscle activation is caused by neurons of this area under hypercapnic conditions (Janczewski and Feldman 2006;Smith et al, 2007;Abdala et al, 2009;Pagliardini et al, 2011) or following peripheral chemoreceptor stimulation (Moraes et al, 2012). Furthermore, serotoninergic or cholinergic muscarinic mechanisms contribute to the appearance of neuronal expiratory activity within the RTN/pFRG region and promote the recruitment of expiratory motoneurons and active expiration (Lemes et al, 2016;Boutin et al, 2017). Neuronal recordings within this structure (Sugiyama et al, 2015) showed that the majority of recorded neurons changed activity in synchrony with coughing and swallowing.…”