Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker–network model

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Abstract

We review a new unified model of respiratory rhythm generation — the hybrid pacemaker–network model. This model represents a comprehensive synthesis of cellular and network mechanisms that can theoretically account for rhythm generation in different functional states, from the most reduced states in the neonatal nervous system in vitro to the intact adult system in vivo. The model incorporates a critical neuronal kernel consisting of a network of excitatory neurons with state-dependent, oscillatory bursting or pacemaker properties. This kernel, located in the pre-Bötzinger complex of the ventrolateral medulla, provides a rudimentary pacemaker network mechanism for generating an inspiratory rhythm, revealed predominately in functionally reduced states in vitro. In vivo the kernel is embedded in a larger network that interacts with the kernel via inhibitory synaptic connections that provide the dynamic control required for the evolution of the complete pattern of inspiratory and expiratory network activity. The resulting hybrid of cellular pacemaker and network properties functionally endows the system with multiple mechanisms of rhythm generation. New biophysically realistic mathematical models of the hybrid pacemaker–network have been developed that illustrate these concepts and provide a computational framework for investigating interactions of cellular and network processes that must be analyzed to understand rhythm generation.

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

References (64)

  • U.J Balis et al.

    Simulations of a ventrolateral medullary neural network for respiratory rhythmogenesis inferred from spike train cross-correlation

    Biol. Cybern.

    (1994)
  • A.L Bianchi et al.

    Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters

    Physiol. Rev.

    (1995)
  • S.M Botros et al.

    Neural network implementation of the three-phase model of respiratory rhythm generation

    Biol. Cybern.

    (1990)
  • J Brochus et al.

    Synaptic inhibition in the isolated respiratory network of neonatal rats

    Eur. J. Neurosci.

    (1988)
  • D Büsselberg et al.

    Rhythm generation after disturbance of synaptic inhibition in the respiratory network

    Soc. Neurosci. Abstr.

    (1999)
  • R.J Butera et al.

    Models of respiratory rhythm generation in the pre-Bötzinger complex. I. Bursting pacemaker neurons

    J. Neurophysiol.

    (1999)
  • R.J Butera et al.

    Models of respiratory rhythm generation in the pre-Bötzinger complex. II. Populations of coupled pacemaker neurons

    J. Neurophysiol.

    (1999)
  • R.J Butera et al.

    Burst generating mechanisms of pre-Bötzinger complex pacemaker neurons: tests with the dynamic clamp

    Soc. Neurosci. Abstr.

    (1999)
  • C.A Del Negro et al.

    Role of excitatory synaptic coupling and cellular heterogeneity in respiratory rhythm generation in the pre-Bötzinger complex

    Soc. Neurosci. Abstr.

    (1999)
  • J Duffin

    A model of respiratory rhythm generation

    NeuroReport

    (1991)
  • J.L Feldman et al.

    Cellular mechanisms underlying modulation of breathing pattern in mammals

    Ann. New York Acad. Sci.

    (1989)
  • J.L Feldman et al.

    Neural control of respiratory pattern in mammals: An overview

  • G.D Funk et al.

    Generation and transmission of respiratory oscillations in medullary slices: role of excitatory amino acids

    J. Neurophysiol.

    (1993)
  • P.A Gray et al.

    Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger complex

    Science

    (1999)
  • G Hilaire et al.

    Maturation of the mammalian respiratory system

    Physiol. Rev.

    (1999)
  • S.M Johnson et al.

    Pacemaker behavior of respiratory neurons in medullary slices from neonatal rat

    J. Neurophysiol.

    (1994)
  • S.M Johnson et al.

    Modulation of respiratory rhythm in vitro. Role of Gi/o-protein regulated conductances

    J. Appl. Physiol.

    (1996)
  • S.M Johnson et al.

    Chemosensitivity of respiratory pacemaker neurons in the pre-Bötzinger complex in vitro

    Soc. Neurosci. Abstr.

    (1999)
  • Johnson, S.M., Del Negro, C., Koshiya, N., Smith, J.C., 2000. Characterization and modulation of the spontaneous...
  • S Klages et al.

    Late expiratory inhibition of stage 2 expiratory neurons in the cat — a correlate of expiratory termination

    J. Neurophysiol.

    (1993)
  • C Koch et al.

    Methods in Neuronal Modeling

    (1998)
  • N Koshiya et al.

    Tonic sympathetic chemoreflex after blockade of respiratory rhythmogenesis in the rat

    J. Physiol. Lond.

    (1996)
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