scholarly journals The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO2

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Pierre-Louis Ruffault ◽  
Fabien D'Autréaux ◽  
John A Hayes ◽  
Marc Nomaksteinsky ◽  
Sandra Autran ◽  
...  
Keyword(s):  
Respiratory Rhythm ◽  
Low Ph ◽  
Glutamatergic Transmission ◽  
Respiratory Response ◽  
Principal Mechanism ◽  
Retrotrapezoid Nucleus ◽  
Arterial Blood ◽  
Nerve Response ◽  
Respiratory Chemoreflex ◽  
Ventral Medullary Surface

Maintaining constant CO2 and H+ concentrations in the arterial blood is critical for life. The principal mechanism through which this is achieved in mammals is the respiratory chemoreflex whose circuitry is still elusive. A candidate element of this circuitry is the retrotrapezoid nucleus (RTN), a collection of neurons at the ventral medullary surface that are activated by increased CO2 or low pH and project to the respiratory rhythm generator. Here, we use intersectional genetic strategies to lesion the RTN neurons defined by Atoh1 and Phox2b expression and to block or activate their synaptic output. Photostimulation of these neurons entrains the respiratory rhythm. Conversely, abrogating expression of Atoh1 or Phox2b or glutamatergic transmission in these cells curtails the phrenic nerve response to low pH in embryonic preparations and abolishes the respiratory chemoreflex in behaving animals. Thus, the RTN neurons expressing Atoh1 and Phox2b are a necessary component of the chemoreflex circuitry.

scholarly journals Lethal avian influenza A (H5N1) virus induces ataxic breathing in mice with apoptosis of pre-Botzinger complex neurons expressing neurokinin-1 receptor

2017 ◽  
Vol 313 (5) ◽  
pp. L772-L780 ◽  
Author(s):  
Jianguo Zhuang ◽  
Na Zang ◽  
Chunyan Ye ◽  
Fadi Xu
Keyword(s):  
Respiratory Failure ◽  
Influenza A ◽  
Early Stage ◽  
Respiratory Rhythm ◽  
Body Weight Loss ◽  
Neurokinin 1 Receptor ◽  
Arterial Blood ◽  
Bötzinger Complex ◽  
Neurokinin 1 ◽  
Active Caspase

Lethal influenza A (H5N1) induces respiratory failure in humans. Although it also causes death at 7 days postinfection (dpi) in mice, the development of the respiratory failure and the viral impact on pre-Botzinger complex (PBC) neurons expressing neurokinin 1 receptor (NK1R), which is the respiratory rhythm generator, have not been explored. Body temperature, weight, ventilation, and arterial blood pH and gases were measured at 0, 2, 4, and 6 dpi in control, lethal HK483, and nonlethal HK486 viral-infected mice. Immunoreactivities (IR) of PBC NK1R, H5N1 viral nucleoprotein (NP), and active caspase-3 (CASP3; a marker for apoptosis) were detected at 6 dpi. HK483, but not HK486, mice showed the following abnormalities: 1) gradual body weight loss and hypothermia; 2) tachypnea at 2–4 dpi and ataxic breathing with long-lasting apneas and hypercapnic hypoxemia at 6 dpi; and 3) viral replication in PBC NK1R neurons with NK1R-IR reduced by 75% and CASP3-IR colabeled at 6 dpi. Lethal H5N1 viral infection causes tachypnea at the early stage and ataxic breathing and apneas (hypercapnic hypoxemia) leading to death at the late stage. Its replication in the PBC induces apoptosis of local NK1R neurons, contributing to ataxic breathing and respiratory failure.

Site of central chemosensitivity in fetal sheep

1975 ◽  
Vol 39 (1) ◽  
pp. 1-6 ◽  
Author(s):  
A. H. Jansen ◽  
V. Chernick
Keyword(s):  
Blood Pressure ◽  
Spinal Cord ◽  
Heart Rate ◽  
Respiratory Response ◽  
Fetal Sheep ◽  
Central Chemosensitivity ◽  
Cord Clamping ◽  
Chemosensitive Areas ◽  
Ventral Medullary Surface ◽  
Histotoxic Hypoxia

The heart rate, blood pressure, and respiratory response to topically applied cyanide on the ventrolateral medullary surface and upper spinal cord was studied on exteriorized sinaortic-denervated fetal lambs under pentobarbital anesthesia. On all sites tested cyanide produced a rapid increase in heart rate and blood pressure (P smaller than 0.05) which was most pronounced from the area adjacent to the nerve roots IX to XI (mean 32%). Respiratory efforts consisting of 1–8 gasps were induced in half the applications to the medulla but never when the pledgets were applied to the spinal cord. The mean delay to response was 43 s (range 13–102 s). After cautery of the chemosensitive areas, topical application of cyanide failed to stimulate gasping, whereas intravenous cyanide or cord clamping still produced a vigorous respiratory response. It is concluded that sympathetic stimulation of the heart and blood vessels can originate centrally in response to local histotoxic hypoxia of the ventral medulla and upper spinal cord. Furthermore, it is proposed that in the apneic fetus histotoxic hypoxia of the medulla initiates respiration possibly by stimulating a special gasping mechanism which is separate from the respiratory center responsible for rhythmic breathing after birth. The responsible neurons must be located at least 2 mm beneath the ventral medullary surface.

A role for NMDA receptors in posthypoxic frequency decline in the rat

1998 ◽  
Vol 274 (6) ◽  
pp. R1546-R1555 ◽  
Author(s):  
Sharon K. Coles ◽  
Paul Ernsberger ◽  
Thomas E. Dick
Keyword(s):  
Nmda Receptors ◽  
Receptor Activation ◽  
Respiratory Pattern ◽  
Breathing Frequency ◽  
Respiratory Response ◽  
Arterial Blood ◽  
Before And After ◽  
High Doses ◽  
The Brain ◽  
Nmda Receptor Activation

Posthypoxic frequency decline (PHFD) refers to the undershoot in respiratory frequency that follows brief hypoxic exposures. Lateral pontine neurons are required for PHFD. The neurotransmitters involved in the circuit that activate and/or are released by these pontine neurons regulating PHFD are unknown. We hypothesized that N-methyl-d-aspartate (NMDA) receptors are required for PHFD, because of the similarity in respiratory pattern after blocking lateral pontine activity or NMDA receptors. Furthermore, we hypothesized that the location of these NMDA receptors could be visualized by optimizing binding affinity with spermidine. In vagotomized, anesthetized rats ( n = 16), cardiorespiratory responses to hypoxia (8% O2, 30–90 s) were recorded before and after dizocilpine (10 μg-1 mg/kg iv), and NMDA receptors were mapped with [3H]dizocilpine ( n = 6). Dizocilpine elicited a dose-related effect on PHFD, blocking PHFD at high doses. Resting arterial blood pressure and breathing frequency decreased with high doses of dizocilpine, but the respiratory response to hypoxia remained intact. Our novel anatomical data indicate that NMDA receptors were widespread but distributed differentially in the brain stem. We conclude that NMDA receptors are located in pontine and medullary respiratory-related regions and that PHFD requires NMDA-receptor activation.

Effects on respiratory pattern of focal cooling in the medulla of the dog

1988 ◽  
Vol 65 (5) ◽  
pp. 2004-2010 ◽  
Author(s):  
M. Adams ◽  
T. Chonan ◽  
N. S. Cherniack ◽  
C. von Euler
Keyword(s):  
Respiratory Rhythm ◽  
Nucleus Ambiguus ◽  
Respiratory Pattern ◽  
Respiratory Drive ◽  
Timing Effect ◽  
Diaphragm Electrical Activity ◽  
Inspiratory Activity ◽  
Ventral Medullary Surface ◽  
Focal Cooling

Studies in cats have shown that, in addition to respiratory neuron groups in the dorsomedial (DRG) and ventrolateral (VRG) medulla, neural structures in the most ventral medullary regions are important for the maintenance of respiratory rhythm. The purpose of this study was to determine whether a similar superficially located ventral region was present in the dog and to assess the role of each of the other regions in the canine medulla important in the control of breathing, in 20 anesthetized, vagotomized, and artificially ventilated dogs, a cryoprobe was used to cool selected regions of the medulla to 15-20 degrees C. Respiratory output was determined from phrenic nerve or diaphragm electrical activity. Cooling in or near the nucleus of the solitary tract altered timing and produced little change in the amplitude or rate of rise of inspiratory activity; lengthening of inspiratory time was the most common timing effect observed. Cooling in ventrolateral regions affected the amplitude and rate of rise of respiratory activity. Depression of neural tidal volume and apnea could be produced by unilateral cooling in two ventrolateral regions: 1) near the nucleus ambiguus and nucleus para-ambiguus and 2) just beneath the ventral medullary surface. These findings indicate that in the dog dorsomedial neural structures influence respiratory timing, whereas more ventral structures are important to respiratory drive.

Patterns of Phrenic Motor Output Evoked by Chemical Stimulation of Neurons Located in the Pre-Bötzinger Complex In Vivo

1999 ◽  
Vol 81 (3) ◽  
pp. 1150-1161 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Judith A. Neubauer
Keyword(s):  
Short Duration ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Chemical Stimulation ◽  
Arterial Blood ◽  
Bötzinger Complex ◽  
Tonic Excitation ◽  
Stimulation Of

Patterns of phrenic motor output evoked by chemical stimulation of neurons located in the pre-Bötzinger complex in vivo. The pre-Bötzinger complex (pre-BötC) has been proposed to be essential for respiratory rhythm generation from work in vitro. Much less, however, is known about its role in the generation and modulation of respiratory rhythm in vivo. Therefore we examined whether chemical stimulation of the in vivo pre-BötC manifests respiratory modulation consistent with a respiratory rhythm generator. In chloralose- or chloralose/urethan-anesthetized, vagotomized cats, we recorded phrenic nerve discharge and arterial blood pressure in response to chemical stimulation of neurons located in the pre-BötC with dl-homocysteic acid (DLH; 10 mM; 21 nl). In 115 of the 122 sites examined in the pre-BötC, unilateral microinjection of DLH produced an increase in phrenic nerve discharge that was characterized by one of the following changes in cycle timing and pattern: 1) a rapid series of high-amplitude, rapid rate of rise, short-duration bursts, 2) tonic excitation (with or without respiratory oscillations), 3) an integration of the first two types of responses (i.e., tonic excitation with high-amplitude, short-duration bursts superimposed), or 4) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a high-amplitude, short-duration burst). In 107 of these sites, the phrenic neurogram response was accompanied by an increase or decrease (≥10 mmHg) in arterial blood pressure. Thus increases in respiratory burst frequency and production of tonic discharge of inspiratory output, both of which have been seen in vitro, as well as modulation of burst pattern can be produced by local perturbations of excitatory amino acid neurotransmission in the pre-BötC in vivo. These findings are consistent with the proposed role of this region as the locus for respiratory rhythm generation.

scholarly journals Breathing with Phox2b

2009 ◽  
Vol 364 (1529) ◽  
pp. 2477-2483 ◽  
Author(s):  
Véronique Dubreuil ◽  
Jacques Barhanin ◽  
Christo Goridis ◽  
Jean-François Brunet
Keyword(s):  
Reverse Genetics ◽  
Human Genetics ◽  
Respiratory Rhythm ◽  
Neuronal Population ◽  
Cellular Level ◽  
Small Population ◽  
Respiratory Neurons ◽  
Retrotrapezoid Nucleus ◽  
Parafacial Respiratory Group

In the last few years, elucidation of the architecture of breathing control centres has reached the cellular level. This has been facilitated by increasing knowledge of the molecular signatures of various classes of hindbrain neurons. Here, we review the advances achieved by studying the homeodomain factor Phox2b , a transcriptional determinant of neuronal identity in the central and peripheral nervous systems. Evidence from human genetics, neurophysiology and mouse reverse genetics converges to implicate a small population of Phox2b -dependent neurons, located in the retrotrapezoid nucleus, in the detection of CO 2 , which is a paramount source of the ‘drive to breathe’. Moreover, the same and other studies suggest that an overlapping or identical neuronal population, the parafacial respiratory group, might contribute to the respiratory rhythm at least in some circumstances, such as for the initiation of breathing following birth. Together with the previously established Phox2b dependency of other respiratory neurons (which we review briefly here), our new data highlight a key role of this transcription factor in setting up the circuits for breathing automaticity.

scholarly journals Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia

2021 ◽  
Author(s):  
Caroline B Ferreira ◽  
Talita M Silva ◽  
Phelipe E Silva ◽  
Catherine Czeisler ◽  
Jose J Otero ◽  
...  
Keyword(s):  
Respiratory Rhythm ◽  
Adult Life ◽  
Respiratory Control ◽  
Lineage Tracing ◽  
Whole Body ◽  
Transgenic Mouse Line ◽  
Ventilatory Responses ◽  
Retrotrapezoid Nucleus ◽  
Adult Mice ◽  
Hypoventilation Syndrome

Retrotrapezoid nucleus (RTN) neurons are involved in central chemoreception and respiratory control. Lineage tracing studies demonstrate RTN neurons to be derived from Phox2b and Atoh1 expressing progenitor cells in rhombere 4. Phox2b exon 3 mutations cause congenital central hypoventilation syndrome (CCHS), producing an impaired respiratory response to hypercapnia and hypoxia. Our goal was to investigate the extent to which a conditional mutation of Phox2b within Atoh1-derived cells might affect a) respiratory rhythm; b) ventilatory responses to hypercapnia and hypoxia and c) number of RTN-chemosensitive neurons. Here, we used a transgenic mouse line carrying a conditional Phox2bΔ8 mutation activated by cre-recombinase. We crossed them with Atoh1Cre mice. Ventilation was measured by whole body plethysmograph during neonate and adult life. In room air, experimental and control groups showed similar basal ventilation; however, Atoh1Cre/Phox2bΔ8 increased breath irregularity. The hypercapnia and hypoxia ventilatory responses were impaired in neonates. In contrast, adult mice recovered ventilatory response to hypercapnia, but not to hypoxia. Anatomically, we observed a reduction of the Phox2b+/TH- expressing neurons within the RTN region. Our data indicates that conditionally expression of Phox2b mutation by Atoh1 affect development of the RTN neurons and are essential for the activation of breathing under hypoxic and hypercapnia condition, providing new evidence for mechanisms related to CCHS neuropathology

Sign in / Sign up

Export Citation Format

Share Document