295 results on '"Hilaire G"'
Search Results
102. Correct application of beam splitters with laser beams of fluctuating polarization.
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Neufeld, C. R., Saint-Hilaire, G., Noël, P., Robert, A., Szili, Z., and Gagné, M.
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- 1977
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103. Effects of [formula omitted] (NMDA) antagonist MK-801 on breathing pattern in rats
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Monteau, R., Gauthier, P., Rega, P., and Hilaire, G.
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- 1990
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104. Serotonergic influences on central respiratory activity: an in vitro study in the newborn rat
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Morin, D., Hennequin, S., Monteau, R., and Hilaire, G.
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- 1990
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105. Endogenous serotonin modulates the fetal respiratory rhythm: an in vitro study in the rat
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Pasquale, E. Di, Monteau, R., and Hilaire, G.
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- 1994
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106. Involvement of the rostral ventro-lateral medulla in respiratory rhythm genesis during the peri-natal period: an in vitro study in newborn and fetal rats
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Pasquale, E. Di, Monteau, R., and Hilaire, G.
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- 1994
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107. Further evidence that various 5-HT receptor subtypes modulate central respiratory activity: in vitro studies with SR 46349B
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Monteau, R., Pasquale, E. Di, and Hilaire, G.
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- 1994
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108. Possible modulation of the medullary respiratory rhythm generator by the noradrenergic A 5 area: an in vitro study in the newborn rat
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Hilaire, G., Monteau, R., and Errchidi, S.
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- 1989
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109. Study of electron-ion recombination mechanism in the vapor of ionized Cs
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Saint-Hilaire, G
- Published
- 1972
110. Prevalence of HTLV-I Infection and Its Association with Tuberculosis among Patients at an Urban Clinic in Haiti.
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Walsh KF, Lee MH, Brejt JA, Reust MJ, Juste MJ, Hilaire G, Pape JW, Koenig S, and Dupnik K
- Abstract
This retrospective case-control study examined the prevalence of HTLV-I and its association with tuberculosis among urban clinic patients in Haiti. Prevalence of HTLV-I among tuberculosis cases was 2.1% and among controls was 2.4%. Prevalence of HLTV-I was higher in females than males (odds ratio [OR] 2.45, P = 0.020). HTLV-I prevalence in those ≥ 50 years was 8.4% compared with 1.3% in those < 50 (OR 6.74, P < 0.001). We found no association between HTLV-I and tuberculosis in this population.
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- 2022
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111. Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome.
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Matarazzo V, Caccialupi L, Schaller F, Shvarev Y, Kourdougli N, Bertoni A, Menuet C, Voituron N, Deneris E, Gaspar P, Bezin L, Durbec P, Hilaire G, and Muscatelli F
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- Animals, Disease Models, Animal, Gene Deletion, Mice, Nerve Tissue Proteins deficiency, Nuclear Proteins deficiency, Serotonin metabolism, Action Potentials, Apnea physiopathology, Nerve Tissue Proteins metabolism, Nuclear Proteins metabolism, Prader-Willi Syndrome physiopathology, Serotonergic Neurons pathology, Serotonin Plasma Membrane Transport Proteins metabolism
- Abstract
Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder that presents with hypotonia and respiratory distress in neonates. The Necdin -deficient mouse is the only model that reproduces the respiratory phenotype of PWS (central apnea and blunted response to respiratory challenges). Here, we report that Necdin deletion disturbs the migration of serotonin (5-HT) neuronal precursors, leading to altered global serotonergic neuroarchitecture and increased spontaneous firing of 5-HT neurons. We show an increased expression and activity of 5-HT Transporter (SERT/Slc6a4) in 5-HT neurons leading to an increase of 5-HT uptake. In Necdin -KO pups, the genetic deletion of Slc6a4 or treatment with Fluoxetine, a 5-HT reuptake inhibitor, restored normal breathing. Unexpectedly, Fluoxetine administration was associated with respiratory side effects in wild-type animals. Overall, our results demonstrate that an increase of SERT activity is sufficient to cause the apneas in Necdin- KO pups, and that fluoxetine may offer therapeutic benefits to PWS patients with respiratory complications.
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- 2017
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112. Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice.
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Borghgraef P, Menuet C, Theunis C, Louis JV, Devijver H, Maurin H, Smet-Nocca C, Lippens G, Hilaire G, Gijsen H, Moechars D, and Van Leuven F
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- Analysis of Variance, Animals, Blotting, Western, Female, Immunohistochemistry, Immunoprecipitation, Mice, Mice, Transgenic, Plethysmography, Pyrans chemical synthesis, Respiratory Mechanics drug effects, Thiazoles chemical synthesis, tau Proteins genetics, Brain metabolism, Nerve Tissue Proteins metabolism, Pyrans pharmacology, Respiratory Mechanics physiology, Tauopathies drug therapy, Tauopathies physiopathology, Thiazoles pharmacology, beta-N-Acetylhexosaminidases antagonists & inhibitors
- Abstract
The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.
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- 2013
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113. [Electrophysiological, molecular and genetic identifications of the pre-Bötzinger complex].
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Viemari JC, Menuet C, and Hilaire G
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- Adult, Animals, Humans, Infant, Newborn, Mammals, Mice, Motor Neurons cytology, Motor Neurons physiology, Periodicity, Electrophysiological Phenomena, Respiration genetics, Respiratory Center embryology, Respiratory Center growth & development, Respiratory Center physiology
- Abstract
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.)
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- 2013
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114. The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival.
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Burgold T, Voituron N, Caganova M, Tripathi PP, Menuet C, Tusi BK, Spreafico F, Bévengut M, Gestreau C, Buontempo S, Simeone A, Kruidenier L, Natoli G, Casola S, Hilaire G, and Testa G
- Subjects
- Animals, Cell Line, Embryo, Mammalian metabolism, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Histones metabolism, Jumonji Domain-Containing Histone Demethylases deficiency, Jumonji Domain-Containing Histone Demethylases genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Perinatal Mortality, Respiratory Burst physiology, Respiratory Insufficiency pathology, Somatostatin metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Neurons metabolism
- Abstract
JMJD3 (KDM6B) antagonizes Polycomb silencing by demethylating lysine 27 on histone H3. The interplay of methyltransferases and demethylases at this residue is thought to underlie critical cell fate transitions, and the dynamics of H3K27me3 during neurogenesis posited for JMJD3 a critical role in the acquisition of neural fate. Despite evidence of its involvement in early neural commitment, however, its role in the emergence and maturation of the mammalian CNS remains unknown. Here, we inactivated Jmjd3 in the mouse and found that its loss causes perinatal lethality with the complete and selective disruption of the pre-Bötzinger complex (PBC), the pacemaker of the respiratory rhythm generator. Through genetic and electrophysiological approaches, we show that the enzymatic activity of JMJD3 is selectively required for the maintenance of the PBC and controls critical regulators of PBC activity, uncovering an unanticipated role of this enzyme in the late structuring and function of neuronal networks., (Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2012
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115. The vesicular glutamate transporter VGLUT3 contributes to protection against neonatal hypoxic stress.
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Miot S, Voituron N, Sterlin A, Vigneault E, Morel L, Matrot B, Ramanantsoa N, Amilhon B, Poirel O, Lepicard E, Mestikawy SE, Hilaire G, and Gallego J
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- Animals, Animals, Newborn, Brain Stem anatomy & histology, Brain Stem physiology, Mice, Mice, Transgenic, Respiration, Serotonin physiology, Stress, Physiological, Amino Acid Transport Systems, Acidic physiology, Hypoxia physiopathology
- Abstract
Neonates respond to hypoxia initially by increasing ventilation, and then by markedly decreasing both ventilation (hypoxic ventilatory decline) and oxygen consumption (hypoxic hypometabolism). This latter process, which vanishes with age, reflects a tight coupling between ventilatory and thermogenic responses to hypoxia. The neurological substrate of hypoxic hypometabolism is unclear, but it is known to be centrally mediated, with a strong involvement of the 5-hydroxytryptamine (5-HT, serotonin) system. To clarify this issue, we investigated the possible role of VGLUT3, the third subtype of vesicular glutamate transporter. VGLUT3 contributes to glutamate signalling by 5-HT neurons, facilitates 5-HT transmission and is expressed in strategic regions for respiratory and thermogenic control. We therefore assumed that VGLUT3 might significantly contribute to the response to hypoxia. To test this possibility, we analysed this response in newborn mice lacking VGLUT3 using anatomical, biochemical, electrophysiological and integrative physiology approaches. We found that the lack of VGLUT3 did not affect the histological organization of brainstem respiratory networks or respiratory activity under basal conditions. However, it impaired respiratory responses to 5-HT and anoxia, showing a marked alteration of central respiratory control. These impairments were associated with altered 5-HT turnover at the brainstem level. Furthermore, under cold conditions, the lack of VGLUT3 disrupted the metabolic rate, body temperature, baseline breathing and the ventilatory response to hypoxia. We conclude that VGLUT3 expression is dispensable under basal conditions but is required for optimal response to hypoxic stress in neonates.
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- 2012
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116. Isoflurane anesthesia precipitates tauopathy and upper airways dysfunction in pre-symptomatic Tau.P301L mice: possible implication for neurodegenerative diseases.
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Menuet C, Borghgraef P, Voituron N, Gestreau C, Gielis L, Devijver H, Dutschmann M, Van Leuven F, and Hilaire G
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- Alzheimer Disease chemically induced, Alzheimer Disease pathology, Alzheimer Disease prevention & control, Animals, Brain Stem drug effects, Brain Stem pathology, Disease Models, Animal, Mice, Mice, Neurologic Mutants, Mice, Transgenic, Nerve Degeneration pathology, Nerve Degeneration prevention & control, Respiratory Insufficiency pathology, Respiratory Insufficiency prevention & control, Tauopathies pathology, Tauopathies prevention & control, Anesthetics, Inhalation toxicity, Isoflurane toxicity, Nerve Degeneration chemically induced, Respiratory Insufficiency chemically induced, Tauopathies chemically induced
- Abstract
The postoperative cognitive decline resulting from volatile anesthesia is gaining acceptance as a major health problem. The common anesthetic isoflurane is suspected to precipitate neurodegeneration in Alzheimer's disease by unknown mechanisms. We previously validated that 8month old Tau.P301L mice suffer upper airways defects related to tauopathy within the Kolliker-Fuse nucleus that controls upper airways function. We now report that isoflurane anesthesia in young, pre-symptomatic Tau.P301L mice triggered precocious upper airways defects and tauopathy in several brainstem nuclei, including the nucleus ambiguus that contains upper airways motor neurons and the Kolliker-Fuse. The prescription drug memantine, identified as an NMDA receptor antagonist, prevented the post-anesthesia upper airways dysfunction and alleviated tauopathy in the nucleus ambiguus and Kolliker-Fuse. We further identified protocols of anesthesia in young Tau.P301L mice that mitigated adverse effects of isoflurane anesthesia. Thus, our experimental findings in a validated mouse model for tauopathy demonstrate the link between isoflurane anesthesia, earlier onset of tauopathy and earlier onset of functional deficits, highlight the implication of NMDA-receptors in the mechanisms mediating the adverse effects of isoflurane, and potentially identify safer protocols for anesthesia in patients with tauopathy., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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117. Dexmedetomidine and clonidine induce long-lasting activation of the respiratory rhythm generator of neonatal mice: possible implication for critical care.
- Author
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Voituron N, Hilaire G, and Quintin L
- Subjects
- Animals, Animals, Newborn, Mice, Respiratory Center physiology, Adrenergic alpha-2 Receptor Agonists pharmacology, Clonidine pharmacology, Dexmedetomidine pharmacology, Respiration drug effects, Respiratory Center drug effects
- Abstract
Dexmedetomidine and clonidine are alpha-2 adrenoceptor agonists increasingly used in the critical care unit as sedative agents for their benzodiazepine-sparing effects and their limited depressing effect on breathing. However adverse effects on breathing have been also reported with alpha-2 adrenoceptor agonists and their central effects on the respiratory rhythm generator are poorly known. We therefore examined the effects of dexmedetomidine, clonidine, the alpha-2 adrenoceptor antagonist yohimbine and the benzodiazepine midazolam on the activity of the isolated respiratory rhythm generator of neonatal mice using medullary preparations where the respiratory rhythm generator continued to function in vitro. For the first time, we showed that 5min bath applications of dexmedetomidine or clonidine activated the respiratory rhythm generator for periods over than 30min. Second, we showed that the long-lasting effect of dexmedetomidine implicated receptors other than alpha-2 adrenoceptors as it persisted after their blockade with yohimbine. Third, we reported that 5min bath applications of the benzodiazepine midazolam significantly depressed the respiratory rhythm generator, and that this depression was prevented by pre-treatment with either dexmedetomidine or clonidine. Although further experiments are still required to identify the mechanisms through which dexmedetomidine and clonidine activate the respiratory rhythm generator, our current in vitro results in neonatal mice support the use of dexmedetomidine and clonidine in the critical care unit., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2012
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118. Impaired ventilatory and thermoregulatory responses to hypoxic stress in newborn phox2b heterozygous knock-out mice.
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Ramanantsoa N, Matrot B, Vardon G, Lajard AM, Voituron N, Dauger S, Denjean A, Hilaire G, and Gallego J
- Abstract
The Phox2b genesis necessary for the development of the autonomic nervous system, and especially, of respiratory neuronal circuits. In the present study, we examined the role of Phox2b in ventilatory and thermoregulatory responses to hypoxic stress, which are closely related in the postnatal period. Hypoxic stress was generated by strong thermal stimulus, combined or not with reduced inspired O(2). To this end, we exposed 6-day-old Phox2b(+/-) pups and their wild-type littermates (Phox2b(+/+)) to hypoxia (10% O(2)) or hypercapnia (8% CO(2)) under thermoneutral (33°C) or cold (26°C) conditions. We found that Phox2b(+/-) pups showed less normoxic ventilation (V(E)) in the cold than Phox2b(+/+) pups. Phox2b(+/-) pups also showed lower oxygen consumption (VO(2)) in the cold, reflecting reduced thermogenesis and a lower body temperature. Furthermore, while the cold depressed ventilatory responses to hypoxia and hypercapnia in both genotype groups, this effect was less pronounced in Phox2b(+/-) pups. Finally, because serotonin (5-HT) neurons are pivotal to respiratory and thermoregulatory circuits and depend on Phox2b for their differentiation, we studied 5-HT metabolism using high pressure liquid chromatography, and found that it was altered in Phox2b(+/-) pups. We conclude that Phox2b haploinsufficiency alters the ability of newborns to cope with metabolic challenges, possibly due to 5-HT signaling impairments.
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- 2011
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119. Raphé tauopathy alters serotonin metabolism and breathing activity in terminal Tau.P301L mice: possible implications for tauopathies and Alzheimer's disease.
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Menuet C, Borghgraef P, Matarazzo V, Gielis L, Lajard AM, Voituron N, Gestreau C, Dutschmann M, Van Leuven F, and Hilaire G
- Subjects
- Alzheimer Disease physiopathology, Animals, Humans, Mice, Mice, Transgenic, Plethysmography methods, Raphe Nuclei physiopathology, Respiratory Mechanics physiology, Tauopathies genetics, Tauopathies metabolism, Tauopathies physiopathology, tau Proteins biosynthesis, tau Proteins genetics, Alzheimer Disease genetics, Alzheimer Disease metabolism, Raphe Nuclei metabolism, Respiratory Mechanics genetics, Serotonin metabolism, tau Proteins metabolism
- Abstract
Tauopathies, including Alzheimer's disease are the most frequent neurodegenerative disorders in elderly people. Patients develop cognitive and behaviour defects induced by the tauopathy in the forebrain, but most also display early brainstem tauopathy, with oro-pharyngeal and serotoninergic (5-HT) defects. We studied these aspects in Tau.P301L mice, that express human mutant tau protein and develop tauopathy first in hindbrain, with cognitive, motor and upper airway defects from 7 to 8 months onwards, until premature death before age 12 months. Using plethysmography, immunohistochemistry and biochemistry, we examined the respiratory and 5-HT systems of aging Tau.P301L and control mice. At 8 months, Tau.P301L mice developed upper airway dysfunction but retained normal respiratory rhythm and normal respiratory regulations. In the following weeks, Tau.P301L mice entered terminal stages with reduced body weight, progressive limb clasping and lethargy. Compared to age 8 months, terminal Tau.P301L mice showed aggravated upper airway dysfunction, abnormal respiratory rhythm and abnormal respiratory regulations. In addition, they showed severe tauopathy in Kolliker-Fuse, raphé obscurus and raphé magnus nuclei but not in medullary respiratory-related areas. Although the raphé tauopathy concerned mainly non-5-HT neurons, the 5-HT metabolism of terminal Tau.P301L mice was altered. We propose that the progressive raphé tauopathy affects the 5-HT metabolism, which affects the 5-HT modulation of the respiratory network and therefore the breathing pattern. Then, 5-HT deficits contribute to the moribund phenotype of Tau.P301L mice, and possibly in patients suffering from tauopathies, including Alzheimer's disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
- Full Text
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120. The benzodiazepine Midazolam mitigates the breathing defects of Mecp2-deficient mice.
- Author
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Voituron N and Hilaire G
- Subjects
- Animals, Benzodiazepines pharmacology, Disease Models, Animal, Methyl-CpG-Binding Protein 2 deficiency, Methyl-CpG-Binding Protein 2 genetics, Mice, Mice, Knockout, Rett Syndrome genetics, Rett Syndrome physiopathology, GABA Agonists pharmacology, Midazolam pharmacology, Rett Syndrome metabolism, gamma-Aminobutyric Acid metabolism
- Abstract
Rett syndrome is a severe neurodevelopmental disease caused by mutations of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) that induce complex, disabling symptoms, including breathing symptoms. Males of Mecp2-deficient mice (Mecp2(-/y)) normally breathe at birth but develop first altered breathing regulations, thereafter erratic breathing with severe apnoeas, aggravating until respiratory distress and premature death. Mecp2(-/y) mice also develop early GABA deficits. To examine whether GABA deficits contributed to breathing defects of Mecp2(-/y) mice, mice were subjected to acute administration of Midazolam, a benzodiazepine of clinical use known to enhance GABA effects. For the first time, we showed that Midazolam abolished, although transiently, the breathing defects of Mecp2(-/y) mice, confirming a crucial role of GABA deficits in their breathing defects., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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121. Differences in serotoninergic metabolism possibly contribute to differences in breathing phenotype of FVB/N and C57BL/6J mice.
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Menuet C, Kourdougli N, Hilaire G, and Voituron N
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- Age Factors, Aging, Animals, Animals, Newborn, Carbon Dioxide metabolism, Disease Models, Animal, Gestational Age, Hypercapnia metabolism, Hypercapnia physiopathology, Hypoxia metabolism, Hypoxia physiopathology, Medulla Oblongata embryology, Mice, Mice, Inbred C57BL, Oxygen metabolism, Phenotype, Phrenic Nerve physiopathology, Plethysmography, Spirometry, Tidal Volume, Medulla Oblongata metabolism, Periodicity, Respiratory Mechanics, Serotonin metabolism
- Abstract
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.
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- 2011
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122. Age-related impairment of ultrasonic vocalization in Tau.P301L mice: possible implication for progressive language disorders.
- Author
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Menuet C, Cazals Y, Gestreau C, Borghgraef P, Gielis L, Dutschmann M, Van Leuven F, and Hilaire G
- Subjects
- Amino Acid Substitution genetics, Animals, Brain Stem pathology, Brain Stem physiopathology, Exhalation, Humans, Language Disorders physiopathology, Mice, Mice, Transgenic, Models, Biological, Mutation genetics, Respiratory System physiopathology, Tauopathies pathology, Tauopathies physiopathology, tau Proteins metabolism, Aging pathology, Language Disorders pathology, Ultrasonics, Vocalization, Animal, tau Proteins genetics
- Abstract
Background: Tauopathies, including Alzheimer's Disease, are the most frequent neurodegenerative diseases in elderly people and cause various cognitive, behavioural and motor defects, but also progressive language disorders. For communication and social interactions, mice produce ultrasonic vocalization (USV) via expiratory airflow through the larynx. We examined USV of Tau.P301L mice, a mouse model for tauopathy expressing human mutant tau protein and developing cognitive, motor and upper airway defects., Methodology/principal Findings: At age 4-5 months, Tau.P301L mice had normal USV, normal expiratory airflow and no brainstem tauopathy. At age 8-10 months, Tau.P301L mice presented impaired USV, reduced expiratory airflow and severe tauopathy in the periaqueductal gray, Kolliker-Fuse and retroambiguus nuclei. Tauopathy in these nuclei that control upper airway function and vocalization correlates well with the USV impairment of old Tau.P301L mice., Conclusions: In a mouse model for tauopathy, we report for the first time an age-related impairment of USV that correlates with tauopathy in midbrain and brainstem areas controlling vocalization. The vocalization disorder of old Tau.P301L mice could be, at least in part, reminiscent of language disorders of elderly suffering tauopathy.
- Published
- 2011
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123. The role of serotonin in respiratory function and dysfunction.
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Hilaire G, Voituron N, Menuet C, Ichiyama RM, Subramanian HH, and Dutschmann M
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- Animals, Brain cytology, Brain metabolism, Developmental Disabilities complications, Developmental Disabilities metabolism, Humans, Nervous System Diseases complications, Nervous System Diseases metabolism, Neurons metabolism, Receptors, Serotonin metabolism, Respiration Disorders pathology, Respiration Disorders physiopathology, Serotonin chemistry, Respiration, Respiration Disorders metabolism, Serotonin metabolism
- Abstract
Serotonin (5-HT) is a neuromodulator-transmitter influencing global brain function. Past and present findings illustrate a prominent role for 5-HT in the modulation of ponto-medullary autonomic circuits. 5-HT is also involved in the control of neurotrophic processes during pre- and postnatal development of neural circuits. The functional implications of 5-HT are particularly illustrated in the alterations to the serotonergic system, as seen in a wide range of neurological disorders. This article reviews the role of 5-HT in the development and control of respiratory networks in the ponto-medullary brainstem. The review further examines the role of 5-HT in breathing disorders occurring at different stages of life, in particular, the neonatal neurodevelopmental diseases such as Rett, sudden infant death and Prader-Willi syndromes, adult diseases such as sleep apnoea and mental illness linked to neurodegeneration., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)
- Published
- 2010
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124. Fluoxetine treatment abolishes the in vitro respiratory response to acidosis in neonatal mice.
- Author
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Voituron N, Shvarev Y, Menuet C, Bevengut M, Fasano C, Vigneault E, El Mestikawy S, and Hilaire G
- Subjects
- Animals, Animals, Newborn, Base Sequence, DNA Primers, In Situ Hybridization, Mice, Mice, Inbred BALB C, RNA, Messenger genetics, Serotonin pharmacology, Serotonin Plasma Membrane Transport Proteins genetics, Acidosis physiopathology, Fluoxetine pharmacology, Respiration drug effects, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
Background: To secure pH homeostasis, the central respiratory network must permanently adapt its rhythmic motor drive to environment and behaviour. In neonates, it is commonly admitted that the retrotrapezoid/parafacial respiratory group of neurons of the ventral medulla plays the primary role in the respiratory response to acidosis, although the serotonergic system may also contribute to this response., Methodology/principal Findings: Using en bloc medullary preparations from neonatal mice, we have shown for the first time that the respiratory response to acidosis is abolished after pre-treatment with the serotonin-transporter blocker fluoxetine (25-50 µM, 20 min), a commonly used antidepressant. Using mRNA in situ hybridization and immunohistology, we have also shown the expression of the serotonin transporter mRNA and serotonin-containing neurons in the vicinity of the RTN/pFRG of neonatal mice., Conclusions: These results reveal that the serotonergic system plays a pivotal role in pH homeostasis. Although obtained in vitro in neonatal mice, they suggest that drugs targeting the serotonergic system should be used with caution in infants, pregnant women and breastfeeding mothers.
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- 2010
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125. Physiological definition of upper airway obstructions in mouse model for Rett syndrome.
- Author
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Voituron N, Menuet C, Dutschmann M, and Hilaire G
- Subjects
- Age Factors, Airway Obstruction genetics, Airway Obstruction pathology, Animals, Disease Models, Animal, Electromyography methods, Male, Methyl-CpG-Binding Protein 2 deficiency, Mice, Mice, Knockout, Plethysmography methods, Pulmonary Ventilation genetics, Respiratory Mechanics genetics, Respiratory Muscles physiopathology, Rett Syndrome genetics, Rett Syndrome pathology, Airway Obstruction etiology, Pulmonary Ventilation physiology, Respiratory Mechanics physiology, Rett Syndrome complications
- Abstract
Rett syndrome is a neuro-developmental disease accompanied by breathing symptoms including breath-hold events, and is caused by mutation of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Males of Mecp2-deficient mice (Mecp2(-/y)) also develop breathing symptoms, with erratic rhythm and life-threatening apnoeas from postnatal day 30 (P30), leading to respiratory distress and premature death at around P60. We investigated the respiratory function of conscious Mecp2(-/y) mice at P40-P60 using conventional whole-body plethysmography, double-chamber plethysmography and chest EMG recordings. Double-chamber plethysmography revealed a persistent increase in respiratory work-load with enlarged chest movements, but no subsequent increase of tidal volume thus revealing a mismatch between airflow and muscle work-load. Apnoeas occurred with cessation of both chest movements and ventilation, but some (40%) developed with persisting rhythmic chest EMG discharges or chest movements without respiratory airflow, suggesting respiratory efforts against obstructed airways. Airway obstruction was maintained even when the respiratory drive increased significantly, triggering large chest EMG discharges and movements. Whole-body plethysmography of Mecp2(-/y) mice revealed significant increases of spirograms, reflecting forced chest movements against partially obstructed airways. The persisting chest EMG discharges and rhythmic chest movements without respiratory airflow suggest that Mecp2 inactivation alters neural circuits controlling the upper airway dilator muscles. The observed breath-hold events in Mecp2(-/y) mice might imply disturbance of neural circuits attached to voluntary control of breathing., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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126. Upper airway dysfunction of Tau-P301L mice correlates with tauopathy in midbrain and ponto-medullary brainstem nuclei.
- Author
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Dutschmann M, Menuet C, Stettner GM, Gestreau C, Borghgraef P, Devijver H, Gielis L, Hilaire G, and Van Leuven F
- Subjects
- Aging genetics, Aging metabolism, Animals, Brain Stem pathology, Disease Models, Animal, Mesencephalon pathology, Mice, Mice, Transgenic, Mutation, Phosphorylation, Plethysmography, Pulmonary Ventilation, Respiration Disorders physiopathology, tau Proteins metabolism, Brain Stem metabolism, Mesencephalon metabolism, Respiration Disorders genetics, Respiration Disorders pathology, Tauopathies complications, Tauopathies pathology, tau Proteins genetics
- Abstract
Tauopathy comprises hyperphosphorylation of the microtubule-associated protein tau, causing intracellular aggregation and accumulation as neurofibrillary tangles and neuropil treads. Some primary tauopathies are linked to mutations in the MAPT gene coding for protein tau, but most are sporadic with unknown causes. Also, in Alzheimer's disease, the most frequent secondary tauopathy, neither the cause nor the pathological mechanisms and repercussions are understood. Transgenic mice expressing mutant Tau-P301L suffer cognitive and motor defects and die prematurely from unknown causes. Here, in situ electrophysiology in symptomatic Tau-P301L mice (7-8 months of age) revealed reduced postinspiratory discharges of laryngeal motor outputs that control laryngeal constrictor muscles. Under high chemical drive (hypercapnia), postinspiratory discharge was nearly abolished, whereas laryngeal inspiratory discharge was increased disproportionally. The latter may suggest a shift of postinspiratory laryngeal constrictor activity into inspiration. In vivo double-chamber plethysmography of Tau-P301L mice showed significantly reduced respiratory airflow but significantly increased chest movements during baseline breathing, but particularly in hypercapnia, confirming a significant increase in inspiratory resistive load. Histological analysis demonstrated hyperphosphorylated tau in brainstem nuclei, directly or indirectly involved in upper airway motor control (i.e., the Kölliker-Fuse, periaqueductal gray, and intermediate reticular nuclei). In contrast, young Tau-P301L mice did not show breathing disorders or brainstem tauopathy. Consequently, in aging Tau-P301L mice, progressive upper airway dysfunction is linked to progressive tauopathy in identified neural circuits. Because patients with tauopathy suffer from upper airway dysfunction, the Tau-P301L mice can serve as an experimental model to study disease-specific synaptic dysfunction in well defined functional neural circuits.
- Published
- 2010
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127. Medullary serotonin defects and respiratory dysfunction in sudden infant death syndrome.
- Author
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Paterson DS, Hilaire G, and Weese-Mayer DE
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Infant, Infant, Newborn, Medulla Oblongata pathology, Neurons metabolism, Neurons pathology, Polymorphism, Genetic, Pregnancy, Prenatal Exposure Delayed Effects etiology, Serotonin genetics, Respiration Disorders complications, Serotonin metabolism, Sudden Infant Death etiology, Sudden Infant Death pathology
- Abstract
Sudden infant death syndrome (SIDS) is defined as the sudden and unexpected death of an infant less than 12 months of age that occurs during sleep and remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history. It is the leading cause of postneonatal mortality in the developed world. The cause of SIDS is unknown, but is postulated to involve impairment of brainstem-mediated homeostatic control. Extensive evidence from animal studies indicates that serotonin (5-HT) neurons in the medulla oblongata play a role in the regulation of multiple aspects of respiratory and autonomic function. A subset of SIDS infants have several abnormalities in medullary markers of 5-HT function and genetic polymorphisms impacting the 5-HT system, informing the hypothesis that SIDS results from a defect in 5-HT brainstem-mediated control of respiratory (and autonomic) regulation. Here we review the evidence from postmortem human studies and animal studies to support this hypothesis and discuss how the pathogenesis of SIDS is likely to originate in utero during fetal development.
- Published
- 2009
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128. Foreword: Respiratory rhythmogenesis.
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Hilaire G and Dutschmann M
- Subjects
- Animals, Humans, Neural Pathways physiology, Neurons physiology, Respiration Disorders pathology, Respiration Disorders physiopathology, Respiratory Center cytology, Respiratory Center pathology, Periodicity, Respiration, Respiratory Center physiology
- Abstract
This special issue of Respiratory Physiology & Neurobiology summarizes the current standing of research concerned with synaptic mechanisms, membrane properties, plasticity, pre- and postnatal development and evolutionary origin of neurones involved in respiratory rhythm generation and central chemosensitivity. Moreover, a variety of articles link pathophysiological alterations of synaptic function in rhythmogenesis and chemosensitivity with breathing disorders in neurodevelopmental diseases.
- Published
- 2009
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129. Early breathing defects after moderate hypoxia or hypercapnia in a mouse model of Rett syndrome.
- Author
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Voituron N, Zanella S, Menuet C, Dutschmann M, and Hilaire G
- Subjects
- Age Factors, Animals, Animals, Newborn, Disease Models, Animal, Male, Methyl-CpG-Binding Protein 2 deficiency, Mice, Mice, Inbred C57BL, Mice, Knockout, Plethysmography methods, Respiration Disorders genetics, Rett Syndrome genetics, Hypercalcemia complications, Hypoxia complications, Respiration Disorders etiology, Rett Syndrome physiopathology
- Abstract
Rett syndrome (RTT) is a rare neurodevelopmental disease caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and accompanied by complex symptoms, including erratic breathing and life-threatening apnoeas. In Mecp2-deficient male mice (Mecp2(-/y)), breathing is normal at birth but becomes altered after postnatal day 30 (P30), with erratic rhythm and apnoeas aggravating until death at around P60. Using plethysmography, we analyzed breathing of unrestrained wild type mice and Mecp2(-/y) at P15, P25 and P30 under air and under short-lasting exposure to moderate hypoxia or hypercapnia. In Mecp2(-/y) with normal resting ventilation, we report exacerbated respiratory responses to hypoxia at P30 and transient apnoeas with erratic rhythm after hypoxia and hypercapnia at P30, P25 and occasionally P15. Then environmental factors may induce breathing defects well before than expected in Mecp2(-/y) and possibly in RTT patients. We therefore suggest avoiding exposure of young RTT patients to environmental situations where they may encounter moderate hypoxia or hypercapnia.
- Published
- 2009
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130. Breathing disorders in Rett syndrome: progressive neurochemical dysfunction in the respiratory network after birth.
- Author
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Katz DM, Dutschmann M, Ramirez JM, and Hilaire G
- Subjects
- Animals, Animals, Newborn, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, Disease Models, Animal, Disease Progression, Humans, Methyl-CpG-Binding Protein 2 deficiency, Methyl-CpG-Binding Protein 2 genetics, Methyl-CpG-Binding Protein 2 metabolism, Mice, Mice, Knockout, Neurochemistry, Respiration Disorders genetics, Respiration Disorders pathology, Respiratory System metabolism, Respiration Disorders etiology, Respiratory System physiopathology, Rett Syndrome complications
- Abstract
Disorders of respiratory control are a prominent feature of Rett syndrome (RTT), a severely debilitating condition caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). RTT patients present with a complex respiratory phenotype that can include periods of hyperventilation, apnea, breath holds terminated by Valsalva maneuvers, forced and deep breathing and apneustic breathing, as well as abnormalities of heart rate control and cardiorespiratory integration. Recent studies of mouse models of RTT have begun to shed light on neurologic deficits that likely contribute to respiratory dysfunction including, in particular, defects in neurochemical signaling resulting from abnormal patterns of neurotransmitter and neuromodulator expression. The authors hypothesize that breathing dysregulation in RTT results from disturbances in mechanisms that modulate the respiratory rhythm, acting either alone or in combination with more subtle disturbances in rhythm and pattern generation. This article reviews the evidence underlying this hypothesis as well as recent efforts to translate our emerging understanding of neurochemical defects in mouse models of RTT into preclinical trials of potential treatments for respiratory dysfunction in this disease.
- Published
- 2009
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131. Prenatal activation of 5-HT2A receptor induces expression of 5-HT1B receptor in phrenic motoneurons and alters the organization of their premotor network in newborn mice.
- Author
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Bras H, Gaytán SP, Portalier P, Zanella S, Pásaro R, Coulon P, and Hilaire G
- Subjects
- Amphetamines pharmacology, Animals, Animals, Newborn anatomy & histology, Animals, Newborn metabolism, Embryo, Mammalian anatomy & histology, Embryo, Mammalian drug effects, Female, Ketanserin pharmacology, Mice, Mice, Inbred C3H, Mice, Transgenic, Motor Neurons cytology, Nerve Net drug effects, Pregnancy, Receptor, Serotonin, 5-HT1B genetics, Receptor, Serotonin, 5-HT2A genetics, Serotonin 5-HT2 Receptor Agonists, Serotonin 5-HT2 Receptor Antagonists, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology, Embryo, Mammalian physiology, Motor Neurons physiology, Nerve Net physiology, Phrenic Nerve cytology, Receptor, Serotonin, 5-HT1B metabolism, Receptor, Serotonin, 5-HT2A metabolism
- Abstract
In newborn mice of the control [C3H/HeJ (C3H)] and monoamine oxidase A-deficient (Tg8) strains, in which levels of endogenous serotonin (5-HT) were drastically increased, we investigated how 5-HT system dysregulation affected the maturation of phrenic motoneurons (PhMns), which innervate the diaphragm. First, using immunocytochemistry and confocal microscopy, we observed a 5-HT(2A) receptor (5-HT(2A)-R) expression in PhMns of both C3H and Tg8 neonates at the somatic and dendritic levels, whereas 5-HT(1B) receptor (5-HT(1B)-R) expression was observed only in Tg8 PhMns at the somatic level. We investigated the interactions between 5-HT(2A)-R and 5-HT(1B)-R during maturation by treating pregnant C3H mice with a 5-HT(2A)-R agonist (2,5-dimethoxy-4-iodoamphetamine hydrochloride). This pharmacological overactivation of 5-HT(2A)-R induced a somatic expression of 5-HT(1B)-R in PhMns of their progeny. Conversely, treatment of pregnant Tg8 mice with a 5-HT(2A)-R antagonist (ketanserin) decreased the 5-HT(1B)-R density in PhMns of their progeny. Second, using retrograde transneuronal tracing with rabies virus injected into the diaphragm of Tg8 and C3H neonates, we studied the organization of the premotor network driving PhMns. The interneuronal network monosynaptically connected to PhMns was much more extensive in Tg8 than in C3H neonates. However, treatment of pregnant C3H mice with 2,5-dimethoxy-4-iodoamphetamine hydrochloride switched the premotoneuronal network of their progeny from a C3H- to a Tg8-like pattern. These results show that a prenatal 5-HT excess affects, via the overactivation of 5-HT(2A)-R, the expression of 5-HT(1B)-R in PhMns and the organization of their premotor network.
- Published
- 2008
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132. Prenatal diazepam exposure alters respiratory control system and GABAA and adenosine receptor gene expression in newborn rats.
- Author
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Picard N, Guénin S, Perrin Y, Hilaire G, and Larnicol N
- Subjects
- Animals, Animals, Newborn, Female, Hypoxia genetics, Hypoxia physiopathology, Pregnancy, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Receptor, Adenosine A1 drug effects, Receptor, Adenosine A2A drug effects, Receptors, GABA-A genetics, Receptors, Purinergic P1 genetics, Respiratory Center growth & development, Respiratory Center metabolism, Respiratory Mechanics drug effects, Tidal Volume drug effects, Diazepam toxicity, GABA Modulators toxicity, Gene Expression Regulation, Developmental drug effects, Prenatal Exposure Delayed Effects, Receptors, GABA-A drug effects, Receptors, Purinergic P1 drug effects, Respiration drug effects, Respiratory Center drug effects
- Abstract
In experimental animals, prenatal diazepam exposure has clearly been associated with behavioral disturbances. Its impact on newborn breathing has not been documented despite potential deleterious consequences for later brain development. We addressed this issue in neonatal rats (0-2 d) born from dams, which consumed 2 mg/kg/d diazepam via drinking fluid throughout gestation. In vivo, prenatal diazepam exposure significantly altered the normoxic-breathing pattern, lowering breathing frequency (105 vs. 125 breaths/min) and increasing tidal volume (16.2 vs. 12.7 mL/kg), and the ventilatory response to hypoxia, inducing an immediate and marked decrease in tidal volume (-30%) absent in controls. In vitro, prenatal diazepam exposure significantly increased the respiratory-like frequency produced by pontomedullary and medullary preparations (+38% and +19%, respectively) and altered the respiratory-like response to application of nonoxygenated superfusate. Both in vivo and in vitro, the recovery from oxygen deprivation challenges was delayed by prenatal diazepam exposure. Finally, real-time PCR showed that prenatal diazepam exposure affected mRNA levels of alpha1 and alpha2 GABAA receptor subunits and of A1 and A2A adenosine receptors in the brainstem. These mRNA changes, which are region-specific, suggest that prenatal diazepam exposure interferes with developmental events whose impact on the respiratory system maturation deserves further studies.
- Published
- 2008
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133. 8-OH-DPAT suppresses spontaneous central apneas in the C57BL/6J mouse strain.
- Author
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Stettner GM, Zanella S, Hilaire G, and Dutschmann M
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Plethysmography, Whole Body, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Serotonin Receptor Agonists pharmacology, Sleep Apnea, Central drug therapy
- Abstract
Apneas are common and prognostically relevant disorders of the central control of breathing, but pharmacological interventions are dissatisfying. The respiratory phenotype of C57BL/6J mice is characterized by the occurrence of spontaneous central apneas with laryngeal closure. In the present study we investigated the impact of the 5-HT(1A) receptor agonist 8-OH-DPAT on apneas in C57BL/6J mice, because of the important role of serotonin in the regulation of breathing and previous reports showing that serotonergic drugs can affect central apneas. Whole-body plethysmography in awake, unrestrained mice revealed that intraperitoneal application of 8-OH-DPAT (10microgkg(-1)) decreased the occurrence of spontaneous apneas from 1.91+/-0.25 to 1.05+/-0.05 apneas min(-1). The efficacy of 5-HT(1A) receptor activation was further verified in the in situ working heart-brainstem preparation. Here the apneas occurred at a frequency of 1.33+/-0.19min(-1). Intra-arterial perfusion with 1-2microM 8-OH-DPAT completely abolished spontaneous apneas. These results suggest that 5-HT(1A) receptor activation may be a potential treatment option for central apneas.
- Published
- 2008
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134. Spontaneous central apneas occur in the C57BL/6J mouse strain.
- Author
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Stettner GM, Zanella S, Huppke P, Gärtner J, Hilaire G, and Dutschmann M
- Subjects
- Animals, Brain Stem physiology, Data Interpretation, Statistical, Electrophysiology, Glottis physiology, Heart physiology, Hypoglossal Nerve physiology, Larynx physiology, Mice, Mice, Inbred C57BL, Peripheral Nerves physiology, Phenotype, Phrenic Nerve physiology, Plethysmography, Vagus Nerve physiology, Apnea physiopathology, Respiratory Mechanics physiology
- Abstract
Despite the clinical significance of central apneas in a wide range of disorders little is known about their pathogenesis. Research in this field has been hindered by the lack of appropriate animal models. Our goal was to determine whether the C57BL/6J mouse strain, which has an inherited predisposition for dysrhythmic breathing, exhibits spontaneous apneas. In vivo plethysmography of unanesthetized, unrestrained adult C57BL/6J mice revealed a regular occurrence of spontaneous apneas. In situ recordings from respiratory outputs (phrenic, vagal, hypoglossal nerves) in the working heart-brainstem preparation (WHBP) also showed spontaneous central apneas accompanied by laryngeal closure as indicated by tonic vagal postinspiratory activity and increase in subglottal pressure. The apneas were further characterized by a hypoglossal discharge with delayed onset compared to the tonic vagal postinspiratory activity. We conclude that spontaneous central apneas with active laryngeal closure occur in C57BL/6J mice. This mouse strain is a useful animal model to study neuronal mechanisms that underlie the generation of spontaneous central apneas.
- Published
- 2008
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135. Necdin gene, respiratory disturbances and Prader-Willi syndrome.
- Author
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Zanella S, Barthelemy M, Muscatelli F, and Hilaire G
- Subjects
- Animals, Animals, Newborn, Brain physiopathology, Disease Models, Animal, Mice, Mice, Knockout, Serotonin physiology, Nerve Tissue Proteins deficiency, Nerve Tissue Proteins genetics, Nuclear Proteins deficiency, Nuclear Proteins genetics, Prader-Willi Syndrome genetics, Respiration Disorders genetics
- Abstract
Prader-Willi Syndrome (PWS) is a complex neurogenetic disease with various symptoms, including breathing deficits and possible alteration of serotonin (5HT) metabolism. As PWS results from the absence of paternal expression of several imprinted genes among which NECDIN (Ndn), we examined whether Ndn deficiency in mice induced breathing and 5HT deficits. In vivo, Ndn-deficient mice (Ndn-/-) had irregular breathing, severe apneas and blunted respiratory response to hypoxia. In vitro, medullary preparations from Ndn-/- neonates produced a respiratory-like rhythm that was highly irregular, frequently interrupted and abnormally regulated by central hypoxia. In wild type (wt) and Ndn-/- neonates, immunohistofluorescence and biochemistry revealed that medullary 5HT neurons expressed Ndn in wt and that the medulla contained abnormally high levels of 5HT in Ndn-/-. Thus, our preliminary results fully confirm a primary role of Ndn in PWS, revealing that Ndn-deficiency in mice induces respiratory and 5HT alterations reminiscent of PWS.
- Published
- 2008
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136. Oral treatment with desipramine improves breathing and life span in Rett syndrome mouse model.
- Author
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Zanella S, Mebarek S, Lajard AM, Picard N, Dutschmann M, and Hilaire G
- Subjects
- Animals, Apnea physiopathology, Female, Locomotion drug effects, Medulla Oblongata metabolism, Methyl-CpG-Binding Protein 2 genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Microcephaly genetics, Microcephaly prevention & control, Norepinephrine metabolism, Plethysmography, Rett Syndrome physiopathology, Antidepressive Agents, Tricyclic therapeutic use, Desipramine therapeutic use, Longevity drug effects, Respiratory Mechanics drug effects, Rett Syndrome drug therapy
- Abstract
Rett syndrome is a neurodevelopmental disease due to Mecp2 gene mutations that is associated to complex neurological symptoms, with bioaminergic deficits and life-threatening apneas related to sudden and unexpected death. In male mice, Mecp2-deficiency similarly induces medullary bioaminergic deficits, severe apneas and short life span. Here, we show that long-term oral treatment of Mecp2-deficient male mice with desipramine, an old drug of clinical use known to block norepinephrine uptake and to strengthen its synaptic effects, significantly alleviates their breathing symptoms and prolongs their life span. Although these mouse results identify desipramine as the first oral pharmacological treatment potentially able to alleviate breathing symptoms of Rett syndrome, we recommend further studies of desipramine effects in Mecp2-deficient mice before attempting any clinical trials in Rett patients.
- Published
- 2008
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137. Brain nuclei controlling the spinal respiratory motoneurons in the newborn mouse.
- Author
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Bévengut M, Coulon P, and Hilaire G
- Subjects
- Animals, Animals, Newborn, Biological Clocks, Diaphragm innervation, Mice, Respiratory Muscles innervation, Brain physiology, Interneurons physiology, Motor Neurons physiology, Respiratory Muscles physiology, Respiratory Physiological Phenomena, Spinal Cord physiology
- Abstract
A retrograde and transneuronal infection with rabies virus was performed in mouse neonates to locate the central nervous structures involved in the motor command of the spinal respiratory motoneurons and to discriminate the location and hierarchical organization of the neurons in and between these infected central nervous structures.
- Published
- 2008
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138. Consequences of prenatal exposure to diazepam on the respiratory parameters, respiratory network activity and gene expression of alpha1 and alpha2 subunits of GABA(A) receptor in newborn rat.
- Author
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Picard N, Guenin S, Perrin Y, Hilaire G, and Larnicol N
- Subjects
- Animals, Animals, Newborn, Body Temperature drug effects, Female, Gene Expression Regulation drug effects, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Diazepam pharmacology, Protein Subunits genetics, Receptors, GABA-A genetics, Respiratory Physiological Phenomena drug effects
- Abstract
Diazepam (DZP) enhances GABA action at GABA(A) receptor. Chronic prenatal administration of DZP delays the appearance of neonatal reflexes. We examined whether maternal intake of DZP might affect respiratory control system in newborn rats (0-3 day-old). This study was conducted on unrestrained animals and medulla-spinal cord preparations. In addition, the level of expression of the genes encoding for the alpha1 and alpha2 subunits of the GABA(A) receptor was assessed by quantitative real-time RT-PCR. In rats exposed to DZP, the respiratory frequency was significantly lower and the tidal volume higher than in controls with no significant alteration of the minute ventilation. The recovery from moderate hypoxia was delayed compared to controls. The respiratory-like frequency of medullary spinal cord preparation from DZP-exposed neonates was higher than in the control group. Acute applications of DZP (1 microM) to these preparations increased respiratory-like frequency in both groups, but this facilitation was attenuated following prenatal DZP exposure. The present data indicate that prenatal exposure to DZP alters both eupneic breathing and the respiratory response to hypoxia. These effects might partly be ascribed to the down-regulation of the expression of genes encoding GABA(A) receptor subunits. On the other hand, the effects of DZP exposure on reduced preparations suggested changes in the GABA(A) receptor efficiency and/or disruption of the normal development of the medullary respiratory network.
- Published
- 2008
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139. Muscarinic receptors and alpha2-adrenoceptors interact to modulate the respiratory rhythm in mouse neonates.
- Author
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Zanella S, Viemari JC, and Hilaire G
- Subjects
- Acetylcholine pharmacology, Action Potentials drug effects, Adrenergic alpha-Antagonists pharmacology, Analysis of Variance, Animals, Animals, Newborn, Brain Stem drug effects, Brain Stem parasitology, Dose-Response Relationship, Drug, Drug Interactions, In Vitro Techniques, Mice, Muscarine pharmacology, Muscarinic Agonists pharmacology, Yohimbine pharmacology, Periodicity, Receptors, Adrenergic, alpha-2 physiology, Receptors, Muscarinic physiology, Respiration drug effects
- Abstract
The respiratory rhythm generator (RRG) is modulated by several endogenous substances, including acetylcholine (ACh) and noradrenaline (NA) that interact in several modulatory processes. To know whether ACh and NA interacted to modulate the RRG activity, we used medullary "en bloc" and slice preparations from neonatal mice where the RRG has been shown to receive a facilitatory modulation from A1/C1 neurons, via a continuous release of endogenous NA and activation of alpha2 adrenoceptors. Applying ACh at 25 microM activated the RRG but ACh had no effects at 50 microM. Applying the ACh receptor agonists nicotine and muscarine facilitated and depressed the RRG, respectively. After yohimbine pre-treatment that blocked the alpha2 facilitation, the nicotinic facilitation was not altered, the muscarinic depression was reversed and ACh 50 microM significantly facilitated the RRG. After L-tyrosine pre-treatment that potentiated the alpha2 facilitation, the muscarinic depression was enhanced. Thus, ACh regulates the RRG activity via nicotinic and muscarinic receptors, the muscarinic receptors interacting with alpha2 adrenoceptors.
- Published
- 2007
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140. Possible modulation of the mouse respiratory rhythm generator by A1/C1 neurones.
- Author
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Zanella S, Roux JC, Viemari JC, and Hilaire G
- Subjects
- Adrenergic alpha-2 Receptor Antagonists, Adrenergic alpha-Antagonists pharmacology, Age Factors, Analysis of Variance, Animals, Animals, Newborn, Catecholamines physiology, Cervical Vertebrae, In Vitro Techniques, Medulla Oblongata physiology, Mice, Neural Pathways cytology, Neural Pathways physiology, Neurons cytology, Respiratory Center cytology, Respiratory Center physiology, Spinal Cord cytology, Spinal Cord physiology, Yohimbine pharmacology, Medulla Oblongata cytology, Neurons physiology, Periodicity, Receptors, Adrenergic, alpha-2 physiology, Respiration
- Abstract
Although compelling evidence exist that the respiratory rhythm generator is modulated by endogenous noradrenaline released from pontine A5 and A6 neurones, we examined whether medullary catecholaminergic neurones also participated in respiratory rhythm modulation. Experiments were performed in neonatal (postnatal days 0-6, P0-P6) and young mice (P14-P18) using "en bloc" medullary preparations (pons resected) and transverse medullary slices. In "en bloc" preparations, blockade of medullary alpha2 adrenoceptors with yohimbine and activation of catecholamine biosynthesis with L-tyrosine significantly depresses and facilitates the respiratory rhythm, respectively. In slices from neonatal and young mice, blockade of medullary alpha2 adrenoceptors also depressed the respiratory rhythm. Yohimbine local applications and lesion-ablation experiments of the dorsal medulla revealed implication of A1/C1 neurones in the yohimbine depressing effect. Although the mechanisms responsible for the yohimbine-depressing effect remain to be elucidated, our in vitro results in neonatal and young mice suggest that endogenous catecholamines released from A1/C1 neurones participate in respiratory rhythm modulation via medullary alpha2 adrenoceptors.
- Published
- 2006
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- View/download PDF
141. Endogenous noradrenaline affects the maturation and function of the respiratory network: possible implication for SIDS.
- Author
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Hilaire G
- Subjects
- Animals, Brain Stem cytology, Brain Stem growth & development, Humans, Infant, Models, Neurological, Neurons physiology, Norepinephrine genetics, Respiratory System embryology, Respiratory System growth & development, Nerve Net physiology, Norepinephrine metabolism, Respiration, Respiratory System metabolism, Sudden Infant Death
- Abstract
Breathing is a vital, rhythmic motor act that is required for blood oxygenation and oxygen delivery to the whole body. Therefore, the brainstem network responsible for the elaboration of the respiratory rhythm must function from the very first moments of extrauterine life. In this review, it is shown that the brainstem noradrenergic system plays a pivotal role in both the modulation and the maturation of the respiratory rhythm generator. Compelling evidence are reported demonstrating that genetically induced alterations of the noradrenergic system in mice affect the prenatal maturation and the perinatal function of the respiratory rhythm generator and have drastic consequences on postnatal survival. Sudden Infant Death Syndrome (SIDS), the leader cause of infant death in industrialised countries, may result from cardiorespiratory disorders during sleep. As several cases of SIDS have been observed in infants having noradrenergic deficits, a possible link between prenatal alteration of the noradrenergic system, altered maturation and function of the respiratory network and SIDS is suggested.
- Published
- 2006
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142. Reduced density of functional 5-HT1A receptors in the brain, medulla and spinal cord of monoamine oxidase-A knockout mouse neonates.
- Author
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Lanoir J, Hilaire G, and Seif I
- Subjects
- Animals, Animals, Newborn, Binding Sites, Brain anatomy & histology, Medulla Oblongata cytology, Mice, Mice, Knockout, Mice, Transgenic, Monoamine Oxidase genetics, Serotonin Plasma Membrane Transport Proteins metabolism, Spinal Cord cytology, Vesicular Monoamine Transport Proteins metabolism, Brain metabolism, Medulla Oblongata metabolism, Monoamine Oxidase metabolism, Receptor, Serotonin, 5-HT1A metabolism, Spinal Cord metabolism
- Abstract
Abnormally high brain 5-HT levels in monoamine oxidase-A knockout (MAO-A KO) mouse neonates raise the question of whether the distribution and density of the 5-HT1A receptors (5-HT1AR) expressed in the brain by postnatal day P7 are affected and, if so, whether the 5-HT1A autoreceptors in the dorsal raphe are modified in the same way as the postsynaptic 5-HT1AR present in raphe target structures. [3H]8-OH-DPAT binding and quantitative autoradiography were performed to answer these questions. Binding specificity was first confirmed in adult wild-type mice and rat brain sections. 5-HT1AR binding was then analyzed in four MAO-A mutant vs. five wild-type neonatal brains, from olfactory bulb to cervical cord. Among 12 structures expressing postsynaptic 5-HT1AR in wild-type neonates, the highest densities involved the retrosplenial cortex, entorhinal cortex, and septum (52-46 fmol/mg tissue); low densities occurred in the hippocampus and spinal cord (24 fmol/mg tissue); in addition, the raphe autoreceptor density was only 20 fmol/mg tissue. In mutants, the distribution of postsynaptic 5-HT1AR was unchanged, but an overall decrease in density occurred (-32% to -63%); the raphe autoreceptors decreased in mutants by at least -79%. Data are discussed with reference to the ectopic 5-HT uptake and accumulation reported to occur during the first 10 postnatal days in wild-type and MAO-A KO mice. As previously suggested to explain the raphe autoreceptor loss in 2-month-old MAO-A KO mice, the overall 5-HT1AR down-regulation in mutant pups probably results from extracellular 5-HT excess in both raphe and target structures. The greater the 5-HT excess, the more the functional receptor density decreases., (Copyright 2006 Wiley-Liss, Inc.)
- Published
- 2006
- Full Text
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143. Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice.
- Author
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Viemari JC, Roux JC, Tryba AK, Saywell V, Burnet H, Peña F, Zanella S, Bévengut M, Barthelemy-Requin M, Herzing LB, Moncla A, Mancini J, Ramirez JM, Villard L, and Hilaire G
- Subjects
- Animals, Disease Models, Animal, Humans, Male, Medulla Oblongata physiopathology, Methyl-CpG-Binding Protein 2 physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Respiratory Mechanics genetics, Respiratory Mechanics physiology, Respiratory System Abnormalities metabolism, Respiratory System Abnormalities physiopathology, Rett Syndrome genetics, Rett Syndrome metabolism, Rett Syndrome physiopathology, Methyl-CpG-Binding Protein 2 deficiency, Methyl-CpG-Binding Protein 2 genetics, Norepinephrine antagonists & inhibitors, Norepinephrine physiology, Respiratory System Abnormalities genetics
- Abstract
Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic deficiencies and life-threatening breathing disturbances. We used in vivo plethysmography, in vitro electrophysiology, neuropharmacology, immunohistochemistry, and biochemistry to characterize the consequences of the MECP2 mutation on breathing in wild-type (wt) and Mecp2-deficient (Mecp2-/y) mice. At birth, Mecp2-/y mice showed normal breathing and a normal number of medullary neurons that express tyrosine hydroxylase (TH neurons). At approximately 1 month of age, most Mecp2-/y mice showed respiratory cycles of variable duration; meanwhile, their medulla contained a significantly reduced number of TH neurons and norepinephrine (NE) content, even in Mecp2-/y mice that showed a normal breathing pattern. Between 1 and 2 months of age, all unanesthetized Mecp2-/y mice showed breathing disturbances that worsened until fatal respiratory arrest at approximately 2 months of age. During their last week of life, Mecp2-/y mice had a slow and erratic breathing pattern with a highly variable cycle period and frequent apneas. In addition, their medulla had a drastically reduced number of TH neurons, NE content, and serotonin (5-HT) content. In vitro experiments using transverse brainstem slices of mice between 2 and 3 weeks of age revealed that the rhythm produced by the isolated respiratory network was irregular in Mecp2-/y mice but could be stabilized with exogenous NE. We hypothesize that breathing disturbances in Mecp2-/y mice, and probably Rett patients, originate in part from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network.
- Published
- 2005
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144. Perinatal maturation of the respiratory rhythm generator in mammals: from experimental results to computational simulation.
- Author
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Achard P, Zanella S, Rodriguez R, and Hilaire G
- Subjects
- Animals, Animals, Newborn, Humans, Infant, Newborn, Computer Simulation, Periodicity, Respiratory Center embryology, Respiratory Center growth & development, Respiratory Physiological Phenomena
- Abstract
The survival of neonatal mammals requires a correct function of the respiratory rhythm generator (RRG), and therefore, the processes that control its prenatal maturation are of vital importance. In humans, lambs and rodents, foetal breathing movements (FBMs) occur early during gestation, are episodic, sensitive to bioamines, central hypoxia and inputs from CNS upper structures, and evolve with developmental age. In vitro, the foetal rodent RRG studied in preparations where the upper CNS structures are lacking continuously produces a rhythmic command, which is sensitive to hypoxia and bioaminergic inputs. The rhythm is slow with variable periods 4 days before birth. It becomes faster 2 days before birth, similar to the postnatal rhythm. Compelling evidence suggests that a region of the RRG called the preBötzinger complex (PBC) contains respiratory pacemaker neurones which play a primary role in perinatal rhythmogenesis. Although the RRG functions during early gestation, no pacemakers are found in the putative PBC area and its electrical stimulation and lesion do not affect the early foetal rhythm. To know whether the early foetal and perinatal rhythms originate from either pacemaker neurones or network connection properties, and to know which maturational processes might explain the appearance of PBC pacemakers and the rhythm increase during perinatal development, we computationally modelled maturing RRG. Our model shows that both network noise and persistent sodium conductance are crucial for rhythmogenesis and that a slight increase in the persistent sodium conductance can solve the pacemaker versus network dilemma in a noisy network.
- Published
- 2005
- Full Text
- View/download PDF
145. Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents.
- Author
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Hilaire G, Viemari JC, Coulon P, Simonneau M, and Bévengut M
- Subjects
- Animals, Animals, Newborn, Mice, Mice, Mutant Strains, Models, Neurological, Neurons classification, Pons cytology, Pons growth & development, Rats, Receptors, Adrenergic physiology, Respiratory Center drug effects, Respiratory Center physiology, Rodentia physiology, Neurons physiology, Norepinephrine physiology, Periodicity, Pons physiology, Respiration
- 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.
- Published
- 2004
- Full Text
- View/download PDF
146. Nasal trigeminal inputs release the A5 inhibition received by the respiratory rhythm generator of the mouse neonate.
- Author
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Viemari JC, Bévengut M, Coulon P, and Hilaire G
- Subjects
- Afferent Pathways drug effects, Afferent Pathways physiology, Animals, Animals, Newborn, Electric Stimulation methods, Mice, Nasal Cavity drug effects, Neural Inhibition drug effects, Piperoxan pharmacology, Respiratory Mechanics drug effects, Trigeminal Nerve drug effects, Nasal Cavity physiology, Neural Inhibition physiology, Respiratory Mechanics physiology, Trigeminal Nerve physiology
- Abstract
Experiments were performed on neonatal mice to analyze why, in vitro, the respiratory rhythm generator (RRG) was silent and how it could be activated. We demonstrated that in vitro the RRG in intact brain stems is silenced by a powerful inhibition arising from the pontine A5 neurons through medullary alpha(2) adrenoceptors and that in vivo nasal trigeminal inputs facilitate the RRG as nasal continuous positive airway pressure increases the breathing frequency, whereas nasal occlusion and nasal afferent anesthesia depress it. Because nasal trigeminal afferents project to the A5 nuclei, we applied single trains of negative electric shocks to the trigeminal nerve in inactive ponto-medullary preparations. They induced rhythmic phrenic bursts during the stimulation and for 2-3 min afterward, whereas repetitive trains produced on-going rhythmic activity up to the end of the experiments. Electrolytic lesion or pharmacological inactivation of the ipsilateral A5 neurons altered both the phrenic burst frequency and occurrence after the stimulation. Extracellular unitary recordings and trans-neuronal tracing experiments with the rabies virus show that the medullary lateral reticular area contains respiratory-modulated neurons, not necessary for respiratory rhythmogenesis, but that may provide an excitatory pathway from the trigeminal inputs to the RRG as their electrolytic lesion suppresses any phrenic activity induced by the trigeminal nerve stimulation. The results lead to the hypothesis that the trigeminal afferents in the mouse neonate involve at least two pathways to activate the RRG, one that may act through the medullary lateral reticular area and one that releases the A5 inhibition received by the RRG.
- Published
- 2004
- Full Text
- View/download PDF
147. MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth.
- Author
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Blanchi B, Kelly LM, Viemari JC, Lafon I, Burnet H, Bévengut M, Tillmanns S, Daniel L, Graf T, Hilaire G, and Sieweke MH
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Afferent Pathways drug effects, Afferent Pathways embryology, Afferent Pathways metabolism, Animals, Animals, Newborn, Biomarkers, DNA-Binding Proteins genetics, Disease Models, Animal, Electric Stimulation, Fetus, Homeodomain Proteins metabolism, MafB Transcription Factor, Mice, Mice, Knockout, Nerve Net drug effects, Nerve Net embryology, Nerve Net metabolism, Neurons drug effects, Neurons pathology, Organ Culture Techniques, Periodicity, Receptors, Neurokinin-1 agonists, Receptors, Neurokinin-1 metabolism, Respiration drug effects, Respiratory Center abnormalities, Respiratory Center pathology, Sleep Apnea, Central metabolism, Sleep Apnea, Central physiopathology, Substance P metabolism, Substance P pharmacology, Transcription Factors genetics, Transcription Factors metabolism, Avian Proteins, DNA-Binding Proteins deficiency, Neurons metabolism, Oncogene Proteins, Respiration genetics, Respiratory Center physiopathology, Sleep Apnea, Central genetics, Transcription Factors deficiency
- Abstract
The genetic basis for the development of brainstem neurons that generate respiratory rhythm is unknown. Here we show that mice deficient for the transcription factor MafB die from central apnea at birth and are defective for respiratory rhythmogenesis in vitro. MafB is expressed in a subpopulation of neurons in the preBötzinger complex (preBötC), a putative principal site of rhythmogenesis. Brainstems from Mafb(-/-) mice are insensitive to preBötC electrolytic lesion or stimulation and modulation of rhythmogenesis by hypoxia or peptidergic input. Furthermore, in Mafb(-/-) mice the preBötC, but not major neuromodulatory groups, presents severe anatomical defects with loss of cellularity. Our results show an essential role of MafB in central respiratory control, possibly involving the specification of rhythmogenic preBötC neurons.
- Published
- 2003
- Full Text
- View/download PDF
148. Monoamine oxidase A-deficiency and noradrenergic respiratory regulations in neonatal mice.
- Author
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Viemari JC and Hilaire G
- Subjects
- Animals, Animals, Newborn, Medulla Oblongata drug effects, Medulla Oblongata enzymology, Mice, Mice, Inbred C3H, Mice, Transgenic, Monoamine Oxidase genetics, Nerve Net drug effects, Nerve Net enzymology, Norepinephrine physiology, Respiratory Mechanics drug effects, Spinal Cord drug effects, Spinal Cord enzymology, Monoamine Oxidase deficiency, Norepinephrine pharmacology, Respiratory Mechanics physiology
- Abstract
In vitro experiments were performed on brainstem-spinal cord preparations from mouse neonates to compare the noradrenergic regulations of the respiratory network in the control C3H/HeJ strain and the transgenic Tg8 strain which has been created from the C3H/HeJ strain by deletion of the gene encoding monoamine oxidase A (MAOA), the main enzyme for serotonin degradation. In both control and MAOA-deficient strains, we show: (i). that the pontine A5 area exerts a potent inhibitory modulation on the respiratory rhythm generator; (ii). that noradrenaline application induces a tonic phrenic activity; and (iii). that noradrenaline increases the respiratory rhythm. The latter effect is however delayed and weak in the Tg8 strain. Therefore, MAOA-deficiency has only slightly altered the noradrenergic regulations of the respiratory network.
- Published
- 2003
- Full Text
- View/download PDF
149. Perinatal maturation of the mouse respiratory rhythm-generator: in vivo and in vitro studies.
- Author
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Viemari JC, Burnet H, Bévengut M, and Hilaire G
- Subjects
- Animals, Animals, Newborn, Electric Stimulation, Hypoxia, Mice, Norepinephrine pharmacology, Norepinephrine physiology, Periodicity, Plethysmography, Substance P pharmacology, Substance P physiology, Medulla Oblongata growth & development, Medulla Oblongata physiology, Respiration
- Abstract
In vivo (plethysmography) and in vitro (en bloc preparations) experiments were performed from embryonic day 16 (E16) to postnatal day 9 (P9) in order to analyse the perinatal maturation of the respiratory rhythm-generator in mice. At E16, delivered foetuses did not ventilate and survive but at E18 they breathed at about 110 cycles/min with respiratory cycles of variable individual duration. From E18 to P0-P2, the respiratory cycles stabilised without changes in the breathing parameters. However, these increased several-fold during the next days. Hypoxia increased breathing frequency from E18-P5 and only significantly affected ventilation from P3 onwards. At E16, in vitro medullary preparations (pons resection) produced rhythmic phrenic bursts at a low frequency (about 5 cycles/min) with variable cycle duration. At E18, their frequency doubled but cycle duration remained variable. After birth, the frequency did not change although cycle duration stabilised. At E18 and P0-P2, the in vitro frequency decreased by around 50% under hypoxia, increased by 40-50% under noradrenaline or substance P and was permanently depressed by the pontine A5 areas. At E16 however, hypoxia had no effects, both noradrenaline and substance P drastically increased the frequency and area A5 inhibition was not expressed at this time. At E18 and P0-P2, electrical stimulation and electrolytic lesion of the rostral ventrolateral medulla affected the in vitro rhythm but failed to induce convincing effects at E16. Thus, a major maturational step in respiratory rhythmogenesis occurs between E16-E18, in agreement with the concept of multiple rhythmogenic mechanisms.
- Published
- 2003
- Full Text
- View/download PDF
150. Genesis and control of the respiratory rhythm in adult mammals.
- Author
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Hilaire G and Pásaro R
- Subjects
- Age Factors, Animals, Mammals, Respiratory Center growth & development, Respiratory Muscles growth & development, Respiratory Muscles innervation, Respiratory Center physiology, Respiratory Mechanics physiology, Respiratory Muscles physiology
- Abstract
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.
- Published
- 2003
- Full Text
- View/download PDF
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