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

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Abstract

The aim of the present review is to summarise available studies dealing with the respiratory control exerted by pontine noradrenergic neurones in neonatal and adult mammals. During the perinatal period, in vitro studies on neonatal rodents have shown that A5 and A6 neurones exert opposite modulations onto the respiratory rhythm generator, inhibitory and facilitatory respectively, that the anatomical support for these modulations already exists at birth, and that genetically induced alterations in the formation of A5 and A6 neurones affect the maturation of the respiratory rhythm generator, leading to lethal respiratory deficits at birth. The A5–A6 modulation of the respiratory rhythm generator is not transient, occurring solely during the perinatal period but it persists throughout life: A5 and A6 neurones display a respiratory-related activity, receive inputs from and send information to the medullary respiratory centres and contribute to the adaptation of adult breathing to physiological needs.

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

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    Department of Organismal Biology and Anatomy University of Chicago, 1027 East 57th Street, Chicago, IL 60637, USA.

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