Modeling the ponto-medullary respiratory network

Abstract

The generation and shaping of the respiratory motor pattern are performed in the lower brainstem and involve neuronal interactions within the medulla and between the medulla and pons. A computational model of the ponto-medullary respiratory network has been developed by incorporating existing experimental data on the medullary neural circuits and possible interactions between the medulla and pons. The model reproduces a number of experimental findings concerning alterations of the respiratory pattern following various perturbations/stimulations applied to the pons and pulmonary afferents. The results of modeling support the concept that eupneic respiratory rhythm generation requires contribution of the pons whereas a gasping-like rhythm (and the rhythm observed in vitro) may be generated within the medulla and involve pacemaker-driven mechanisms localized within the medullary pre-Bötzinger Complex. The model and experimental data described support the concept that during eupnea the respiration-related pontine structures control the medullary network mechanisms for respiratory phase transitions, suppress the intrinsic pacemaker-driven oscillations in the pre-BötC and provide inspiration-inhibitory and expiration-facilitatory reflexes which are independent of the pulmonary Hering–Breuer reflex but operate through the same medullary phase switching circuits.

Introduction

The normal respiratory pattern (“eupnea”) in mammals is generated in the lower brainstem and may involve several medullary and pontine regions (e.g., Lumsden, 1923, Cohen, 1979). Early studies of Lumsden (1923) and a series of later investigations have demonstrated that a removal of the rostral pons or perturbations applied to some areas within this region convert eupnea to apneusis, an abnormal pattern characterized by sustained or significantly prolonged inspiration, whereas the complete removal of the pons results in a gasping-like pattern (Cohen, 1979, Wang et al., 1993, Jodkowski et al., 1994, Morrison et al., 1994, St.-John, 1998). Although some medullary regions, e.g., the pre-Bötzinger Complex can generate a respiration-related rhythm in vitro (e.g., Smith et al., 1991, Rekling and Feldman, 1998, Koshiya and Smith, 1999, Lieske et al., 2000), many researches maintain that the in vitro rhythm essentially differs from eupnea and that the reduced medullary preparations without the pons cannot generate the eupneic pattern (e.g., see Duffin, 2003, St.-John and Paton, 2003a). The reduced medullary preparations cannot also reproduce apneusis, which is consistent with the suggestion that the rhythmogenesis in these preparations differs from the rhythmogenesis of eupnea. These observations support the concept that respiration-related pontine regions are necessary parts of the brainstem respiratory network responsible for the generation of eupnea (Wang et al., 1993, Dick et al., 1994, St.-John, 1998, Rybak et al., 2001, Rybak et al., 2002, St.-John et al., 2002, St.-John and Paton, 2003a, St.-John and Paton, 2003b). However the specific ponto-medullary interactions involved in the generation, shaping and control of the respiratory pattern have not been well characterized. Here we present and analyze a computational model of the ponto-medullary respiratory network and compare its performance under different conditions with both the existing experimental data and the results of our experiments performed for evaluation of some modeling predictions. The model is considered a basis for future interactive modeling-experimental studies of the role of the pons in respiratory rhythm and pattern generation.