scholarly journals Maturation of the Mammalian Respiratory System

1999 ◽  
Vol 79 (2) ◽  
pp. 325-360 ◽  
Author(s):  
Gérard Hilaire ◽  
Bernard Duron
Keyword(s):  
Respiratory Activity ◽  
Respiratory Rhythm ◽  
Ventrolateral Medulla ◽  
Pacemaker Neurons ◽  
Inhibitory Processes ◽  
Respiratory Rhythmogenesis ◽  
Respiratory Network ◽  
Network Functions

In this review, the maturational changes occurring in the mammalian respiratory network from fetal to adult ages are analyzed. Most of the data presented were obtained on rodents using in vitro approaches. In gestational day 18 (E18) fetuses, this network functions but is not yet able to sustain a stable respiratory activity, and most of the neonatal modulatory processes are not yet efficient. Respiratory motoneurons undergo relatively little cell death, and even if not yet fully mature at E18, they are capable of firing sustained bursts of potentials. Endogenous serotonin exerts a potent facilitation on the network and appears to be necessary for the respiratory rhythm to be expressed. In E20 fetuses and neonates, the respiratory activity has become quite stable. Inhibitory processes are not yet necessary for respiratory rhythmogenesis, and the rostral ventrolateral medulla (RVLM) contains inspiratory bursting pacemaker neurons that seem to constitute the kernel of the network. The activity of the network depends on CO2 and pH levels, via cholinergic relays, as well as being modulated at both the RVLM and motoneuronal levels by endogenous serotonin, substance P, and catecholamine mechanisms. In adults, the inhibitory processes become more important, but the RVLM is still a crucial area. The neonatal modulatory processes are likely to continue during adulthood, but they are difficult to investigate in vivo. In conclusion, 1) serotonin, which greatly facilitates the activity of the respiratory network at all developmental ages, may at least partly define its maturation; 2) the RVLM bursting pacemaker neurons may be the kernel of the network from E20 to adulthood, but their existence and their role in vivo need to be further confirmed in both neonatal and adult mammals.

Genesis and Control of the Respiratory Rhythm in Adult Mammals

Physiology ◽  
2003 ◽  
Vol 18 (1) ◽  
pp. 23-28 ◽  
Author(s):  
Gérard Hilaire ◽  
Rosario Pásaro
Keyword(s):  
Respiratory Rhythm ◽  
Neural Mechanisms ◽  
Pacemaker Neurons ◽  
Respiratory Rhythmogenesis ◽  
Respiratory Network ◽  
And Control ◽  
Vitro Data ◽  
In Vitro Data

The neural mechanisms responsible for respiratory rhythmogenesis in mammals were studied first in vivo in adults and subsequently in vitro in neonates. In vitro data have suggested that the pacemaker neurons are the kernel of the respiratory network. These data are reviewed, and their relevance to adults is discussed.

scholarly journals Pacemakers handshake synchronization mechanism of mammalian respiratory rhythmogenesis

2008 ◽  
Vol 105 (46) ◽  
pp. 18000-18005 ◽  
Author(s):  
Steffen Wittmeier ◽  
Gang Song ◽  
James Duffin ◽  
Chi-Sang Poon
Keyword(s):  
Feedback Inhibition ◽  
Experimental Testing ◽  
Respiratory Rhythm ◽  
Synchronization Mechanism ◽  
Respiratory Rhythmogenesis ◽  
Underlying Mechanisms ◽  
Safe Mechanism ◽  
Parafacial Respiratory Group

Inspiratory and expiratory rhythms in mammals are thought to be generated by pacemaker-like neurons in 2 discrete brainstem regions: pre-Bötzinger complex (preBötC) and parafacial respiratory group (pFRG). How these putative pacemakers or pacemaker networks may interact to set the overall respiratory rhythm in synchrony remains unclear. Here, we show that a pacemakers 2-way “handshake” process comprising pFRG excitation of the preBötC, followed by reverse inhibition and postinhibitory rebound (PIR) excitation of the pFRG and postinspiratory feedback inhibition of the preBötC, can provide a phase-locked mechanism that sequentially resets and, hence, synchronizes the inspiratory and expiratory rhythms in neonates. The order of this handshake sequence and its progression vary depending on the relative excitabilities of the preBötC vs. the pFRG and resultant modulations of the PIR in various excited and depressed states, leading to complex inspiratory and expiratory phase-resetting behaviors in neonates and adults. This parsimonious model of pacemakers synchronization and mutual entrainment replicates key experimental data in vitro and in vivo that delineate the developmental changes in respiratory rhythm from neonates to maturity, elucidating their underlying mechanisms and suggesting hypotheses for further experimental testing. Such a pacemakers handshake process with conjugate excitation–inhibition and PIR provides a reinforcing and evolutionarily advantageous fail-safe mechanism for respiratory rhythmogenesis in mammals.

Differences in serotoninergic metabolism possibly contribute to differences in breathing phenotype of FVB/N and C57BL/6J mice

2011 ◽  
Vol 110 (6) ◽  
pp. 1572-1581 ◽  
Author(s):  
Clément Menuet ◽  
Nazim Kourdougli ◽  
Gérard Hilaire ◽  
Nicolas Voituron
Keyword(s):  
Breathing Pattern ◽  
Minute Ventilation ◽  
Respiratory Rhythm ◽  
Inbred Strains ◽  
Interstrain Differences ◽  
Respiratory Network ◽  
Blood Gas Parameters ◽  
And Function

Mouse readiness for gene manipulation allowed the production of mutants with breathing defects reminiscent of breathing syndromes. As C57BL/6J and FVB/N inbred strains were often used as background strains for producing mutants, we compared their breathing pattern from birth onwards. At birth, in vivo and in vitro approaches revealed robust respiratory rhythm in FVB/N, but not C57BL/6J, neonates. With aging, rhythm robustness difference persisted, and interstrain differences in tidal volume, minute ventilation, breathing regulations, and blood-gas parameters were observed. As serotonin affected maturation and function of the medullary respiratory network, we examined the serotoninergic metabolism in the medulla of C57BL/6J and FVB/N neonates and aged mice. Interstrain differences in serotoninergic metabolism were observed at both ages. We conclude that differences in serotoninergic metabolism possibly contribute to differences in breathing phenotype of FVB/N and C57BL/6J mice.

scholarly journals Mechanisms Underlying Adaptation of Respiratory Network Activity to Modulatory Stimuli in the Mouse Embryo

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Marc Chevalier ◽  
Rafaël De Sa ◽  
Laura Cardoit ◽  
Muriel Thoby-Brisson
Keyword(s):  
Ph Regulation ◽  
Respiratory Rhythm ◽  
Network Activity ◽  
Pacemaker Neurons ◽  
Functional Flexibility ◽  
Respiratory Rhythmogenesis ◽  
Brainstem Slice ◽  
Respiratory Network ◽  
The Impact

Breathing is a rhythmic behavior that requires organized contractions of respiratory effector muscles. This behavior must adapt to constantly changing conditions in order to ensure homeostasis, proper body oxygenation, and CO2/pH regulation. Respiratory rhythmogenesis is controlled by neural networks located in the brainstem. One area considered to be essential for generating the inspiratory phase of the respiratory rhythm is the preBötzinger complex (preBötC). Rhythmogenesis emerges from this network through the interplay between the activation of intrinsic cellular properties (pacemaker properties) and intercellular synaptic connections. Respiratory activity continuously changes under the impact of numerous modulatory substances depending on organismal needs and environmental conditions. The preBötC network has been shown to become active during the last third of gestation. But only little is known regarding the modulation of inspiratory rhythmicity at embryonic stages and even less on a possible role of pacemaker neurons in this functional flexibility during the prenatal period. By combining electrophysiology and calcium imaging performed on embryonic brainstem slice preparations, we provide evidence showing that embryonic inspiratory pacemaker neurons are already intrinsically sensitive to neuromodulation and external conditions (i.e., temperature) affecting respiratory network activity, suggesting a potential role of pacemaker neurons in mediating rhythm adaptation to modulatory stimuli in the embryo.

scholarly journals Inspiratory Off-Switch Mediated by Optogenetic Activation of Inhibitory Neurons in the preBötzinger Complex In Vivo

2021 ◽  
Vol 22 (4) ◽  
pp. 2019
Author(s):  
Swen Hülsmann ◽  
Liya Hagos ◽  
Volker Eulenburg ◽  
Johannes Hirrlinger
Keyword(s):  
Respiratory Rate ◽  
Respiratory Rhythm ◽  
Inhibitory Neurons ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Transgenic Mouse Line ◽  
Respiratory Network ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

The role of inhibitory neurons in the respiratory network is a matter of ongoing debate. Conflicting and contradicting results are manifold and the question whether inhibitory neurons are essential for the generation of the respiratory rhythm as such is controversial. Inhibitory neurons are required in pulmonary reflexes for adapting the activity of the central respiratory network to the status of the lung and it is hypothesized that glycinergic neurons mediate the inspiratory off-switch. Over the years, optogenetic tools have been developed that allow for cell-specific activation of subsets of neurons in vitro and in vivo. In this study, we aimed to identify the effect of activation of inhibitory neurons in vivo. Here, we used a conditional transgenic mouse line that expresses Channelrhodopsin 2 in inhibitory neurons. A 200 µm multimode optical fiber ferrule was implanted in adult mice using stereotaxic surgery, allowing us to stimulate inhibitory, respiratory neurons within the core excitatory network in the preBötzinger complex of the ventrolateral medulla. We show that, in anesthetized mice, activation of inhibitory neurons by blue light (470 nm) continuously or with stimulation frequencies above 10 Hz results in a significant reduction of the respiratory rate, in some cases leading to complete cessation of breathing. However, a lower stimulation frequency (4–5 Hz) could induce a significant increase in the respiratory rate. This phenomenon can be explained by the resetting of the respiratory cycle, since stimulation during inspiration shortened the associated breath and thereby increased the respiratory rate, while stimulation during the expiratory interval reduced the respiratory rate. Taken together, these results support the concept that activation of inhibitory neurons mediates phase-switching by inhibiting excitatory rhythmogenic neurons in the preBötzinger complex.

Sulfide-induced perturbations of the neuronal mechanisms controlling breathing in rats

1995 ◽  
Vol 78 (2) ◽  
pp. 433-440 ◽  
Author(s):  
J. J. Greer ◽  
R. J. Reiffenstein ◽  
A. F. Almeida ◽  
J. E. Carter
Keyword(s):  
Respiratory Rhythm ◽  
Intraperitoneal Administration ◽  
Experimental Models ◽  
Neonatal Rat ◽  
Ventrolateral Medulla ◽  
Neonatal Rats ◽  
Breathing Patterns ◽  
Adult Rats

The effects of sulfide on neonatal rat respiration were studied. Two in vitro experimental models were utilized: the isolated brain stem-spinal cord preparation and the medullary slice preparation containing respiratory rhythm-generating regions from neonatal rats. Plethysmographic measurements of the effects of sulfide on the breathing patterns of unanesthetized neonatal rats were also made to compare the sensitivities of neonatal and adult rats to sulfide toxicity. In vitro, sulfide acted at sites within the ventrolateral medulla to depress the frequency of respiratory rhythmic discharge by approximately 50–60%. However, the neuronal network underlying respiratory rhythmogenesis continued to function in the presence of concentrations of sulfide far beyond those deemed to be lethal in vivo. Intraperitoneal administration of sulfide caused a dose-dependent decrease in the frequency and amplitude of breathing of neonatal rats of all ages (0–19 days postnatal), although the sensitivity to sulfide increased with age. We hypothesize that the rapid suppression of breathing caused by sulfide is due to changes in neuronal excitability within respiratory rhythm-generating centers rather than, as previously hypothesized, to perturbations of cellular oxidative metabolism.

Ventilatory responses to cooling the ventrolateral medullary surface of awake and anesthetized goats

1995 ◽  
Vol 78 (1) ◽  
pp. 247-257 ◽  
Author(s):  
P. J. Ohtake ◽  
H. V. Forster ◽  
L. G. Pan ◽  
T. F. Lowry ◽  
M. J. Korducki ◽  
...  
Keyword(s):  
Pulmonary Ventilation ◽  
Respiratory Rhythm ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Arterial Pco2 ◽  
Respiratory Rhythmogenesis ◽  
Ventilatory Responses ◽  
Anesthesia Breathing ◽  
A Site ◽  
Caudal Area

The ventrolateral medulla (VLM) has been reported to be important as a source of tonic facilitation of dorsal respiratory neurons and as a site critical for respiratory rhythmogenesis. We investigated these theories in awake and anesthetized goats (n = 13) by using chronically implanted thermodes to create reversible neuronal dysfunction at superficial VLM sites between the first hypoglossal rootlet and the pontomedullary junction (area M (rostral) and area S). During halothane anesthesia (arterial PCO2 = 57.4 +/- 4.5 Torr), bilateral cooling (thermode temperature = 20 degrees C) of 60–100% of areas M and S for 30 s produced a sustained apnea (46 +/- 4 s) that lasted beyond the period of cooling. While the animals were awake (arterial PCO2 = 36.0 +/- 1.9 Torr), cooling the identical region in the same goats resulted in a decrease (approximately 50%) in pulmonary ventilation, with a brief apnea seen only in one goat. Reductions in both tidal volume and frequency were observed. Qualitatively similar responses were obtained when cooling caudal area M-rostral area S and rostral area M, but the responses were less pronounced. Minimal effects were seen in response to cooling caudal area S. During anesthesia, breathing is critically dependent on superficial VLM neurons, whereas in the awake state these neurons are not essential for the maintenance of respiratory rhythm. Our data are consistent with these superficial VLM neuronal regions providing tonic facilitation to more dorsal respiratory neurons in both the anesthetized and awake states.

Neuronal excitation by angiotensin II in the rostral ventrolateral medulla of the rat in vitro

1995 ◽  
Vol 268 (1) ◽  
pp. R272-R277 ◽  
Author(s):  
Y. W. Li ◽  
P. G. Guyenet
Keyword(s):  
Angiotensin Ii ◽  
Excitatory Amino Acid ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Excitatory Amino Acid Receptor ◽  
Neuronal Excitation ◽  
Uk 14,304

We examined the effects of angiotensin II (ANG II) on spontaneous unit activity in slices of the rat rostral ventrolateral medulla (RVLM), ANG II (1-3 microM) excited 61% of a population of slowly and irregularly firing RVLM neurons (predrug, 1.2 +/- 0.1 spikes/s; postdrug, 4.6 +/- 0.3 spikes/s; n = 52). ANG II had no effect on pacemaker-like rapidly firing neurons (predrug, 8.6 +/- 0.4 spikes/s; n = 33). The effect of ANG II on slowly firing cells was repeatable and was reduced 75% by 3 microM losartan (baseline, 1.7 +/- 0.4 spikes/s; ANG II, 5.3 +/- 0.7 spikes/s; ANG II+losartan, 2.4 +/- 0.6 spikes/s; n = 12). The ongoing activity of slowly firing neurons was unaffected by 0.5-1 mM kynurenic acid (an ionotropic excitatory amino acid receptor antagonist). Most ANG II-responsive neurons (10 of 11) were inhibited by the alpha 2-adrenergic receptor agonist UK-14,304, but pacemaker-like neurons were not. In conclusion, the RVLM contains neurons excited by AT1 receptor agonists. These neurons are distinct from the previously described pacemaker nonadrenergic presympathetic cells. They may be responsible for the pressor effects produced by injecting ANG II into the RVLM in vivo.

Reconfiguration of the Respiratory Network at the Onset of Locust Flight

1998 ◽  
Vol 80 (6) ◽  
pp. 3137-3147 ◽  
Author(s):  
Jan-Marino Ramirez
Keyword(s):  
Respiratory Activity ◽  
Respiratory Rhythm ◽  
Quiescent State ◽  
Suboesophageal Ganglion ◽  
Rhythm Generator ◽  
Locust Flight ◽  
Respiratory Network ◽  
Intracellular Stimulation ◽  
Tonic Stimulation ◽  
Stimulation Of

Ramirez, Jan-Marino. Reconfiguration of the respiratory network at the onset of locust flight. J. Neurophysiol. 80: 3137–3147, 1998. The respiratory interneurons 377, 378, 379 and 576 were identified within the suboesophageal ganglion (SOG) of the locust. Intracellular stimulation of these neurons excited the auxillary muscle 59 (M59), a muscle that is involved in the control of thoracic pumping in the locust. Like M59, these interneurons did not discharge during each respiratory cycle. However, the SOG interneurons were part of the respiratory rhythm generator because brief intracellular stimulation of these interneurons reset the respiratory rhythm and tonic stimulation increased the frequency of respiratory activity. At the onset of flight, the respiratory input into M59 and the SOG interneurons was suppressed, and these neurons discharged in phase with wing depression while abdominal pumping movements remained rhythmically active in phase with the slower respiratory rhythm (Fig. 9 ). The suppression of the respiratory input during flight seems to be mediated by the SOG interneuron 388. This interneuron was tonically activated during flight, and intracellular current injection suppressed the respiratory rhythmic input into M59. We conclude that the respiratory rhythm generator is reconfigured at flight onset. As part of the rhythm-generating network, the interneurons in the SOG are uncoupled from the rest of the respiratory network and discharge in phase with the flight rhythm. Because these SOG interneurons have a strong influence on thoracic pumping, we propose that this neural reconfiguration leads to a behavioral reconfiguration. In the quiescent state, thoracic pumping is coupled to the abdominal pumping movements and has auxillary functions. During flight, thoracic pumping is coupled to the flight rhythm and provides the major ventilatory movements during this energy-demanding locomotor behavior.

scholarly journals Rhythmic Properties of Neurons in the Rostral Ventrolateral Medulla of the Rat In Vitro: Effects of Clonidine

2002 ◽  
Vol 88 (5) ◽  
pp. 2262-2279 ◽  
Author(s):  
Antonio R. Granata ◽  
Morton I. Cohen
Keyword(s):  
Interspike Interval ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Type I ◽  
Slice Preparation ◽  
Different Populations ◽  
In Vitro Effects ◽  
Spike Firing

The rostral ventrolateral medulla (RVLM) is thought to be the main central site for generation of tonic sympathetic activity. In the rat in vitro slice preparation, we used intracellular recordings to identify different populations of neurons in the RVLM: 43 spontaneously active neurons with regular (R) or irregular (I) patterns of spike firing and 10 silent neurons. The degree of regularity was quantified by the coefficient of variation (CV = SD/mean) of interspike interval durations, as well as by the rhythmic properties of the spike autospectrum and autocorrelation. The distribution of CVs was clustered: R and I neurons were defined as those with CVs ≤12% ( n = 21) or >12% ( n = 22), respectively. The R-type and I-type neurons resemble the type II and type I neurons, respectively, which were previously characterized in the RVLM in vivo as barosensitive and bulbospinal. Both types may be important in generation of sympathetic tone. Clonidine (1–100 μM) was applied to 10 R-type neurons and 16 I-type neurons. The firing of 21/26 was depressed to the point of silence. However, 18/26 neurons were excited earlier in the perfusion. The later depression of firing occurred in both I and R neurons and in different cases was associated with either hyperpolarization or depolarization.

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