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From birth onwards, rhythmic breathing is required for blood oxygenation and survival in mammals. During their lifespan, human or mouse or elephant will spontaneously produce several hundreds of millions of respiratory movements. The central nervous command responsible for these spontaneous rhythmic movements is elaborated by a complex neural network extending within the brainstem. In the medulla, a special part of this network contains respiratory pacemaker neurons that play a crucial role in respiratory rhythmogenesis: the pre-Bötzinger complex. This review summarizes and discusses the main electrophysiological, molecular and genetic mechanisms contributing to the function and the perinatal maturation of the pre-Bötzinger complex., (© 2013 médecine/sciences – Inserm.)

1 We have studied the unit activity of 88 pulmonary stretch receptors (RPI) in the vagus nerve of the cat by using the single fibre technique. 2 In spite of a 38% decrease in tidal volume, the discharge frequency of RPI is statistically unchanged during polypnea, However, RPI are recruited earlier, but their discharge overlaps expiration. 3 Individual influences of tidal volume, temperature, and FACO2 on RPI activities are tested. During polypnea, the excitatory influences of hyperthermia and hypocapnia act against the depressing action of tidal volume reduction: RPI are still active. 4 During polypnea, respiratory rhythm and tidal volume are unchanged after bivagotomy. RPI activity seems functionally insignificant. This result suggests that the thermally induced respiratory response is mediated by structures in the upper brain stem (probably the preoptic anterior hypothalamus) and is not dependent on the integrity of the vagus nerve.

10 The activity of 107 medullary inspiratory neurones has been recorded extracellularly in anesthetized cats (urethane-chloralose). According to their localization in the medulla and to their axonal pathways (tested by antidromic activation), these neurones were classified as: bulbo-spinal neurones (NBSI) which send their axons to the spinal cord; they are located in the dorsal or the ventral respiratory nucleus; propriobulbar neurons (NPBI) whose axons are probably entirely located within the medulla; they are found only in the ventral nucleus. 20 Summation of gross discharges from phrenic (C5 ventral root) or inspiratory intercostal (from T4 to T10) nerves was triggered by spikes from medullary respiratory neurones. If the studied neurone controls the activity of the recorded motor fibres, after sommation of a great number of sweeps (3,000 to 5,000), the summed nerve activity displays a short delay excitatory wave, indicating that the activity of the motoneurones is increased after the onset of the medullary potential. On the other hand, there is a flat summed nerve activity if the nerve discharge is not directly dependent on the medullary recorded activity. 30 The dorsal nucleus NBSIs send their axon to the contralateral phrenic motoneurones (as it is revealed by the excitatory wave noted on the summed phrenic nerve activity, fig. 1 and 4) and not to the intercostal motoneurones (fig. 4). 40 The ventral nucleus NBSIs control contralateral intercostal motoneurones (fig. 5). Some of them send their axons only to these motoneurones, but the majority also act on phrenic motoneurones (fig. 2 and 5). 50 Connections between NBSIs and phrenic motoneurones are monosynaptic and probably also those between NBSIs and intercostal motoneurones. 60 No excitatory wave has been observed on phrenic or intercostal summed activity when summation was triggered by NPBI spikes (fig. 3). This confirms the accuracy of the "antidromic stimulation test" used to classify medullary respiratory neurons.

We have compared in "encéphale isolé bas" cats the activity of medullary respiratory neurones during polypnea triggered by electrical stimulation (PSt) or by heating (PTh) of the hypothalamus. The medullary respiratory neurones are classified according to:--their anatomical localization (dorsal or ventral respiratory nucleus);--their axon destination (spinal : bulbo-spinal respiratory neurones; non spinal : propriobulbar neurones);--their discharge pattern;--the correlation coefficient between the number of spikes delivered in each burst and the duration of the corresponding respiratory phase (HILAIRE et MONTEAU, 1975). 1. During the two polypneas (PSt and PTh), we observe:--a reduction of activity that preferentially affects some groups of neurones (propriobulbar neurones) (fig. 3);--an inversion of the discharge firing rate, which increases during inspiration in normopnea and decreases in polypnea (fig. 1; fig. 6);--a decrease of the maximal discharge firing rate for the neurones of different groups (Table V). 2. However, two differences exist : during PSt, the maximal discharge firing rate increases for the inspiratory bulbo-spinal neurones of the dorsal nucleus and for the early-burster inspiratory propriobulbar neurones. The recruitment of the bulbo-spinal inspiratory neurones seems to be different; they are activated earlier during PSt than during PTh (Table VI). 3. Some of the observed differences are probably quantitative and we think that polypnea triggered by hypothalamic electrical stimulation is a good model for thermal polypnea.

1 In "encephale isole" cats with a spinal section in C7, we have recorded the activity of 108 medullary inspiratory or expiratory neurones during normopnea or polypnea induced by local warming of the anterior hypothalamic region. The neurones were grouped according to their axon destination, their discharge pattern, and the correlation level between their unit activity and the phrenic neurogram. 2 In polypnea, 71% of inspiratory neurones remain active. Their firing rates, which increase during inspiratory discharges in normopnea, decrease during inspiratory discharges in polypnea. However, this inversion of discharge pattern is less marked than with phrenic motoneurones. 3 The reduction of activity in polypnea preferentially strikes certain types of neurones. While bulbo-spinal inspiratory neurones all remain active, the propriobulbar inspiratory neurones can be grouped into those which remain active and whose activity is well correlated with the phrenic neurogram, and those which become silent and showing a poor correlation. As a general rule, activity in polypnea and correlation (in normopnea) go together. 4 In polypnea, 56% of expiratory neurones cease discharging. This activity decrease applies to bulbo-spinal expiratory neurones (5 out of 14) and to propriobulbar expiratory neurones (20 out of 31). Among the expiratory neurones, only those with an elevated discharge firing rate and significant correlation coefficient values remain active in polypnea. At this time they generally exhibit a decreasing firing rate and emit only a few spikes in each burst. 5 The results suggest that during polypnea the genesis of the respiratory rhythm is dependent upon a different mechanism than in normopnea.

1. We have studied the activity of 162 medullary respiratory neurones in the "encephale isole bas" cat. These neurones were classed into three groups : bulbospinal inspiratory (NBSI : 39) or expiratory (NBSE : 15) neurones whose axons enter the spinal cord ; inspiratory or expiratory laryngeal motoneurones (MLI : 17; MLE : 10) antidromically activated by vagus nerve stimulation ; propriobulbar inspiratory (NPBI : 59) or expiratory (NPBE : 22) neurones whose axons lie perhaps entirely within the medulla. 2. Correlation coefficients between number of spikes delivered in each burst and the duration of the corresponding respiratory phase (inspiration for NBSI, MLI, NPBI ; expiration for NBSE, MLE, NPBE) have been calculated for each neurone. 3. The activity of most of the NBSI and MLI is significantly correlated with the duration of the inspiration. These two groups of neurones are probably homogenous. 4. On the basis of this correlation test, NPBI do not constitute an homogeneous population ; 50% of NPBI are not significantly correlated. The same results are obtained if correlations are calculated between the number of spikes delivered and the amplitude of integrated phrenic nerve acitivty. According to the discharge pattern and correlation test, we can consider three groups of NPBI : early recruited neurones with decreasing frequency and non significantly correlated activity (23,7%); early and late neurones with increasing frequency and significantly correlated activity (32,2%); early and late neurones with increasing frequency and non significantly correlated acitivty (44,1%). 5. The activity of most of the NBSE and NPBE with increasing frequency is significantly correlated with the duration of the expiration. Among the MLE and NPBE with a decreasing frequency, a great number of neurones are not significantly correlated. 6. The functional significantion of the different neuronal types is discussed from these correlation tests and from the pattern of activity and axonal pathways.