Modelling of synaptic interactions between two brainstem half-centre oscillators that coordinate breathing and swallowing

Abstract

AO_SCPLOWBSTRACTC_SCPLOWRespiration and swallowing are vital orofacial motor behaviours that require the coordination of the activity of two brainstem central pattern generators (r-CPG, sw-CPG). Here, we use computational modelling to further elucidate the neural substrate for breathing-swallowing coordination. We progressively construct several computational models of the breathing-swallowing circuit, starting from two interacting half-centre oscillators for each CPG. The models are based exclusively on neuronal nodes with spike-frequency adaptation, having a parsimonious description of intrinsic properties. These basic models undergo a stepwise integration of synaptic connectivity between central sensory relay, sw- and r-CPG neuron populations to match experimental data obtained in a perfused brainstem preparation. In the model, stimulation of the superior laryngeal nerve (SLN, 10s) reliably triggers sequential swallowing with concomitant glottal closure and suppression of inspiratory activity, consistent with the motor pattern in experimental data. Short SLN stimulation (100ms) evokes single swallows and respiratory phase resetting yielding similar experimental and computational phase response curves. Subsequent phase space analysis of model dynamics provides further understanding of SLN-mediated respiratory phase resetting. Consistent with experiments, numerical circuit-busting simulations show that deletion of ponto-medullary synaptic interactions triggers apneusis and eliminates glottal closure during sequential swallowing. Additionally, systematic variations of the synaptic strengths of distinct network connections predict vulnerable network connections that can mediate clinically relevant breathing-swallowing disorders observed in the elderly and patients with neurodegenerative disease. Thus, the present model provides novel insights that can guide future experiments and the development of efficient treatments for prevalent breathing-swallowing disorders. KO_SCPLOWEYC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWPOINTSC_SCPLOWO_LIThe coordination of breathing and swallowing depends on synaptic interactions between two functionally distinct central pattern generators (CPGs) in the dorsal and ventral brainstem. C_LIO_LIWe model both CPGs as half-centre oscillators with spike-frequency adaptation to identify the minimal connectivity sufficient to mediate physiologic breathing-swallowing interactions. C_LIO_LIThe resultant computational model(s) can generate sequential swallowing patterns including concomitant glottal closure during simulated 10s stimulation of the superior laryngeal nerve (SLN) consistent with experimental data. C_LIO_LIIn silico, short (100 ms) SLN stimulation triggers a single swallow which modulates the respiratory cycle duration consistent with experimental recordings. C_LIO_LIBy varying the synaptic connectivity strengths between the two CPGs and the sensory relay neurons, and by inhibiting specific nodes of the network, the model predicts vulnerable network connections that may mediate clinically relevant breathing-swallowing disorders. C_LI