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

scholarly journals Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Elizabeth Elliot-Portal ◽  
Christian Arias-Reyes ◽  
Sofien Laouafa ◽  
Rose Tam ◽  
Richard Kinkead ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Stress Hormones ◽  
Respiratory Control ◽  
Early Life Stress ◽  
Whole Body ◽  
Wild Type ◽  
Adult Mice ◽  
Respiratory Disturbance

Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3–12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.

scholarly journals Membrane progesterone receptor-β, but not -α, in dorsal brain stem establishes sex-specific chemoreflex responses and reduces apnea frequency in adult mice

2016 ◽  
Vol 121 (3) ◽  
pp. 781-791 ◽  
Author(s):  
Ryma Boukari ◽  
Orlane Rossignol ◽  
Cécile Baldy ◽  
François Marcouiller ◽  
Aida Bairam ◽  
...  
Keyword(s):  
Brain Stem ◽  
Progesterone Receptors ◽  
Respiratory Control ◽  
Staining Intensity ◽  
Whole Body ◽  
Male And Female ◽  
Female Mice ◽  
Adult Mice ◽  
Specific Effects ◽  
Membrane Progesterone Receptor

We tested the hypothesis that membrane progesterone receptors (mPR) contribute to respiratory control in adult male and female mice. Mice were implanted with osmotic minipumps for continuous infusion of small interfering RNA (siRNA) directed against mPRα, mPRβ, or a control solution in the fourth ventricle (to target brain stem respiratory areas) for 14 days. We then performed respiratory and metabolic recordings by whole body plethysmography at rest and in response to hypoxia (12% O2) or hypercapnia (5% CO2, 5 min each). For each treatment, we have verified with immunohistochemistry that the staining intensity of mPRα or mPRβ in the brain stem is decreased. At rest, the siRNA against mPRα and mPRβ increased respiratory frequency in males only. The siRNA against mPRβ almost tripled the frequency of apneas in male and in female mice, while the siRNA against mPRα had no effect. Regarding respiratory chemoreflex, the siRNA against mPRβ suppressed the response to hypoxia in male and female mice and reduced by ∼50% the response to hypercapnia, while the siRNA against mPRα had more limited effects. Interestingly, control females had higher ventilatory response to hypoxia and hypercapnia than males, and these sex-specific effects were suppressed by the siRNA against mPRβ, whereas they were still present after treatment with the siRNA against mPRα. We conclude that mPRβ reduces apnea frequency in male and female mice and establishes sex-specific ventilatory chemoreflex.

Cardiorespiratory responses to systemic administration of a protein kinase C inhibitor in conscious rats

1998 ◽  
Vol 84 (2) ◽  
pp. 641-648 ◽  
Author(s):  
David Gozal ◽  
Gavin R. Graff ◽  
José E. Torres ◽  
Sanjay G. Khicha ◽  
Gautam S. Nayak ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Respiratory Control ◽  
Systemic Administration ◽  
Whole Body ◽  
Expiratory Time ◽  
Conscious Rats ◽  
Ventilatory Responses ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

Gozal, David, Gavin R. Graff, José E. Torres, Sanjay G. Khicha, Gautam S. Nayak, Narong Simakajornboon, and Evelyne Gozal.Cardiorespiratory responses to systemic administration of a protein kinase C inhibitor in conscious rats. J. Appl. Physiol. 84(2): 641–648, 1998.—Although protein kinase C (PKC) is an essential component of multiple neurally mediated events, its role in respiratory control remains undefined. The ventilatory effects of a systemically active PKC inhibitor (Ro-32-0432; 100 mg/kg ip) were assessed by whole body plethysmography during normoxia, hypoxia (10% O2), and hyperoxia (100% O2) in unrestrained Sprague-Dawley rats. A sustained expiratory time increase occurred within 8–10 min of injection in room air [mean 44.8 ± 5.2 (SE) % ], was similar to expiratory time prolongations after Ro-32-0432 administration during 100% O2 (45.5 ± 8.1%; not significant), and was associated with mild minute ventilation (V˙e) decreases. Hypercapnic ventilatory responses (5% CO2) remained unchanged after Ro-32-0432. During 10% O2,V˙e increased from 122.6 ± 15.6 to 195.7 ± 10.1 ml/min in vehicle-treated rats ( P < 0.001). In contrast, marked attenuation of V˙e hypoxic responses occurred after Ro-32-0432 [86.2 ± 6.2 ml/min in room air to 104.1 ± 7.1 ml/min in 10% O2; pre- vs. post-Ro32–0432, P < 0.001 (analysis of variance)]. Overall, PKC activity was reduced and increases with hypoxia were abolished in the particulate subcellular fraction of brain tissue after Ro-32-0432 treatment, indicating that this compound readily crosses the blood-brain barrier. We conclude that systemic PKC inhibition elicits significant centrally mediated expiratory prolongations and ventilatory reductions as well as blunted ventilatory responses to hypoxia but not to hypercapnia. We postulate that PKC plays an important role in signal transduction pathways within brain regions underlying respiratory control.

Neural control of breathing: insights from genetic mouse models

2008 ◽  
Vol 104 (5) ◽  
pp. 1522-1530 ◽  
Author(s):  
C. Gaultier ◽  
J Gallego
Keyword(s):  
Mouse Models ◽  
Neural Control ◽  
Respiratory Control ◽  
Whole Body ◽  
Neuron Network ◽  
Newborn Mice ◽  
Hypoventilation Syndrome ◽  
New Treatments ◽  
Genetically Determined

Recent studies described the in vivo ventilatory phenotype of mutant newborn mice with targeted deletions of genes involved in the organization and development of the respiratory-neuron network. Whole body flow barometric plethysmography is the noninvasive method of choice for studying unrestrained newborn mice. Breathing-pattern abnormalities with apneas occur in mutant newborn mice that lack genes involved in the development and modulation of rhythmogenesis. Studies of deficits in ventilatory responses to hypercapnia and/or hypoxia helped to identify genes involved in chemosensitivity to oxygen and carbon dioxide. Combined studies in mutant newborn mice and in humans have shed light on the pathogenesis of genetically determined respiratory-control abnormalities such as congenital central hypoventilation syndrome, Rett syndrome, and Prader-Willi syndrome. The development of mouse models has opened up the field of research into new treatments for respiratory-control disorders in humans.

scholarly journals Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation

2021 ◽  
Vol 12 ◽  
Author(s):  
Isato Fukushi ◽  
Kotaro Takeda ◽  
Mieczyslaw Pokorski ◽  
Yosuke Kono ◽  
Masashi Yoshizawa ◽  
...  
Keyword(s):  
Acute Hypoxia ◽  
Whole Body ◽  
High Dose ◽  
Ventilatory Responses ◽  
Adult Mice ◽  
Term Potentiation ◽  
Before And After ◽  
Whole Body Plethysmography ◽  
Hypoxic Gas Mixture

Acute hypoxia increases ventilation. After cessation of hypoxia loading, ventilation decreases but remains above the pre-exposure baseline level for a time. However, the mechanism of this post-hypoxic persistent respiratory augmentation (PHRA), which is a short-term potentiation of breathing, has not been elucidated. We aimed to test the hypothesis that astrocytes are involved in PHRA. To this end, we investigated hypoxic ventilatory responses by whole-body plethysmography in unanesthetized adult mice. The animals breathed room air, hypoxic gas mixture (7% O2, 93% N2) for 2min, and again room air for 10min before and after i.p. administration of low (100mg/kg) and high (300mg/kg) doses of arundic acid (AA), an astrocyte inhibitor. AA suppressed PHRA, with the high dose decreasing ventilation below the pre-hypoxic level. Further, we investigated the role of the astrocytic TRPA1 channel, a putative ventilatory hypoxia sensor, in PHRA using astrocyte-specific Trpa1 knockout (asTrpa1−/−) and floxed Trpa1 (Trpa1f/f) mice. In both Trpa1f/f and asTrpa1−/− mice, PHRA was noticeable, indicating that the astrocyte TRPA1 channel was not directly involved in PHRA. Taken together, these results indicate that astrocytes mediate the PHRA by mechanisms other than TRPA1 channels that are engaged in hypoxia sensing.

scholarly journals Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice

2018 ◽  
Vol 115 (51) ◽  
pp. 13021-13026 ◽  
Author(s):  
Luis Rodrigo Hernandez-Miranda ◽  
Daniel M. Ibrahim ◽  
Pierre-Louis Ruffault ◽  
Madeleine Larrosa ◽  
Kira Balueva ◽  
...  
Keyword(s):  
Respiratory Rhythm ◽  
Respiratory Control ◽  
Small Subset ◽  
Cell Culture Model ◽  
Retrotrapezoid Nucleus ◽  
Genome Wide ◽  
Culture Model ◽  
A Cell ◽  
Central Hypoventilation ◽  
Small Subpopulation

The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO2. Here we identify a LBX1 frameshift (LBX1FS) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1. Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1FS (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control.

Neonatal stress affects the aging trajectory of female rats on the endocrine, temperature, and ventilatory responses to hypoxia

2015 ◽  
Vol 308 (7) ◽  
pp. R659-R667 ◽  
Author(s):  
Sébastien Fournier ◽  
Roumiana Gulemetova ◽  
Cécile Baldy ◽  
Vincent Joseph ◽  
Richard Kinkead
Keyword(s):  
Adult Female ◽  
Maternal Separation ◽  
Respiratory Control ◽  
Female Rats ◽  
Whole Body ◽  
Hormone Regulation ◽  
Adult Rats ◽  
Ventilatory Responses ◽  
Neonatal Stress ◽  
The Impact

Human and animal studies on sleep-disordered breathing and respiratory regulation show that the effects of sex hormones are heterogeneous. Because neonatal stress results in sex-specific disruption of the respiratory control in adult rats, we postulate that it might affect respiratory control modulation induced by ovarian steroids in female rats. The hypoxic ventilatory response (HVR) of adult female rats exposed to neonatal maternal separation (NMS) is ∼30% smaller than controls (24), but consequences of NMS on respiratory control in aging female rats are unknown. To address this issue, whole body plethysmography was used to evaluate the impact of NMS on the HVR (12% O2, 20 min) of middle-aged (MA; ∼57 wk old) female rats. Pups subjected to NMS were placed in an incubator 3 h/day for 10 consecutive days (P3 to P12). Controls were undisturbed. To determine whether the effects were related to sexual hormone decline or aging per se, experiments were repeated on bilaterally ovariectomized (OVX) young (∼12 wk old) adult female rats. OVX and MA both reduced the HVR significantly in control rats but had little effect on the HVR of NMS females. OVX (but not aging) reduced the anapyrexic response in both control and NMS animals. These results show that hormonal decline decreases the HVR of control animals, while leaving that of NMS female animals unaffected. This suggests that neonatal stress alters the interaction between sex hormone regulation and the development of body temperature, hormonal, and ventilatory responses to hypoxia.

scholarly journals Volatile Anesthetics Activate a Leak Sodium Conductance in Retrotrapezoid Nucleus Neurons to Maintain Breathing during Anesthesia in Mice

2020 ◽  
Vol 133 (4) ◽  
pp. 824-838 ◽  
Author(s):  
Yaoxin Yang ◽  
Mengchan Ou ◽  
Jin Liu ◽  
Wenling Zhao ◽  
Lamu Zhuoma ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Neuronal Excitability ◽  
Ventilatory Response ◽  
Brain Slices ◽  
Respiratory Control ◽  
Volatile Anesthetics ◽  
Whole Body ◽  
Control Center ◽  
Leak Channel ◽  
Retrotrapezoid Nucleus

Background Volatile anesthetics moderately depress respiratory function at clinically relevant concentrations. Phox2b-expressing chemosensitive neurons in the retrotrapezoid nucleus, a respiratory control center, are activated by isoflurane, but the underlying mechanisms remain unclear. The hypothesis of this study was that the sodium leak channel contributes to the volatile anesthetics-induced modulation of retrotrapezoid nucleus neurons and to respiratory output. Methods The contribution of sodium leak channels to isoflurane-, sevoflurane-, and propofol-evoked activity of Phox2b-expressing retrotrapezoid nucleus neurons and respiratory output were evaluated in wild-type and genetically modified mice lacking sodium leak channels (both sexes). Patch-clamp recordings were performed in acute brain slices. Whole-body plethysmography was used to measure the respiratory activity. Results Isoflurane at 0.42 to 0.50 mM (~1.5 minimum alveolar concentration) increased the sodium leak channel–mediated holding currents and conductance from −75.0 ± 12.9 to −130.1 ± 34.9 pA (mean ± SD, P = 0.002, n = 6) and 1.8 ± 0.5 to 3.6 ± 1.0 nS (P = 0.001, n = 6), respectively. At these concentrations, isoflurane increased activity of Phox2b-expressing retrotrapezoid nucleus neurons from 1.1 ± 0.2 to 2.8 ± 0.2 Hz (P &lt; 0.001, n = 5), which was eliminated by bath application of gadolinium or genetic silencing of sodium leak channel. Genetic silencing of sodium leak channel in the retrotrapezoid nucleus resulted in a diminished ventilatory response to carbon dioxide in mice under control conditions and during isoflurane anesthesia. Sevoflurane produced an effect comparable to that of isoflurane, whereas propofol did not activate sodium leak channel–mediated holding conductance. Conclusions Isoflurane and sevoflurane increase neuronal excitability of chemosensitive retrotrapezoid nucleus neurons partly by enhancing sodium leak channel conductance. Sodium leak channel expression in the retrotrapezoid nucleus is required for the ventilatory response to carbon dioxide during anesthesia by isoflurane and sevoflurane, thus identifying sodium leak channel as a requisite determinant of respiratory output during anesthesia of volatile anesthetics. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Distinct Changes in Gut Microbiota Are Associated with Estradiol-Mediated Protection from Diet-Induced Obesity in Female Mice

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 499
Author(s):  
Kalpana D. Acharya ◽  
Hye L. Noh ◽  
Madeline E. Graham ◽  
Sujin Suk ◽  
Randall H. Friedline ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Glucose Turnover ◽  
Female Mice ◽  
Adult Mice ◽  
Diet Induced Obesity ◽  
Metabolic Dysregulation ◽  
Regulation Of Metabolism ◽  
Junction Protein

A decrease in ovarian estrogens in postmenopausal women increases the risk of weight gain, cardiovascular disease, type 2 diabetes, and chronic inflammation. While it is known that gut microbiota regulates energy homeostasis, it is unclear if gut microbiota is associated with estradiol regulation of metabolism. In this study, we tested if estradiol-mediated protection from high-fat diet (HFD)-induced obesity and metabolic changes are associated with longitudinal alterations in gut microbiota in female mice. Ovariectomized adult mice with vehicle or estradiol (E2) implants were fed chow for two weeks and HFD for four weeks. As reported previously, E2 increased energy expenditure, physical activity, insulin sensitivity, and whole-body glucose turnover. Interestingly, E2 decreased the tight junction protein occludin, suggesting E2 affects gut epithelial integrity. Moreover, E2 increased Akkermansia and decreased Erysipleotrichaceae and Streptococcaceae. Furthermore, Coprobacillus and Lactococcus were positively correlated, while Akkermansia was negatively correlated, with body weight and fat mass. These results suggest that changes in gut epithelial barrier and specific gut microbiota contribute to E2-mediated protection against diet-induced obesity and metabolic dysregulation. These findings provide support for the gut microbiota as a therapeutic target for treating estrogen-dependent metabolic disorders in women.

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