Modelling respiratory rhythmogenesis: focus on phase switching mechanisms.

It has been established that the normal respiratory pattern (“eupnoea”) in mammals is generated in the lower brainstem1,2 and may involve several medullary and pontine regions. Although some researchers suggest that a smaller region within the medulla (e.g., the pre-Botzinger Complex (pre-BotC) may be sufficient for the respiratory rhythm generation3, 4, 5, the eupnoeic respiratory rhythm (as well as apneustic breathing) has never been reproduced in reduced medullary preparations without the pons. At the same time, the specific ponto-medullary interactions related to genesis, shaping and control of the respiratory pattern have not been well characterized so far. Here we present a preliminary computational model of the ponto-medullary respiratory network that is considered a basis for the future interactive modeling-experimental studies. The model has been developed using a series of assumptions. Specifically, we have suggested that, under normal conditions in vivo, the eupnoeic respiratory rhythm is generated by a ponto-medullary network. Hence, although the pre-BotC is a necessary part of this network, the intrinsic oscillations in this region are suppressed during eupnoea by ponto-medullary interactions. These endogenous oscillations, however, may be released under some specific conditions, e.g., in vitro, because of the lack of the pons, or during hypoxia in vivo 6. We have also assumed that the medullary part of the respiratory network contains special neural circuits performing the respiratory phase switching. Moreover, these circuits are also targets for pulmonary feedback and inputs from the pons and major afferent nerves, which use the same medullary switching circuits to regulate the timing of phase transitions and modulate the respiratory motor pattern7.