Pacemakers handshake synchronization mechanism of mammalian respiratory rhythmogenesis

Abstract

Inspiratory and expiratory rhythms in mammals are thought to be generated by pacemaker-like neurons in 2 discrete brainstem regions: pre-Bö tzinger complex (preBö tC) and parafacial respiratory group (pFRG). How these putative pacemakers or pacemaker networks may interact to set the overall respiratory rhythm in synchrony remains unclear. Here, we show that a pacemakers 2-way ''handshake'' process comprising pFRG excitation of the preBö tC, followed by reverse inhibition and postinhibitory rebound (PIR) excitation of the pFRG and postinspiratory feedback inhibition of the preBö tC, can provide a phase-locked mechanism that sequentially resets and, hence, synchronizes the inspiratory and expiratory rhythms in neonates. The order of this handshake sequence and its progression vary depending on the relative excitabilities of the preBö tC vs. the pFRG and resultant modulations of the PIR in various excited and depressed states, leading to complex inspiratory and expiratory phase-resetting behaviors in neonates and adults. This parsimonious model of pacemakers synchronization and mutual entrainment replicates key experimental data in vitro and in vivo that delineate the developmental changes in respiratory rhythm from neonates to maturity, elucidating their underlying mechanisms and suggesting hypotheses for further experimental testing. Such a pacemakers handshake process with conjugate excitation-inhibition and PIR provides a reinforcing and evolutionarily advantageous fail-safe mechanism for respiratory rhythmogenesis in mammals.entrainment ͉ parafacial respiratory group ͉ postinhibitory rebound ͉ preBö tzinger complex ͉ rhythm P acemaker bursting and beating are profound emergent behaviors at the single-cell level that are fundamental to a myriad of biological rhythms (1, 2). How distinct oscillators may synchronize at the network level to produce an ensemble rhythm in unison is an important question for many periodic phenomena in nature (3-5). In mammalian respiration, pacemaker-like neurons have been identified in 2 discrete regions in the rostral ventrolateral medulla (VLM): the pre-Bötzinger complex (preBötC) (6) and parafacial respiratory group (pFRG) (7-9). The demonstrated plurality of respiratory-related pacemakers has led to divergent hypotheses regarding the mechanism of respiratory rhythmogenesis in mammals: (i) the preBötC and pFRG rhythmogenic populations represent coupled inspiratory and expiratory rhythm generators (IRG, ERG) that separately drive inspiration and expiration (10-13); and (ii) pFRG neurons represent the master rhythm generator that not only sets the expiratory rhythm but also entrains inspiratory bursts (9,14).Both hypotheses appear to be well-founded and supported by relevant experimental data. Yet, both leave major questions unanswered. For one, how can the IRG and ERG synchronize without a master rhythm generator? Conversely, if the pFRG is a master rhythm generator, then why does breathing persist after its lesioning (9, 15)?To resolve the dilemma, we propose a mathematical model...

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