Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents
Introduction
Our knowledge concerning the role of the pons in respiration started with the ponto-medullary transection experiments performed by Lumsden (1923) which demonstrated that some pontine structures, the pneumotaxic centres, were involved in the maintenance of a normal breathing pattern in vagotomised and anaesthetised adult cats. The elimination of the rostral pons evoked a specific breathing pattern named apneusis with long lasting and sustained inspirations interrupted by short expiratory pauses. However, the occurrence of apneusis not only required the elimination of the pons but also vagotomy (Stella, 1938) and anaesthesia (St John et al., 1972). Electrical stimulations, electrolytic lesions and recordings have localised the pneumotaxic centres in the parabrachialis medialis and Kölliker-Fuse nuclei (Bertrand and Hugelin, 1971, Bertrand et al., 1973, Bertrand et al., 1974, Vibert et al., 1976). Respiratory-related neurones from these pontine nuclei might control the medullary inspiratory off-switch via NMDA receptors since apneusis could be pharmacologically induced in cats by blockade of these receptors (Foutz et al., 1988, Borday et al., 1998).
However, the story might be more complex than summarised above. First, Bolme and Fuxe (1973) hypothesised that central noradrenergic neurones also play a role in respiratory control in rats since “after bilateral lesion of the locus coeruleus, apneustic respiration is obtained with maximal inspiratory depths”. Second, the existence of pontine pneumotaxic centres in rats was questioned (Monteau et al., 1989) and, if apneusis could be induced in rats by blockade of NMDA receptors, very large doses of NMDA receptor antagonists have to be used when compared to the efficient doses in cats (Monteau et al., 1990). Third, lesions in the ventrolateral pons were reported to induce apneustic breathing in rats (Jodkowski et al., 1994) and the destroyed area might correspond to the A5 catecholaminergic area. Since the first report showing that the isolated ponto-medullary respiratory network of the neonatal rat retains the ability to produce rhythmic phrenic bursts (PBs) for several hours in vitro (Suzue, 1984), most of the studies performed on this in vitro preparation have been focused onto the medulla, revealing the existence of respiratory pace-maker neurones in a restricted area of the rostral ventrolateral medulla, the PreBotzinger Complex, which might be the kernel of the medullary respiratory rhythm generator, the RRG (Smith et al., 1991, Ballanyi et al., 1999, Hilaire and Duron, 1999, McCrimmon et al., 2001). Even if less attention has been paid to the pons, it has soon been shown that the activity of the isolated RRG of neonatal rodents is affected by endogenous noradrenaline (NA) released from pontine structures.
The aim of this review is to summarise the available studies on this topic in both neonatal and adult rodents. We will show (i) that NA neurones belonging to the pontine A5 and A6 nuclei modulate the activity of the neonatal RRG in both rats and wild type mice, (ii) that the anatomical support for these modulations are present at birth, and (iii) that foetuses from mutant mice with genetically induced alterations of pontine NA neurones have respiratory deficits fully supporting the NA modulation of respiration. Furthermore, we will show that the NA modulation of the RRG is not a transient mechanism to secure respiration during delivery and early life but persists throughout life in order to adapt the vital RRG activity to physiological needs.
Section snippets
Exogenous NA induces mixed excitatory and inhibitory effects on the medullary RRG of neonatal rodents
After resection of the pons, the isolated medullary respiratory network from both neonatal rats and mice continues to produce rhythmic PBs in vitro at a frequency around 10 cycles per min (c min−1) (Suzue, 1984, Hilaire et al., 1989, Viemari et al., 2003). Adding an anaesthetic to the bathing medium superfusing these medullary preparations does not induce apneusis-like activity despite the lack of vagal and pontine inputs to the RRG (Monteau et al., 1989). However, bath application of exogenous
During the neonatal period
In ponto-medullary preparations from neonatal rats, rhythmic PBs occur at a frequency around 5 c min−1, i.e. half the frequency observed in medullary preparations. The elimination of the pons by transection immediately increases the PB frequency up to around 10 c min−1 (Fig. 2A1–B1), revealing that some pontine structures inhibit the medullary RRG (Hilaire et al., 1989). Localised electrolytic lesion (Fig. 2C1) and electrical stimulation experiments suggest that the inhibition of the medullary RRG
Possible facilitation of the in vitro RRG by endogenous NA released from the A6 group
In neonatal mice, we wondered whether the facilitatory effect of exogenous NA via α1 adrenoceptors might reflect some facilitatory modulation masked by the potent α2 inhibition from the A5 group (Viemari et al., 2004a, Viemari et al., 2004b). To test this hypothesis, the A5 inhibition of the RRG was first eliminated in ponto-medullary preparations by performing bilateral electrolytic lesion of the A5 nuclei; then, NA agents were applied solely onto the medulla while normal saline was applied
Neurones from the pontine A5 and A6 groups are connected to the medullary respiratory network of neonatal mice
The above physiological data argue for a dual and opposite modulation of the neonatal RRG by the A5 and A6 groups but do anatomical pathways support projections from the A5 and A6 neurones to the medullary respiratory network in neonatal and adult rodents? As already reported in adult rats (Dobbins and Feldman, 1994) and mice (Burnet et al., 2001, Gaytan et al., 2002), transneuronal tracing experiments with neurotropic viruses taking phrenic motoneurones as port of entry show that some A5 and
Conclusions – functional significance of the dual A5 and A6 control of the rodent RRG
Both A5 and A6 groups were first known to be involved in nociception, sleep, and cardiovascular regulations (Loewy et al., 1976, Close et al., 1982, Andrade and Aghajanian, 1982, Guyenet, 1984, Byrum and Guyenet, 1987). Today, numerous evidences show that they affect RRG activity both in foetal, neonatal and adult rodents.
During the perinatal period, both A5 and A6 neurones participate in the modulation of the RRG activity, the anatomical pathways which support these modulatory mechanisms are
References (92)
- et al.
Trigeminal autonomic pathways involved in nociception-induced reflex cardiovascular responses
Brain Res.
(1997) - et al.
Cell activity in the noradrenergic A-5 region: responses to drug and peripheral manipulations of blood pressure
Brain Res.
(1982) - et al.
Respiratory network function in the isolated brainstem-spinal cord of newborn rats
Prog. Neurobiol.
(1999) - et al.
Respiratory effects of glutamate receptor antagonists in neonate and adult mammals
Eur. J. Pharmacol.
(1998) - et al.
Catecholaminergic depressant effects on bulbar respiratory mechanisms
Brain Res.
(1979) - et al.
Action of N-methyl aspartate and its antagonist aminophosphonovalerate on the A5 catecholamine cell group in the rat
Brain Res.
(1982) - et al.
Effects of locus coeruleus lesions on vigilance and attentive behaviour in cat
Behav. Brain Res.
(1993) - et al.
N-methyl-d-aspartate (NMDA) receptors control respiratory off-switch in cat
Neurosci. Lett.
(1988) - et al.
Genes modulating chemical breathing control: lessons from mutant animals
Respir. Physiol. Neurobiol.
(2003) - et al.
Identification of central nervous system neurons innervating the respiratory muscles of the mouse: a transneuronal tracing study
Brain Res. Bull.
(2002)
Baroreceptor mediated inhibition of A5 noradrenergic neurons
Brain Res.
Central noradrenergic neurons: the autonomic connection
Prog. Brain Res.
CO2-induced c-fos expression in the CNS catecholaminergic neurons
Respir. Physiol. Neurobiol.
Possible modulation of the medullary respiratory rhythm generator by the noradrenergic A5 area: an in vitro study in the newborn rat
Brain Res.
Functional significance of the dorsal respiratory group in adult and newborn rats: in vivo and in vitro studies
Neurosci. Lett.
Rostral ventrolateral medulla and respiratory rhythmogenesis in mice
Neurosci. Lett.
A ’pneumotaxic centre’ in rats
Neurosci. Lett.
Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin
Neuroscience
Fos immunohistochemical determination of brainstem neuronal activation in the muskrat after nasal stimulation
Neuroscience
Pneumotaxic centre and apneustic breathing: interspecies differences between rat and cat
Neurosci. Lett.
Effects of N-methyl-d-aspartate antagonist MK-801 on breathing pattern in rats
Neurosci. Lett.
Origin of the noradrenergic innervation of the superior olivary complex in the rat
J. Chem. Neuroanat.
Alterations of catecholamine enzymes in several brain region of victims of sudden infant death syndrome
Life Sci.
Catecholaminergic neurons in the diencephalon and basal ganglia of SIDS
Pediatr. Neurol.
Trigemino-autonomic connections in the muskrat: the neural substrate for the diving response
Brain Res.
Specification of the central noradrenergic phenotype by the homeobox gene Phox2b
Mol. Cell. Neurosci.
Clonidine modulates locus coeruleus metabolic hyperactivity induced by stress in behaving rats
Brain Res.
Lower brainstem afferents to the cat posterior hypothalamus: a double-labeling study
Brain Res. Bull.
Three dimensional representation of bulbo-pontine respiratory networks architecture from density maps
Brain Res.
Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats
Pflügers Arch.
The adrenergic modulation of firings of respiratory rhythm-generating neurons in medulla-spinal cord preparation from newborn rat
Exp. Brain Res.
Mammalian brainstem chemosensitive neurones: linking them to respiration in vitro
J. Physiol. (Lond.)
Respiratory synchronizing function of nucleus parabrachialis medialis: pneumotaxic mechanisms
J. Neurophysiol.
Quantitative study of anatomical distribution of respiration related neurons in the pons
Exp. Brain Res.
A stereologic model of pneumotaxic oscillator based on spatial and temporal distributions of neuronal bursts
J. Neurophysiol.
Pharmacological studies on a possible role of central norepinephrine neurons in respiratory control
J. Pharm. Pharmacol.
Altered respiratory activity and respiratory regulations in adult monoamine oxidase A-deficient mice
J. Neurosci.
Afferent and efferent connections of the A5 noradrenergic cell group in the rat
J. Comp. Neurol.
Changes in cerebrospinal fluid monoamine metabolites, tryptophan, and gamma-aminobutyric acid during the 1st year of life in normal infants. Comparison with victims of sudden infant death syndrome
Biol. Neonate
Immunohistochemical absence of adrenergic neurons in the dorsal part of the solitary tract nucleus in sudden infant death syndrome
C R Acad. Sci. (Paris)
Neurons in the ventrolateral pons are required for post-hypoxic frequency decline in rat
J. Physiol. (Lond.)
Anatomical specificity of noradrenergic inputs to the paraventricular and supraoptic nuclei of the rat hypothalamus
J. Comp. Neurol.
Respiratory effect of stimulation of cell bodies of the A5 region in the anaesthetised rat
Pflügers Arch.
In vitro study of central respiratory-like activity of the fetal rat
Exp. Brain Res.
Brainstem network controlling descending drive to phrenic motoneurons in rat
J. Comp. Neurol.
Central regulation of respiration by endogenous neurotransmitters and neuromodulators
Ann. Rev. Physiol.
Cited by (145)
Machine learning-based data analytic approaches for evaluating post-natal mouse respiratory physiological evolution
2021, Respiratory Physiology and NeurobiologyCitation Excerpt :It has been postulated that the serotonergic and catecholaminergic neurotransmitter systems are key contributors to this developmental maturation. For instance, pontine-derived projections, presumably through A5-dependent projections to the ventral lateral medulla, show different extents of inhibition in early preparations (∼P0/1) relative to late preparations (∼P3-P5) rats (Hilaire et al., 2004), and the number of A5 neurons in the rat pup reportedly decreases with advanced post-natal age (Ito et al., 2002). Biochemical evidence indicates that several neurotransmitters, including noradrenaline and serotonin, increase with advanced post-natal age at rates independent of total brain weight (Ide et al., 2005).
The hypocretin (orexin) system: from a neural circuitry perspective
2020, NeuropharmacologyEffect of temperature, age and the pons on respiratory rhythm in the rat brainstem-spinal cord
2020, Respiratory Physiology and NeurobiologyCitation Excerpt :Corcoran and Milsom (2009) reported that at P0 the pons provides an excitatory input that disappears by P2 and is replaced by an inhibitory input by P4. Other studies have also observed early excitatory effects of the pons on respiratory frequency in embryos (Borday et al., 1997) and in fetuses (Di Pasquale et al., 1994; Hilaire and Duron, 1999) that are replaced by a net inhibitory input to the medullary respiratory centers during development (Hilaire et al., 1989, 2004; Errchidi et al., 1990, 1991). During cooling, respiratory frequency decreased in all preparations, young and old, with and without the pons intact, just as it does in vivo (Adolph, 1948a; Fairchild, 1948; Tattersall and Milsom, 2003).
An age- and sex-dependent role of catecholaminergic neurons in the control of breathing and hypoxic chemoreflex during postnatal development
2020, Brain ResearchCitation Excerpt :Interestingly, this tonic modulation occurs only in early life, since no lesion effect was observed during normoxia at older ages. This corroborates the fact that the A5 inhibitory role on respiratory rhythmogenesis is predominant at early neonatal stages than at older ages (Hilaire et al., 2004). We have also observed a decrease in breathing variability during normoxic conditions in both male and female lesioned P7-8 rats.
- 1
Department of Organismal Biology and Anatomy University of Chicago, 1027 East 57th Street, Chicago, IL 60637, USA.