Respiration Physiology
Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker–network model
Introduction
Understanding mechanisms of respiratory rhythm generation remains a central problem in unraveling the neural control of breathing in mammals. Over the past decade, there has been controversy and debate — the critical issues have been discussed in a number of recent reviews (Bianchi et al., 1995, Feldman and Smith, 1995, Smith et al., 1995, Richter, 1996, Ramirez and Richter, 1996, Smith, 1997, Rekling and Feldman, 1998). Is the rhythm generated mainly by a network of inhibitory interneurons as an emergent property of network synaptic interactions, or from excitatory pacemaker-like neurons with intrinsic oscillatory bursting properties? Or does rhythmogenesis involve some combination of both types of mechanisms?
This debate has stemmed largely from studies in reduced, rhythmically-active in vitro preparations from neonatal rodents (reviewed in Smith et al. (1995)) that have become experimental models for the neonatal system and have produced new data and mechanistic models involving pacemaker neurons (see Smith et al., 1995, Smith, 1997, Rekling and Feldman, 1998). These models depart from earlier models (Richter et al., 1986, Ezure, 1990, Richter et al., 1992, Balis et al., 1994, Bianchi et al., 1995) involving purely network mechanisms derived from in vivo studies in anesthetized adult mammals. Contributing to this debate has been the growing understanding that complex interactions between cellular and network-level properties are involved in rhythmogenesis (e.g. Richter et al., 1992, Smith et al., 1995, Richter, 1996, Ramirez and Richter, 1996, Smith, 1997), as established for other oscillatory networks (for recent reviews see Stein et al., 1997, Marder and Calabrese, 1996). It is also recognized that the respiratory oscillator may be functionally plastic — capable of transformation between states involving pacemaker-like cellular oscillations and those where network interactions are fundamental (Smith et al., 1995, Richter, 1996, Smith, 1997); such plasticity has been documented for other rhythmic motor pattern generation networks (see Marder and Calabrese (1996)). Indeed, pacemaker mechanisms studied in the highly reduced neonatal preparations in vitro are assumed to undergo transformation when embedded in the intact nervous system in vivo (Smith et al., 1995, Richter, 1996, Smith, 1997). Transformations may occur during development (e.g. Hilaire and Duron (1999)). The most comprehensive models must account for mechanisms expressed in different states of the respiratory network (e.g. in vitro vs. in vivo) during different stages of development.
In this review, we discuss our unified model — the hybrid pacemaker–network model — developed from a synthesis of models and data derived from studies in the neonatal system in vitro and adult nervous system in vivo. This model can theoretically account for rhythm generation mechanisms in these different states. We review the main principles of operation of the model, the experimental evidence, and indicate significant gaps in our understanding. Many of these principles were first outlined in earlier reviews (Smith et al., 1995, Smith, 1997), supplemented here with results from new experimental and computational studies. We have developed mathematical models of respiratory neurons incorporating ‘realistic’ cellular biophysical properties, based on Hodgkin–Huxley-like analytical formulations for membrane conductance mechanisms (e.g. see Nelson and Rinzel, 1995, Koch and Segev, 1998), and model networks of these cells with realistic synaptic interactions (Smith, 1995, Smith et al., 1995, Smith, 1996, Butera et al., 1999a, Butera et al., 1999b; see also Rybak et al., 1997a, Rybak et al., 1997b). These models provide mechanistic insights and test the plausibility of the mechanisms discussed below. The models differ significantly from earlier mathematical models of rhythm generation (Botros and Bruce, 1990, Ogilvie et al., 1992, Balis et al., 1994) that have lacked many of the biophysical and synaptic properties of neurons required to mimic the behavior of real networks, particularly the complex dynamic interactions of cellular and network processes underlying rhythm generation. Although ‘realistic’, the models reviewed are ‘minimal’, with highly simplified neuronal and network geometries (see discussions in Smith, 1996, Butera et al., 1999a, Butera et al., 1999b), and in some cases with mathematically minimal formulations from membrane conductances (Butera et al., 1999a, Butera et al., 1999b). This approach has enabled us to analyze and clarify essential mechanisms.
Section snippets
Concept and locus of the kernel — the pre-Bötzinger complex
The fundamental new concept, derived initially from neonatal in vitro studies (Smith et al., 1991), is that there exists a critical population of excitatory inspiratory interneurons — the neuronal kernel for rhythm generation (Smith et al., 1991, Smith et al., 1995, Rekling and Feldman, 1998) — segregated in the pre-Bötzinger complex (pre-BötC, Fig. 1) (Smith et al., 1991, Smith et al., 1995), a structurally and functionally specialized subregion of the ventral respiratory group (VRG) in the
Embedded kernel: the complete hybrid pacemaker–network model
A major problem that is only beginning to be addressed experimentally and theoretically is the analysis of rhythm generation mechanisms when the kernel is embedded in the respiratory network in intact states of the system, particularly in the adult in vivo. This embedding results in a more complex hybrid pacemaker–network. A simplified schematic of the hybrid model is shown in Fig. 3, where the inspiratory burst-generating kernel is embedded in a larger network of highly interconnected
Developmental transformations
Rhythm generation mechanisms are assumed to undergo some developmental elaboration postnatally (e.g. Funk and Feldman, 1995, Richter, 1996, Smith, 1997, Hilaire and Duron, 1999). However, developmental analysis of cellular and synaptic properties of the critical interneurons in the pre-BötC kernel has not been done experimentally in vitro or in vivo (Ramirez et al., 1996, Ramirez et al., 1997, Hilaire and Duron, 1999). The central issue is whether there are changes in neuronal pacemaker
Synopsis
There is an emerging understanding in the field that rhythm generation is mechanistically more complex and interesting than previously recognized, requiring a new synthesis of older ideas about pacemaker and network mechanisms. The hybrid pacemaker–network model discussed here represents the beginning of this synthesis. The hybrid pacemaker–network is obviously a complex system, and many questions remain about the detailed cellular and network properties and their integration for rhythm
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