Elsevier

Current Opinion in Neurobiology

Volume 41, December 2016, Pages 53-61
Current Opinion in Neurobiology

Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives

https://doi.org/10.1016/j.conb.2016.08.003Get rights and content

Highlights

  • Excitatory mechanisms are critical for rhythmicity in respiratory microcircuits.

  • Inhibition shapes activity within and between distinct rhythm generators.

  • Each phase of breathing in the mammal is associated with its own CPG.

  • CPGs may have been recruited during evolution, increasing breathing complexity.

Rhythmicity is critical for the generation of rhythmic behaviors and higher brain functions. This review discusses common mechanisms of rhythm generation, including the role of synaptic inhibition and excitation, with a focus on the mammalian respiratory network. This network generates three phases of breathing and is highly integrated with brain regions associated with numerous non-ventilatory behaviors. We hypothesize that during evolution multiple rhythmogenic microcircuits were recruited to accommodate the generation of each breathing phase. While these microcircuits relied primarily on excitatory mechanisms, synaptic inhibition became increasingly important to coordinate the different microcircuits and to integrate breathing into a rich behavioral repertoire that links breathing to sensory processing, arousal, and emotions as well as learning and memory.

Introduction

Rhythmicity is involved in almost all behaviors and brain functions [1••, 2]. This includes the generation of rhythmic behaviors, communication, encoding, attention, learning and memory [3, 4]. Thus, understanding rhythmogenesis is a core issue in neuroscience. Rhythmogenesis can be studied in microcircuits isolated from invertebrates [5, 6], mammalian [7•, 8•, 9, 10, 11•, 12], and non-mammalian vertebrates [13, 14••, 15•, 16] as well as fully integrated behavioral systems [17••, 18, 19, 20, 21•, 22, 23]. Yet, the quest to unravel the mechanisms underlying rhythmogenesis has been a difficult journey. Concepts developed using intact systems have often conflicted with those obtained from isolated networks. In particular in mammalian studies, some discrepancies have been attributed to developmental differences, since many in vivo studies were conducted in adults, while in vitro experiments have often been limited to neonates [24], a difficulty that can be overcome by studying non-mammalian model systems [25].

Mechanisms commonly found in rhythm generating networks include reciprocal inhibition [26•, 27, 28], rhythmic pacemaker properties [11•, 29, 30, 31, 32, 33] and recurrent excitatory network mechanisms [10, 34•, 35, 36•]. However, their roles within a given network vary and are often different than originally hypothesized. We learned that the relative contribution of neuronal mechanisms is not fixed, but dynamically regulated, resulting in state-dependent reconfiguration of neuronal networks [37, 38, 39, 40]. Mechanisms that are essential in one condition can become non-essential contributors in another state even within the same network [41].

This review will discuss the mechanisms underlying rhythm generation in a variety of brain networks with a focus on the respiratory rhythm-generating network. This network has well-defined physiological roles and it is amenable to a rigorous cellular analysis [17••, 42, 43, 44]. Moreover, the respiratory rhythm is integrated with the activity of numerous networks distributed throughout the brainstem and forebrain [45•, 46]. A comparative approach among vertebrates may provide important insights into how multiple rhythmic circuits become functionally intertwined to produce and coordinate ventilatory and non-ventilatory behaviors. By unraveling the complexities of the breathing rhythm, we may also gain insights into rhythmicity involved in other CNS functions ranging from locomotion to memory and emotion.

Section snippets

Rhythm generating networks and the role of synaptic inhibition

Most rhythm generating networks are heterogeneous, consisting of silent, tonic and rhythmically bursting neurons (Figure 1a) [2, 47]. Neurons endowed with these discharge patterns form the building blocks of neuronal networks and are often incorporated into computational models. One of those models, the so-called half-center oscillator (HCO) was one of the first models to mechanistically explain rhythmogenesis [48, 49, 50] and has been particularly influential. In this model, two non-rhythmic

The role of excitatory mechanisms in rhythm generation

The critical role of synaptic excitation within the respiratory network has never been questioned. Two principle rhythmogenic mechanisms have been proposed for excitatory networks in general: (1) Interconnected endogenous bursting, pacemaker neurons: In its extreme, the temporal characteristics of amplitude and period are defined by the intrinsic membrane properties of pacemakers [63, 64]. (2) Excitatory interactions between non-pacemakers: In this configuration temporal and amplitude

The role of glia in the generation of rhythmic activity

Neuron–glia interactions are increasingly being considered important for generating physiological and pathophysiological rhythmicity in the brain [78]. Although glia do not synchronize with each other through mechanisms of glutamatergic synaptic transmission, they are capable of synchronous activity via other mechanisms such as gap junctions [79]. The resulting Ca+2 oscillations or ‘waves’ between interconnected glia have important network functions [80], and models of astrocyte–neuron

Coupled oscillators in respiratory rhythmogenesis and their evolution

The preBötC likely originated from similar rhythm generating structures present in early vertebrates [15]. In lamprey, the respiratory rhythm generator is located in the pons, in the so-called para-trigeminal respiratory group (pTRG) (Figure 3a). This differs from the respiratory rhythm-generating network of dogfish, carp and tench that seems to span the length of the brainstem [14••] including medullary regions. Evidence for a localized microcircuit comes from bullfrogs: the gill/buccal

Conflicts of interest statement

The authors do not have any conflict of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Supported by grants from the National Institute of Health (HL090554 and HL126523-01.

References (101)

  • B.G. Lindsey et al.

    Computational models and emergent properties of respiratory neural networks

    Compr Physiol

    (2012)
  • S. Wittmeier et al.

    Pacemakers handshake synchronization mechanism of mammalian respiratory rhythmogenesis

    Proc Natl Acad Sci U S A

    (2008)
  • T.M. Anderson et al.

    A novel excitatory network for the control of breathing

    Nature

    (2016)
  • M.S. Carroll et al.

    Patterns of inspiratory phase-dependent activity in the in vitro respiratory network

    J Neurophysiol

    (2013)
  • P. Morquette et al.

    An astrocyte-dependent mechanism for neuronal rhythmogenesis

    Nat Neurosci

    (2015)
  • G.D. Funk et al.

    Neuroglia and their roles in central respiratory control; an overview

    Comp Biochem Physiol A Mol Integr Physiol

    (2015)
  • J. Albersheim-Carter et al.

    Testing the evolutionary conservation of vocal motoneurons in vertebrates

    Respir Physiol Neurobiol

    (2016)
  • B.O. Watson et al.

    Sleep, memory & brain rhythms

    Daedalus

    (2015)
  • J.M. Ramirez et al.

    Pacemaker neurons and neuronal networks: an integrative view

    Curr Opin Neurobiol

    (2004)
  • E. Marder et al.

    Complicating connectomes: electrical coupling creates parallel pathways and degenerate circuit mechanisms

    Dev Neurobiol

    (2016)
  • A.L. Revill et al.

    Dbx1 precursor cells are a source of inspiratory XII premotoneurons

    Elife

    (2015)
  • D.B. Salkoff et al.

    Synaptic mechanisms of tight spike synchrony at gamma frequency in cerebral cortex

    J Neurosci

    (2015)
  • S.P. Lieske et al.

    Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps

    Nat Neurosci

    (2000)
  • H. Song et al.

    Mechanisms Leading to rhythm cessation in the respiratory prebotzinger complex due to piecewise cumulative neuronal deletions (1,2,3)

    eNeuro

    (2015)
  • W.S. Phillips et al.

    Organotypic slice cultures containing the preBotzinger complex generate respiratory-like rhythms

    J Neurophysiol

    (2016)
  • J.C. Smith et al.

    Pre-Botzinger complex: a brainstem region that may generate respiratory rhythm in mammals

    Science

    (1991)
  • M.I. Baghdadwala et al.

    Three brainstem areas involved in respiratory rhythm generation in bullfrogs

    J Physiol

    (2015)
  • M.I. Baghdadwala et al.

    Diving into the mammalian swamp of respiratory rhythm generation with the bullfrog

    Respir Physiol Neurobiol

    (2016)
  • M. Hoffman et al.

    Evolution of lung breathing from a lungless primitive vertebrate

    Respir Physiol Neurobiol

    (2016)
  • E. Cinelli et al.

    Inhibitory control of ascending glutamatergic projections to the lamprey respiratory rhythm generator

    Neuroscience

    (2016)
  • P. Li et al.

    The peptidergic control circuit for sighing

    Nature

    (2016)
  • W.A. Janczewski et al.

    Role of inhibition in respiratory pattern generation

    J Neurosci

    (2013)
  • R.T. Huckstepp et al.

    Role of parafacial nuclei in control of breathing in adult rats

    J Neurosci

    (2015)
  • W.M. Roberts et al.

    A stochastic neuronal model predicts random search behaviors at multiple spatial scales in C. elegans

    Elife

    (2016)
  • D.W. Richter et al.

    Respiratory rhythm generation in vivo

    Physiology (Bethesda)

    (2014)
  • F. Bongianni et al.

    Neural mechanisms underlying respiratory rhythm generation in the lamprey

    Respir Physiol Neurobiol

    (2016)
  • E. Rosa et al.

    Effects of reciprocal inhibitory coupling in model neurons

    Biosystems

    (2015)
  • N. Kintos et al.

    Convergent neuromodulation onto a network neuron can have divergent effects at the network level

    J Comput Neurosci

    (2016)
  • D. Schlingloff et al.

    Mechanisms of sharp wave initiation and ripple generation

    J Neurosci

    (2014)
  • A. Firl et al.

    Elucidating the role of AII amacrine cells in glutamatergic retinal waves

    J Neurosci

    (2015)
  • R.M. Hooper et al.

    Feedback control of variability in the cycle period of a central pattern generator

    J Neurophysiol

    (2015)
  • S.M. Johnson et al.

    Respiratory neuron characterization reveals intrinsic bursting properties in isolated adult turtle brainstems (Trachemys scripta)

    Respir Physiol Neurobiol

    (2016)
  • A.I. Selverston

    Invertebrate central pattern generator circuits

    Philos Trans R Soc Lond B Biol Sci

    (2010)
  • J.M. Budd

    Theta oscillations by synaptic excitation in a neocortical circuit model

    Proc Biol Sci

    (2005)
  • A. Nieto-Posadas et al.

    Change in network connectivity during fictive-gasping generation in hypoxia: prevention by a metabolic intermediate

    Front Physiol

    (2014)
  • M. Sinha et al.

    HCN channels enhance spike phase coherence and regulate the phase of spikes and LFPs in the theta-frequency range

    Proc Natl Acad Sci U S A

    (2015)
  • H. Koch et al.

    Network reconfiguration and neuronal plasticity in rhythm-generating networks

    Integr Comp Biol

    (2011)
  • J.M. Weimann et al.

    Neurons that form multiple pattern generators: identification and multiple activity patterns of gastric/pyloric neurons in the crab stomatogastric system

    J Neurophysiol

    (1991)
  • F. Pena et al.

    Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia

    Neuron

    (2004)
  • M.C. Picardo et al.

    Physiological and morphological properties of Dbx1-derived respiratory neurons in the pre-Botzinger complex of neonatal mice

    J Physiol

    (2013)
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