Frontiers review
Bioaminergic neuromodulation of respiratory rhythm in vitro

https://doi.org/10.1016/j.resp.2009.03.011Get rights and content

Abstract

Bioamines, such as norepinephrine and serotonin are key neurotransmitters implicated in multiple physiological and pathological brain mechanisms. Evolutionarily, the bioaminergic neuromodulatory system is widely distributed throughout the brain and is among the earliest neurotransmitters to arise within the hindbrain. In both vertebrates and invertebrates, monoamines play a critical role in the control of respiration. In mammals, both norepinephrine and serotonin are involved in the maturation of the respiratory network, as well as in the neuromodulation of intrinsic and synaptic properties, that not only differentially alters the activity of individual respiratory neurons but also the activity of the network during normoxic and hypoxic conditions. Here, we review the basic noradrenergic and serotonergic pathways and their impact on the activity of the pre-Bötzinger Complex inspiratory neurons and network activity.

Introduction

Bioamines, such as norepinephrine (NE) and serotonin (5-HT) are involved in the maturation of mammalian neural network as well as in the modulation of its intrinsic and synaptic properties. By changing the synaptic and intrinsic properties of a rhythmogenic network, these neuromodulators, in turn alter the frequency and phasing of the motor patterns produced by a given neuronal circuit (for review see: Marder and Bucher, 2007, Doi and Ramirez, 2008). The respiratory network is no exception and, as neuromodulators, NE and 5-HT in particular, have multiple functions in controlling respiratory rhythmic activity.

The respiratory network has to be continuously active throughout life to insure survival. During this time, the neural network controlling breathing is under influence of multiple neuromodulators, among which, bioamines are the earliest neurotransmitters to arise in the brainstem. During life, bioamines are released in a state-dependent manner from different nuclei that participate in the control of vital functions and arousal and their influence is an integral part of the neural network that generates breathing (Mason et al., 2007).

The respiratory rhythm is thought to be generated by neural networks located within the ventral respiratory column and the parafacial respiratory group (pFRG) (Alheid et al., 2002, Feldman and Del Negro, 2006). Within the ventral respiratory column is the Bötzinger Complex (BötC) which primarily contains expiratory neurons and the pre-Bötzinger Complex (pre-BötC) that is critical for generating inspiratory activity (Smith et al., 1991, Ramirez et al., 1998).

Over the past 20 years, the use of in vitro preparations, the “en bloc” developed by Suzue (1984) as well as slices (Smith et al., 1991), has improved the understanding of the basic principles of the generation and modulation of the inspiratory rhythm. After discussing how the respiratory rhythm may be generated, we will discuss the role of NE and 5-HT in the modulation of the respiratory rhythm generation with emphasis on own data collected from slices preparation containing the pre-BötC that generates inspiratory breathing activity that we will compare with others in vivo and in vitro data. Then, we will focus on the cellular mechanisms involved in this neuromodulation. Finally, we will review the role of bioamines in pathologies affecting the control of breathing. In this review article we will not consider membrane properties of motoneurons and discuss motoneuronal activities as the monitored rhythmic activity from the respiratory rhythm generator.

Section snippets

Generation of the inspiratory like rhythm

The neural network underlying inspiratory rhythm generation is proposed to be located in the ventrolateral medulla so called, the pre-BötC (Smith et al., 1991, Ramirez et al., 1998). When isolated in a transverse brain-slice preparation, the pre-BötC generates inspiratory rhythmic activities, that resemble eupnea, sighs, and during hypoxia, the network generates fictive gasps Lieske et al. (2000, Fig. 2). Recent studies described an additional network for respiratory rhythm generation: the pFRG

Bioaminergic modulation of the respiratory network in vitro

The respiratory network is continuously modulated by endogenous bioamines that are required for its normal operation. Several studies suggest that endogenous NE and 5-HT are required for the maturation of the respiratory neuronal network (Bou-Flores et al., 2000, Viemari et al., 2004, Viemari, 2008). Nevertheless, Pet-1 null mice which lack ∼70% of all 5-HT neurons show normal gross anatomy of most brain structures (Hendricks et al., 2003). Similarly, Lmx1bf/f/p mice with near complete absence

Bioamines and respiratory diseases

Sudden Infant Death Syndrome has been associated with serotonin but also with disturbance in the noradrenergic systems (Hilaire, 2006). A study by Weese-Mayer et al. (2004) revealed that catecholaminergic neurons are abnormal in SIDS. But, abnormalities in the serotonergic modulation of respiratory nuclei are proposed to be a major risk factor for Sudden Infant Death Syndrome (Kinney, 2005, Paterson et al., 2006, Weese-Mayer et al., 2008). Sudden Infant Death Syndrome victims displayed a

Conclusions

The mechanisms underlying respiratory rhythm generation in a neural network where the dynamic interactions between synaptic and intrinsic properties are highly modulated, is difficult and complex. Many very creative approaches to this issue have contributed to a better understanding, and we have only touched on a few of these approaches here, largely in vitro studies, which have the benefit of being able to dissect cellular and central network mechanisms, but may be limited regarding the entire

Acknowledgement

This work was supported by NIH Grant R01-HL 079294 to A.K.T.

References (82)

  • G. Hilaire et al.

    Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents

    Respir. Physiol. Neurobiol.

    (2004)
  • M.R. Hodges et al.

    Interaction between defects in ventilatory and thermoregulatory control in mice lacking 5-HT neurons

    Respir. Physiol. Neurobiol.

    (2008)
  • N.M. Mellen et al.

    Opioid-induced quantal slowing reveals dual networks for respiratory rhythm generation

    Neuron

    (2003)
  • R. Monteau et al.

    Further evidence that various 5-HT receptor subtypes modulate central respiratory activity: in vitro studies with SR 46349B

    Eur. J. Pharmacol.

    (1994)
  • D. Morin et al.

    Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat

    Brain Res.

    (1990)
  • F. Peña et al.

    Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo

    Neurosci. Lett.

    (2007)
  • F. Peña et al.

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

    Neuron

    (2004)
  • J.M. Ramirez et al.

    Pacemaker neurons and neuronal networks: an integrative view

    Curr. Opin. Neurobiol.

    (2004)
  • D.W. Richter et al.

    Serotonin receptors: guardians of stable breathing

    Trends Mol. Med.

    (2003)
  • G.M. Stettner et al.

    Spontaneous central apneas occur in the C57BL/6J mouse strain

    Respir. Physiol. Neurobiol.

    (2008)
  • T.H. Svensson et al.

    Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine

    Brain Res.

    (1975)
  • S.W. Schwarzacher et al.

    Serotonergic modulation of respiratory motoneurons and interneurons in brainstem slices of perinatal rats

    Neuroscience

    (2002)
  • J.C. Viemari

    Noradrenergic modulation of the respiratory neural network

    Respir. Physiol. Neurobiol.

    (2008)
  • D.E. Weese-Mayer et al.

    Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation

    Respir. Physiol. Neurobiol.

    (2008)
  • B. Wilken et al.

    Treatment of apneustic respiratory disturbance with a serotonin-receptor agonist

    J. Pediatr.

    (1997)
  • S. Zanella et al.

    Oral treatment with desipramine improves breathing and life span in Rett syndrome mouse model

    Respir. Physiol. Neurobiol.

    (2008)
  • S. Zanella et al.

    Possible modulation of the mouse respiratory rhythm generator by A1/C1 neurones

    Respir. Physiol. Neurobiol.

    (2006)
  • G.F. Alheid et al.

    Parvalbumin in respiratory neurons of the ventrolateralmedulla of the adult rat

    J. Neurocytol.

    (2002)
  • Z.A. Al-Zubaidy et al.

    Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats

    Pflugers Arch.

    (1996)
  • R.E. Amir et al.

    Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

    Nat. Genet.

    (1999)
  • A. Arata et al.

    The adrenergic modulation of firings of respiratory rhythm-generating neurons in medulla–spinal cord preparation from newborn rat

    Exp. Brain Res.

    (1998)
  • G. Aston-Jones et al.

    The locus coeruleus, A5 and A7 noradrenergic cell groups

  • C. Bou-Flores et al.

    Abnormal phrenic motoneuron activity and morphology in neonatal monoamine oxidase A-deficient transgenic mice: possible role of a serotonin excess

    J. Neurosci.

    (2000)
  • H. Bras et al.

    Prenatal activation of 5-HT2A receptor induces expression of 5-HT1B receptor in phrenic motoneurons and alters the organization of their premotor network in newborn mice

    Eur. J. Neurosci.

    (2008)
  • M. Chevalier et al.

    Background sodium current underlying respiratory rhythm regularity

    Eur. J. Neurosci.

    (2008)
  • C.A. Del Negro et al.

    A ‘group pacemaker’ mechanism for respiratory rhythm generation

    J. Physiol.

    (2008)
  • C.A. Del Negro et al.

    Sodium and calcium current-mediated pacemaker neurons and respiratory rhythm generation

    J. Neurosci.

    (2005)
  • M. Elian et al.

    EEG and respiration in Rett syndrome

    Acta Neurol. Scand.

    (1991)
  • J.L. Feldman et al.

    Looking for inspiration: new perspectives on respiratory rhythm

    Nat. Rev. Neurosci.

    (2006)
  • M.G. Fortuna et al.

    Botzinger expiratory-augmenting neurons and the parafacial respiratory group

    J. Neurosci.

    (2008)
  • S. Günther et al.

    Endogenous 5-HT2B receptor activation regulates neonatal respiratory activity in vitro

    J. Neurobiol.

    (2006)
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