Frontiers reviewBioaminergic neuromodulation of respiratory rhythm in vitro
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)
- et al.
Afferent regulation of locus coeruleus neurons: anatomy, physiology and pharmacology
Prog. Brain Res.
(1991) - et al.
Respiratory network function in the isolated brainstem–spinal cord of newborn rats
Prog. Neurobiol.
(1999) Noradrenergic responses of neurones in the mediolateral part of the lateral septum: alpha1-adrenergic depolarization and rhythmic bursting activities, and alpha2-adrenergic hyperpolarization from guinea pig brain slices
Brain Res. Bull.
(1999)- et al.
Postnatal changes in the respiratory response of the conscious rat to serotonin 2A/2C receptor activation are reflected in the developmental pattern of fos expression in the brainstem
Brain Res.
(2002) - et al.
Endogenous serotonin modulates the fetal respiratory rhythm: an in vitro study in the rat
Brain Res. Dev. Brain Res.
(1994) - et al.
Serotonergic modulation of the respiratory rhythm generator at birth: an in vitro study in the rat
Neurosci. Lett.
(1992) - et al.
Neuromodulation and the orchestration of the respiratory rhythm
Respir. Physiol. Neurobiol.
(2008) - et al.
Noradrenergic augmentation of escitalopram response by risperidone: electrophysiologic studies in the rat brain
Biol. Psychiatry
(2007) - et al.
Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior
Neuron
(2003) Endogenous noradrenaline affects the maturation and function of the respiratory network: possible implication for SIDS
Auton. Neurosci.
(2006)
Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents
Respir. Physiol. Neurobiol.
Interaction between defects in ventilatory and thermoregulatory control in mice lacking 5-HT neurons
Respir. Physiol. Neurobiol.
Opioid-induced quantal slowing reveals dual networks for respiratory rhythm generation
Neuron
Further evidence that various 5-HT receptor subtypes modulate central respiratory activity: in vitro studies with SR 46349B
Eur. J. Pharmacol.
Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat
Brain Res.
Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo
Neurosci. Lett.
Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia
Neuron
Pacemaker neurons and neuronal networks: an integrative view
Curr. Opin. Neurobiol.
Serotonin receptors: guardians of stable breathing
Trends Mol. Med.
Spontaneous central apneas occur in the C57BL/6J mouse strain
Respir. Physiol. Neurobiol.
Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine
Brain Res.
Serotonergic modulation of respiratory motoneurons and interneurons in brainstem slices of perinatal rats
Neuroscience
Noradrenergic modulation of the respiratory neural network
Respir. Physiol. Neurobiol.
Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation
Respir. Physiol. Neurobiol.
Treatment of apneustic respiratory disturbance with a serotonin-receptor agonist
J. Pediatr.
Oral treatment with desipramine improves breathing and life span in Rett syndrome mouse model
Respir. Physiol. Neurobiol.
Possible modulation of the mouse respiratory rhythm generator by A1/C1 neurones
Respir. Physiol. Neurobiol.
Parvalbumin in respiratory neurons of the ventrolateralmedulla of the adult rat
J. Neurocytol.
Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats
Pflugers Arch.
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2
Nat. Genet.
The adrenergic modulation of firings of respiratory rhythm-generating neurons in medulla–spinal cord preparation from newborn rat
Exp. Brain Res.
The locus coeruleus, A5 and A7 noradrenergic cell groups
Abnormal phrenic motoneuron activity and morphology in neonatal monoamine oxidase A-deficient transgenic mice: possible role of a serotonin excess
J. Neurosci.
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.
Background sodium current underlying respiratory rhythm regularity
Eur. J. Neurosci.
A ‘group pacemaker’ mechanism for respiratory rhythm generation
J. Physiol.
Sodium and calcium current-mediated pacemaker neurons and respiratory rhythm generation
J. Neurosci.
EEG and respiration in Rett syndrome
Acta Neurol. Scand.
Looking for inspiration: new perspectives on respiratory rhythm
Nat. Rev. Neurosci.
Botzinger expiratory-augmenting neurons and the parafacial respiratory group
J. Neurosci.
Endogenous 5-HT2B receptor activation regulates neonatal respiratory activity in vitro
J. Neurobiol.
Cited by (25)
The sigh and related behaviors
2022, Handbook of Clinical NeurologyEarly ethanol pre-exposure alters breathing patterns by disruptions in the central respiratory network and serotonergic balance in neonate rats
2021, Behavioural Brain ResearchCitation Excerpt :Respiration is an essential neurovegetative behavior coordinated by complex central circuits [1] which it is widely recognized to exhibit considerable plasticity [2].
Sex differences in breathing
2019, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative PhysiologyCitation Excerpt :Finally, the absolute VT values did not change with age in Holley´s study, which is in disagreement with previous data (Huang et al., 2004; Joseph et al., 2000; Ohtake et al., 2000; Olson, 1994). Strong evidence has shown that maturation of the catecholaminergic (CA) system is important for normal respiratory network development (Funk et al., 2011; Hilaire, 2006; Viemari and Tryba, 2009; Viemari et al., 2004). Taking this into account, we have recently evaluated the role of the brainstem CA system in ventilatory control under resting conditions during different phases of postnatal development (P7–8, P14–15 and P20–21) in male and female rats (Patrone et al., 2018).
Negative emotional stimulation decreases respiratory sensory gating in healthy humans
2014, Respiratory Physiology and NeurobiologyCitation Excerpt :The amygdala is an essential structure for respiratory response to stress (Bondarenko et al., 2014) although the exact neuronal pathway between amygdala and respiratory centers remain unknown. The central neural generator of respiration might be directly activated by the amygdala (Frysinger and Harper, 1989; Masaoka and Homma, 2004; Onimaru and Homma, 2007) through the effect of the norepinephrine (Viemari and Tryba, 2009) and/or orexin (Liu and Shen, 2010; Young et al., 2005; Zhang et al., 2009), two neuromodulators released during negative emotional experiences and able to bind receptors in the pre-Botzinger complex. However, in our study, we cannot exclude a participation of the cortical breathing command in response to the increase of respiratory sensations.
Raphé tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: Possible implications for tauopathies and Alzheimer's disease
2011, Respiratory Physiology and NeurobiologyCitation Excerpt :Identifying the neurotransmitter phenotype of the numerous AT8+ but non-5-HT raphé neurons requires further experiments. The RRG is composed of two coupled, interacting networks, the pre-BötzC and the RTN/pFRG, and is modulated by endogenous 5-HT (Hilaire et al., 2010; Doi and Ramirez, 2010; Viemari and Tryba, 2009; Bou-Flores et al., 2000). Pharmacological reduction of the 5-HT facilitation of the RRG slows down its activity in neonates and almost stops it in fetuses (Di Pasquale et al., 1994).
Context-dependent modulation of auditory processing by serotonin
2011, Hearing ResearchCitation Excerpt :The basic principles by which serotonin modulates auditory processing are similar to those that have been observed in motor systems in a wide range of animals for decades. As in motor systems, serotonin release in the auditory system is triggered by behaviorally important cues, and serotonin achieves selective effects by acting on specific cell types that express particular serotonin receptors and effector proteins to produce adaptive changes in behavior (Kiehn and Harris-Warrick, 1992; Zhang and Harris-Warrick, 1994; Katz, 1998; Sakurai et al., 2006; Viemari and Tryba, 2009; Harris-Warrick and Johnson, 2010). Despite, or perhaps even because of, the increasing characterization of the diversity of serotonergic effectors and effects within the auditory system, the question remains: what does serotonin do?