Modeling the ponto-medullary respiratory network
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.
Section snippets
Model description
The model (Fig. 1) contains interacting populations of respiratory neurons that have been characterized in the rostroventolateral medulla (RVLM) and pons in vivo. The medullary component of the model includes three major regions: rostral ventral respiratory group (rVRG), pre-Bötzinger Complex (pre-BötC), and Bötzinger Complex (BötC). The pontine component is conditionally subdivided into a rostral (rPons) and caudal (cPons) parts. The neural populations of the rPons in the model are considered
Model performance: comparison with experimental data
The model generates a stable “eupneic” respiratory rhythm and exhibits realistic firing patterns and membrane potential trajectories of individual respiratory neurons (see Fig. 2A). Specifically, the firing bursts of individual ramp-I neurons as well as the bursts of phrenic discharges exhibit “augmenting” patterns (Fig. 2A).
In the model, the pulmonary feedback provides the HB reflex via an increase of excitability of late-I neurons by the direct excitatory input, an indirect excitation through
Experimental studies
The model described above suggests that the medullary post-inspiratory neurons significantly contribute to both the irreversible IOS by inhibition of inspiratory neurons (early-I, ramp-I, late-I) and the regulation of expiratory duration through inhibition of pre-I and aug-E neurons (see Fig. 1). Moreover, the post-I neurons are considered key elements of both phase switching mechanism (IOS and EOS) and operate under control of both vagal feedback and inputs from the rostral pons. According to
Discussion and conclusion
The model presented here was based on a series of assumptions and simplifications concerning both the medullary mechanisms (including these for respiratory phase transitions) and ponto-medullary connectivities. Specifically, many connections in the model, especially these from pulmonary afferents to the ponto-medullary circuitry and between the pons and medulla, have been considered monosynaptic, despite they are most likely polysynaptic; interactions among the pontine populations have not been
Acknowledgements
This study was supported by NSF (0091942) and NIH (NS046062-02 and HL072415-01) grants.
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