Adaptation to hypobaric hypoxia involves GABAA receptors in the pons

2008 ◽  
Vol 294 (2) ◽  
pp. R549-R557 ◽  
Author(s):  
Yee-Hsee Hsieh ◽  
Thomas E. Dick ◽  
Ruth E. Siegel
Keyword(s):  
Brain Stem ◽  
Hypobaric Hypoxia ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Acute Hypoxia ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Low Oxygen ◽  
Subunit Expression ◽  
The Brain

Survival in low-oxygen environments requires adaptation of sympathorespiratory control networks located in the brain stem. The molecular mechanisms underlying adaptation are unclear. In naïve animals, acute hypoxia evokes increases in phrenic (respiratory) and splanchnic (sympathetic) nerve activities that persist after repeated challenges (long-term facilitation, LTF). In contrast, our studies show that conditioning rats to chronic hypobaric hypoxia (CHH), an environment characteristic of living at high altitude, diminishes the response to hypoxia and attenuates LTF in a time-dependent manner. Phrenic LTF decreases following 7 days of CHH, and both sympathetic and phrenic LTF disappear following 14 days of CHH. Previous studies demonstrated that GABA is released in the brain stem during hypoxia and depresses respiratory activity. Furthermore, the sensitivity of brain stem neurons to GABA is increased following prolonged hypoxia. In this study, we demonstrate that GABAA receptor expression changes along with the CHH-induced physiological changes. Expression of the GABAA receptor α4 subunit mRNA increases two-fold in animals conditioned to CHH for 7 days. In addition, de novo expression of δ and α6, a subunit normally found exclusively in the cerebellum, is observed after 14 days. Consistent with these changes, diazepam-insensitive binding sites, characteristic of GABAA receptors containing α4 and α6 subunits, increase in the pons. Immunohistochemistry revealed that CHH-induced GABAA receptor subunit expression is localized in regions of sympathorespiratory control within the pons. Our findings suggest that a GABAA receptor mediated-mechanism participates in adaptation of the sympathorespiratory system to hypobaric hypoxia.

Serotonin elicits long-lasting enhancement of rhythmic respiratory activity in turtle brain stems in vitro

2001 ◽  
Vol 91 (6) ◽  
pp. 2703-2712 ◽  
Author(s):  
Stephen M. Johnson ◽  
Julia E. R. Wilkerson ◽  
Daniel R. Henderson ◽  
Michael R. Wenninger ◽  
Gordon S. Mitchell
Keyword(s):  
Brain Stem ◽  
Respiratory Activity ◽  
Dependent Manner ◽  
Frequency Increase ◽  
Burst Frequency ◽  
Bath Application ◽  
Burst Amplitude ◽  
Dose Dependent ◽  
The Brain

Brain stem preparations from adult turtles were used to determine how bath-applied serotonin (5-HT) alters respiration-related hypoglossal activity in a mature vertebrate. 5-HT (5–20 μM) reversibly decreased integrated burst amplitude by ∼45% ( P < 0.05); burst frequency decreased in a dose-dependent manner with 20 μM abolishing bursts in 9 of 13 preparations ( P < 0.05). These 5-HT-dependent effects were mimicked by application of a 5-HT1A agonist, but not a 5-HT1B agonist, and were abolished by the broad-spectrum 5-HT antagonist, methiothepin. During 5-HT (20 μM) washout, frequency rebounded to levels above the original baseline for 40 min ( P < 0.05) and remained above baseline for 2 h. A 5-HT3 antagonist (tropesitron) blocked the post-5-HT rebound and persistent frequency increase. A 5-HT3 agonist (phenylbiguanide) increased frequency during and after bath application ( P < 0.05). When phenylbiguanide was applied to the brain stem of brain stem/spinal cord preparations, there was a persistent frequency increase ( P < 0.05), but neither spinal-expiratory nor -inspiratory burst amplitude were altered. The 5-HT3receptor-dependent persistent frequency increase represents a unique model of plasticity in vertebrate rhythm generation.

scholarly journals Prolactin independent rescue of mouse corpus luteum life span: identification of prolactin and luteinizing hormone target genes

2009 ◽  
Vol 297 (3) ◽  
pp. E676-E684 ◽  
Author(s):  
Anne Bachelot ◽  
Julie Beaufaron ◽  
Nathalie Servel ◽  
Cécile Kedzia ◽  
Philippe Monget ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Corpus Luteum ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Ovarian Function ◽  
De Novo ◽  
Embryo Implantation ◽  
Receptor Expression ◽  
Corpora Lutea ◽  
Mrna Expression Profiling

The corpus luteum (CL) plays a central role in the maintenance of pregnancy in rodents, mainly by secreting progesterone. Female mice lacking prolactin (PRL) receptor (R) are sterile due to a failure of embryo implantation, which is a consequence of decreased luteinizing hormone (LH) receptor expression in the CL and inadequate levels of progesterone. We attempted to treat PRLR−/− females with human chorionic gonadotropin (hCG) and showed a de novo expression of LHR mRNA in the corpora lutea. Binding analysis confirmed that the LHR in hCG-treated PRLR−/− animals was functional. This was accompanied with increased expression of steroidogenic enzymes involved in progesterone synthesis. Despite these effects, no embryo implantation was observed because of high expression of 20α-hydroxysteroid dehydrogenase. To better appreciate the molecular mechanisms underlying maintenance of the CL, a series of mRNA expression-profiling experiments was performed on isolated corpora lutea of PRLR−/− and hCG-treated PRLR−/− mice. This approach revealed several novel candidate genes with potentially pivotal roles in ovarian function, among them, p27, VE-cadherin, Pten, and sFRP-4, a member of the Wnt/frizzled family. This study showed the differential role of PRL and LH in CL function and identified new targets of these hormones in luteal cells.

Early Defects of GABAergic Synapses in the Brain Stem of a MeCP2 Mouse Model of Rett Syndrome

2008 ◽  
Vol 99 (1) ◽  
pp. 112-121 ◽  
Author(s):  
L. Medrihan ◽  
E. Tantalaki ◽  
G. Aramuni ◽  
V. Sargsyan ◽  
I. Dudanova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Brain Stem ◽  
Rett Syndrome ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Ventrolateral Medulla ◽  
Diagnostic Tools ◽  
The Brain

Rett syndrome is a neurodevelopmental disorder caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and represents the leading genetic cause for mental retardation in girls. MeCP2-mutant mice have been generated to study the molecular mechanisms of the disease. It was suggested that an imbalance between excitatory and inhibitory neurotransmission is responsible for the behavioral abnormalities, although it remained largely unclear which synaptic components are affected and how cellular impairments relate to the time course of the disease. Here, we report that MeCP2 KO mice present an imbalance between inhibitory and excitatory synaptic transmission in the ventrolateral medulla already at postnatal day 7. Focusing on the inhibitory synaptic transmission we show that GABAergic, but not glycinergic, synaptic transmission is strongly depressed in MeCP2 KO mice. These alterations are presumably due to both decreased presynaptic γ-aminobutyric acid (GABA) release with reduced levels of the vesicular inhibitory transmitter transporter and reduced levels of postsynaptic GABAA-receptor subunits α2 and α4. Our data indicate that in the MeCP2 −/y mice specific synaptic molecules and signaling pathways are impaired in the brain stem during early postnatal development. These observations mandate the search for more refined diagnostic tools and may provide a rationale for the timing of future therapeutic interventions in Rett patients.

Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury

2012 ◽  
Vol 303 (1) ◽  
pp. L43-L53 ◽  
Author(s):  
Koji Sakamoto ◽  
Naozumi Hashimoto ◽  
Yasuhiro Kondoh ◽  
Kazuyoshi Imaizumi ◽  
Daisuke Aoyama ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Acute Hypoxia ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Alveolar Cells ◽  
Mesenchymal Transition ◽  
Twist Expression

Hypoxia contributes to the development of fibrosis with epithelial-mesenchymal transition (EMT) via stimulation of hypoxia-inducible factor 1α (HIF-1α) and de novo twist expression. Although hypoxemia is associated with increasing levels of surfactant protein D (SP-D) in acute lung injury (ALI), the longitudinal effects of hypoxia on SP-D expression in lung tissue injury/fibrosis have not been fully evaluated. Here, the involvement of hypoxia and SP-D modulation was evaluated in a model of bleomycin-induced lung injury. We also investigated the molecular mechanisms by which hypoxia might modulate SP-D expression in alveolar cells, by using a doxycycline (Dox)-dependent HIF-1α expression system. Tissue hypoxia and altered SP-D levels were present in bleomycin-induced fibrotic lesions. Acute hypoxia induced SP-D expression, supported by the finding that Dox-induced expression of HIF-1α increased SP-D expression. In contrast, persistent hypoxia repressed SP-D expression coupled with an EMT phenotype and twist expression. Long-term expression of HIF-1α caused SP-D repression with twist expression. Ectopic twist expression repressed SP-D expression. The longitudinal observation of hypoxia and SP-D levels in ALI in vivo was supported by the finding that HIF-1α expression stabilized by acute hypoxia induced increasing SP-D expression in alveolar cells, whereas persistent hypoxia induced de novo twist expression in these cells, causing repression of SP-D and acquisition of an EMT phenotype. Thus this is the first study to demonstrate the molecular mechanisms, in which SP-D expression under acute and persistent hypoxia in acute lung injury might be differentially modulated by stabilized HIF-1α expression and de novo twist expression.

scholarly journals Comparative Transcriptomic Analysis of the Brain in Takifugu Rubripes Shows Its Tolerance to Acute Hypoxia

2021 ◽  
Author(s):  
Mingxiu Bao ◽  
Fengqin Shang ◽  
Fujun Liu ◽  
Ziwen Hu ◽  
Shengnan Wang ◽  
...  
Keyword(s):  
Acute Hypoxia ◽  
Enrichment Analysis ◽  
Takifugu Rubripes ◽  
Low Oxygen ◽  
Short Term ◽  
Protection Mechanism ◽  
Complete Set ◽  
Self Protection ◽  
The Brain ◽  
Comparative Transcriptomic Analysis

Abstract Hypoxia is reduced levels of oxygen. Especially in water, due to the complex environment, hypoxic situations often occur. Although fish can survive in low-oxygen waters, this survival ability depends on a complete set of coping mechanisms such as oxygen perception and gene-protein interaction regulation. The research on this mechanism is very meaningful. The present study was undertaken to examine the short-term effects of hypoxia on the brain in Takifugu rubripes. We sequenced the transcriptomes of the brain in T. rubripes to studied their response mechanism to acute hypoxia. Total 167 genes with adjusted P values<0.05 were differentially expressed in the brain of T. rubripes exposed to acute hypoxia. However, hif1a, the master transcriptional regulator of the adaptive response to hypoxia, was not significantly regulated, which indicated that the T. rubripes brain might prevent the HIF-1 signaling pathway. Then Gene Ontology and KEGG Enrichment Analysis were carried out. The results indicated that hypoxia could cause metabolic and neurological changes, showing the clues of their adaptation to acute hypoxia. Overall, the sequenced transcriptomes of the brain in T. rubripes showed small changes under acute hypoxia. As the most complex and important organ, the brain of T. rubripes might be able to create a self-protection mechanism to resist or reduce damage caused by acute hypoxia stress.

Regulation of Synaptic Inputs to Paraventricular-Spinal Output Neurons by α2 Adrenergic Receptors

2005 ◽  
Vol 93 (1) ◽  
pp. 393-402 ◽  
Author(s):  
De-Pei Li ◽  
Lindsay M. Atnip ◽  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Brain Stem ◽  
Adrenergic Receptors ◽  
Dependent Manner ◽  
Paired Pulse ◽  
Synaptic Inputs ◽  
Pulse Ratio ◽  
Output Neurons ◽  
Immunofluorescence Labeling ◽  
The Brain

Neurons in the paraventricular nucleus (PVN) that project to the brain stem and spinal cord are important for autonomic regulation. The excitability of preautonomic PVN neurons is controlled by the noradrenergic input from the brain stem. In this study, we determined the role of α2 adrenergic receptors in the regulation of excitatory and inhibitory synaptic inputs to spinally projecting PVN neurons. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were recorded using whole cell voltage-clamp techniques on PVN neurons labeled by a retrograde fluorescence tracer injected into the thoracic spinal cord of rats. Bath application of 5–20 μM clonidine, an α2 receptor agonist, significantly reduced the amplitude of evoked GABAergic IPSCs in a dose-dependent manner. Also, 10 μM clonidine significantly decreased the frequency (from 2.68 ± 0.41 to 1.22 ± 0.40 Hz) but not the amplitude of miniature IPSCs (mIPSCs), and this effect was blocked by the α2 receptor antagonist yohimbine. Furthermore, clonidine increased the paired-pulse ratio of evoked IPSCs from 1.25 ± 0.05 to 1.61 ± 0.08 ( P < 0.05). On the other hand, clonidine had little effect on evoked glutamatergic EPSCs, mEPSCs, and the paired-pulse ratio of evoked EPSCs in most labeled cells examined. Additionally, immunofluorescence labeling revealed that the α2A receptor and GABA immunoreactivities were co-localized in close apposition to labeled PVN neurons. Collectively, these data suggest that stimulation of α2 adrenergic receptors primarily attenuates GABAergic inputs to PVN output neurons to the spinal cord. The presynaptic α2 receptors function as heteroreceptors to modulate synaptic GABA release and contribute to the hypothalamic regulation of sympathetic outflow.

scholarly journals Pancytopenia, Recurrent Infection, Poor Wound Healing, Heterotopia of the Brain Probably Associated with A Candidate Novel de Novo CDC42 Gene Defect: Expanding the Molecular and Phenotypic Spectrum

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 294
Author(s):  
Abdulaziz Asiri ◽  
Deemah Alwadaani ◽  
Muhammad Umair ◽  
Kheloud M. Alhamoudi ◽  
Mohammed H. Almuhanna ◽  
...  
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
De Novo ◽  
Functional Characterization ◽  
Substantial Reduction ◽  
Recurrent Infection ◽  
First Case ◽  
The Brain

CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the CDC42 gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of CDC42 pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the CDC42 gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the CDC42 gene associated with aberrant cell migration and immune response.

VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism

2000 ◽  
Vol 278 (4) ◽  
pp. C853-C860 ◽  
Author(s):  
Douglas S. Steinbrech ◽  
Babak J. Mehrara ◽  
Pierre B. Saadeh ◽  
Joshua A. Greenwald ◽  
Jason A. Spector ◽  
...  
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Oxygen Sensing ◽  
Dependent Manner ◽  
Metallic Ions ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Mrna Stabilization ◽  
Sensing Mechanism

Angiogenesis is essential for the increased delivery of oxygen and nutrients required for the reparative processes of bone healing. Vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, has been implicated in this process. We have previously shown that hypoxia specifically and potently regulates the expression of VEGF by osteoblasts. However, the molecular mechanisms governing this interaction remain unknown. In this study, we hypothesized that the hypoxic regulation of VEGF expression by osteoblasts occurs via an oxygen-sensing mechanism similar to the regulation of the erythropoietin gene (EPO). To test this hypothesis, we examined the kinetics of oxygen concentration on osteoblast VEGF expression. In addition, we analyzed the effects of nickel and cobalt on the expression of VEGF in osteoblastic cells because these metallic ions mimic hypoxia by binding to the heme portion of oxygen-sensing molecules. Our results indicated that hypoxia potently stimulates VEGF mRNA expression. In addition, we found that nickel and cobalt both stimulate VEGF gene expression in a similar time- and dose-dependent manner, suggesting the presence of a hemelike oxygen-sensing mechanism similar to that of the EPO gene. Moreover, actinomycin D, cycloheximide, dexamethasone, and mRNA stabilization studies collectively established that this regulation is predominantly transcriptional, does not require de novo protein synthesis, and is not likely mediated by the transcriptional activator AP-1. These studies demonstrate that hypoxia, nickel, and cobalt regulate VEGF expression in osteoblasts via a similar mechanism, implicating the involvement of a heme-containing oxygen-sensing molecule. This may represent an important mechanism of VEGF regulation leading to increased angiogenesis in the hypoxic microenvironment of healing bone.

Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage

2007 ◽  
Vol 293 (6) ◽  
pp. H3750-H3758 ◽  
Author(s):  
Saema Ansar ◽  
Petter Vikman ◽  
Marianne Nielsen ◽  
Lars Edvinsson
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Molecular Mechanisms ◽  
Cerebral Arteries ◽  
Temporal Correlation ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Ang Ii ◽  
Contractile Responses ◽  
Protein Levels ◽  
Receptor Mrna

We hypothesize that cerebral ischemia leads to enhanced expression of endothelin (ET), 5-hydroxytryptamine (5-HT), and angiotensin II (ANG II) receptors in the vascular smooth muscle cells. Our aim is to correlate the upregulation of cerebrovascular receptors and the underlying molecular mechanisms with the reduction in regional and global cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH). SAH was induced by injecting 250 μl blood into the prechiasmatic cistern in rats. The cerebral arteries were removed 0, 1, 3, 6, 12, 24, and 48 h after the SAH for functional and molecular studies. The contractile responses to ET-1, 5-carboxamidotryptamine (5-CT), and ANG II were investigated with myograph. The receptor mRNA and protein levels were analyzed by quantitative real-time PCR and immunohistochemistry, respectively. In addition, regional and global CBFs were measured by an autoradiographic method. As a result, SAH resulted in enhanced contractions to ET-1 and 5-CT. ANG II [via ANG II type 1 (AT1) receptors] induced increased contractile responses [in the presence of the ANG II type 2 (AT2) receptor antagonist PD-123319]. In parallel the ETB, 5-HT1B, and AT1 receptor, mRNA and protein levels were elevated by time. The regional and global CBF showed a successive reduction with time after SAH. In conclusion, the results demonstrate for the first time that SAH induces the upregulation of ETB, 5-HT1B, and AT1 receptors in a time-dependent manner both at functional, mRNA, and protein levels. These changes occur in parallel with a successive decrease in CBF. Thus there is a temporal correlation between the changes in receptor expression and CBF reduction, suggesting a linkage.

scholarly journals MicroRNA network changes in the brain stem underlie the development of hypertension

2015 ◽  
Vol 47 (9) ◽  
pp. 388-399 ◽  
Author(s):  
Danielle DeCicco ◽  
Haisun Zhu ◽  
Anthony Brureau ◽  
James S. Schwaber ◽  
Rajanikanth Vadigepalli
Keyword(s):  
Brain Stem ◽  
Differential Expression ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Network Motif ◽  
Microrna Expression ◽  
Negative Regulator ◽  
Ventrolateral Medulla ◽  
Wistar Kyoto ◽  
The Brain

Hypertension is a major chronic disease whose molecular mechanisms remain poorly understood. We compared neuroanatomical patterns of microRNAs in the brain stem of the spontaneous hypertensive rat (SHR) to the Wistar Kyoto rat (WKY, control). We quantified 419 well-annotated microRNAs in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), from SHR and WKY rats, during three main stages of hypertension development. Changes in microRNA expression were stage- and region-dependent, with a majority of SHR vs. WKY differential expression occurring at the hypertension onset stage in NTS versus at the prehypertension stage in RVLM. Our analysis identified 24 microRNAs showing time-dependent differential expression in SHR compared with WKY in at least one brain region. We predicted potential gene regulatory targets corresponding to catecholaminergic processes, neuroinflammation, and neuromodulation using the miRWALK and RNA22 databases, and we tested those bioinformatics predictions using high-throughput quantitative PCR to evaluate correlations of differential expression between the microRNAs and their predicted gene targets. We found a novel regulatory network motif consisting of microRNAs likely downregulating a negative regulator of prohypertensive processes such as angiotensin II signaling and leukotriene-based inflammation. Our results provide new evidence on the dynamics of microRNA expression in the development of hypertension and predictions of microRNA-mediated regulatory networks playing a region-dependent role in potentially altering brain-stem cardiovascular control circuit function leading to the development of hypertension.

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