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1.
Physiol Genomics ; 55(11): 487-503, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37602394

RESUMEN

Chronic hypercapnia (CH) is a hallmark of respiratory-related diseases, and the level of hypercapnia can acutely or progressively become more severe. Previously, we have shown time-dependent adaptations in steady-state physiology during mild (arterial Pco2 ∼55 mmHg) and moderate (∼60 mmHg) CH in adult goats, including transient (mild CH) or sustained (moderate CH) suppression of acute chemosensitivity suggesting limitations in adaptive respiratory control mechanisms as the level of CH increases. Changes in specific markers of glutamate receptor plasticity, interleukin-1ß, and serotonergic modulation within key nodes of cardiorespiratory control do not fully account for the physiological adaptations to CH. Here, we used an unbiased approach (bulk tissue RNA sequencing) to test the hypothesis that mild or moderate CH elicits distinct gene expression profiles in important brain stem regions of cardiorespiratory control, which may explain the contrasting responses to CH. Gene expression profiles from the brain regions validated the accuracy of tissue biopsy methodology. Differential gene expression analyses revealed greater effects of CH on brain stem sites compared with the medial prefrontal cortex. Mild CH elicited an upregulation of predominantly immune-related genes and predicted activation of immune-related pathways and functions. In contrast, moderate CH broadly led to downregulation of genes and predicted inactivation of cellular pathways related to the immune response and vascular function. These data suggest that mild CH leads to a steady-state activation of neuroinflammatory pathways within the brain stem, whereas moderate CH drives the opposite response. Transcriptional shifts in immune-related functions may underlie the cardiorespiratory network's capability to respond to acute, more severe hypercapnia when in a state of progressively increased CH.NEW & NOTEWORTHY Mild chronic hypercapnia (CH) broadly upregulated immune-related genes and a predicted activation of biological pathways related to immune cell activity and the overall immune response. In contrast, moderate CH primarily downregulated genes related to major histocompatibility complex signaling and vasculature function that led to a predicted inactivation of pathways involving the immune response and vascular endothelial function. The severity-dependent effect on immune responses suggests that neuroinflammation has an important role in CH and may be important in the maintenance of proper ventilatory responses to acute and chronic hypercapnia.


Asunto(s)
Hipercapnia , Transcriptoma , Humanos , Hipercapnia/genética , Hipercapnia/metabolismo , Hipercapnia/patología , Transcriptoma/genética , Encéfalo/metabolismo , Perfilación de la Expresión Génica , Inmunidad
2.
Am J Physiol Regul Integr Comp Physiol ; 322(6): R467-R485, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35348007

RESUMEN

Hypertension characterized by low circulating renin activity accounts for roughly 25%-30% of primary hypertension in humans and can be modeled experimentally via deoxycorticosterone acetate (DOCA)-salt treatment. In this model, phenotypes develop in progressive phases, although the timelines and relative contributions of various mechanisms to phenotype development can be distinct between laboratories. To explore interactions among environmental influences such as diet formulation and dietary sodium (Na) content on phenotype development in the DOCA-salt paradigm, we examined an array of cardiometabolic endpoints in young adult male C57BL/6J mice during sham or DOCA-salt treatments when mice were maintained on several common, commercially available laboratory rodent "chow" diets including PicoLab 5L0D (0.39% Na), Envigo 7913 (0.31% Na), Envigo 2920x (0.15% Na), or a customized version of Envigo 2920x (0.4% Na). Energy balance (weight gain, food intake, digestive efficiency, and energy efficiency), fluid and electrolyte homeostasis (fluid intake, Na intake, fecal Na content, hydration, and fluid compartmentalization), renal functions (urine production rate, glomerular filtration rate, urine Na excretion, renal expression of renin, vasopressin receptors, aquaporin-2 and relationships among markers of vasopressin release, aquaporin-2 shedding, and urine osmolality), and blood pressure, all exhibited changes that were subject to interactions between diet and DOCA-salt. Interestingly, some of these phenotypes, including blood pressure and hydration, were dependent on nonsodium dietary components, as Na-matched diets resulted in distinct phenotype development. These findings provide a broad and robust illustration of an environment × treatment interaction that impacts the use and interpretation of a common rodent model of low-renin hypertension.


Asunto(s)
Acetato de Desoxicorticosterona , Hipertensión , Animales , Acuaporina 2 , Presión Sanguínea/fisiología , Desoxicorticosterona/farmacología , Acetato de Desoxicorticosterona/farmacología , Dieta , Hipertensión/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Renina/metabolismo , Sodio/metabolismo
3.
Am J Physiol Lung Cell Mol Physiol ; 316(3): L506-L518, 2019 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-30652496

RESUMEN

Infants born very prematurely (<28 wk gestation) have immature lungs and often require supplemental oxygen. However, long-term hyperoxia exposure can arrest lung development, leading to bronchopulmonary dysplasia (BPD), which increases acute and long-term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we assessed potential age-dependent adaptations in the control of breathing in an established rat model of BPD associated with hyperoxia. Hyperoxia exposure ( FIO2 ; 0.9 from 0 to 10 days of life) led to a BPD-like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (V̇e) and age-dependent changes in breath-to-breath variability. Hyperoxia-exposed rats had normal oxygen saturation ( SpO2 ) in room air but greater reductions in SpO2 during acute hypoxia (12% O2) that were likely due to lung injury. Moreover, acute ventilatory sensitivity was reduced at P12 to P14. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within six of eight or one of eight key brainstem regions, respectively, controlling breathing, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD-like phenotype and age-dependent adaptations in V̇e that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD.


Asunto(s)
Displasia Broncopulmonar/metabolismo , Hiperoxia/metabolismo , Hipoxia/metabolismo , Lesión Pulmonar/metabolismo , Factores de Edad , Animales , Displasia Broncopulmonar/patología , Modelos Animales de Enfermedad , Hiperoxia/patología , Hipertensión Pulmonar/metabolismo , Hipoxia/patología , Pulmón/metabolismo , Pulmón/patología , Lesión Pulmonar/patología , Ratas
4.
Am J Respir Cell Mol Biol ; 56(3): 362-371, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27805412

RESUMEN

Loss of extracellular superoxide dismutase 3 (SOD3) contributes to inflammatory and fibrotic lung diseases. The human SOD3 R213G polymorphism decreases matrix binding, redistributing SOD3 from the lung to extracellular fluids, and protects against LPS-induced alveolar inflammation. We used R213G mice expressing a naturally occurring single-nucleotide polymorphism, rs1799895, within the heparin-binding domain of SOD3, which results in an amino acid substitution at position 213 to test the hypothesis that the redistribution of SOD3 into the extracellular fluids would impart protection against bleomycin-induced lung fibrosis and secondary pulmonary hypertension (PH). In R213G mice, SOD3 content and activity was increased in extracellular fluids and decreased in lung at baseline, with greater increases in bronchoalveolar lavage fluid (BALF) SOD3 compared with wild-type mice 3 days after bleomycin. R213G mice developed less fibrosis based on pulmonary mechanics, fibrosis scoring, collagen quantification, and gene expression at 21 days, and less PH by right ventricular systolic pressure and pulmonary arteriole medial wall thickening at 28 days. In wild-type mice, macrophages, lymphocytes, neutrophils, proinflammatory cytokines, and protein increased in BALF on Day 7 and/or 21. In R213G mice, total BALF cell counts increased on Day 7 but resolved by 21 days. At 1 or 3 days, BALF pro- and antiinflammatory cytokines and BALF protein were higher in R213G mice, resolving by 21 days. We conclude that the redistribution of SOD3 as a result of the R213G single-nucleotide polymorphism protects mice from bleomycin-induced fibrosis and secondary PH by improved resolution of alveolar inflammation.


Asunto(s)
Neumonía/complicaciones , Neumonía/genética , Polimorfismo de Nucleótido Simple/genética , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/genética , Superóxido Dismutasa/genética , Células Epiteliales Alveolares/metabolismo , Animales , Bleomicina , Líquido del Lavado Bronquioalveolar , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Ratones Endogámicos C57BL , Modelos Biológicos , Neumonía/sangre , Neumonía/enzimología , Neumonía/fisiopatología , Fibrosis Pulmonar/sangre , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/fisiopatología , Superóxido Dismutasa/sangre , Remodelación Vascular
5.
J Physiol ; 593(2): 415-30, 2015 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-25630262

RESUMEN

Raphé-derived serotonin (5-HT) and thyrotropin-releasing hormone (TRH) play important roles in fundamental, homeostatic control systems such as breathing and specifically the ventilatory CO2 chemoreflex. Brown Norway (BN) rats exhibit an inherent and severe ventilatory insensitivity to hypercapnia but also exhibit relatively normal ventilation at rest and during other conditions, similar to multiple genetic models of 5-HT system dysfunction in mice. Herein, we tested the hypothesis that the ventilatory insensitivity to hypercapnia in BN rats is due to altered raphé gene expression and the consequent deficiencies in raphé-derived neuromodulators such as TRH. Medullary raphé transcriptome comparisons revealed lower expression of multiple 5-HT neuron-specific genes in BN compared to control Dahl salt-sensitive rats, predictive of reduced central nervous system monoamines by bioinformatics analyses and confirmed by high-performance liquid chromatography measurements. In particular, raphé Trh mRNA and peptide levels were significantly reduced in BN rats, and injections of the stable TRH analogue Taltirelin (TAL) stimulated breathing dose-dependently, with greater effects in BN versus control Sprague-Dawley rats. Importantly, TAL also effectively normalized the ventilatory CO2 chemoreflex in BN rats, but TAL did not affect CO2 sensitivity in control Sprague-Dawley rats. These data establish a molecular basis of the neuromodulatory deficiency in BN rats, and further suggest an important functional role for TRH signalling in the mammalian CO2 chemoreflex.


Asunto(s)
Hipercapnia/metabolismo , Núcleos del Rafe/metabolismo , Hormona Liberadora de Tirotropina/metabolismo , Transcriptoma , Animales , Dióxido de Carbono/farmacología , Hipercapnia/genética , Neurotransmisores/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Núcleos del Rafe/efectos de los fármacos , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Reflejo , Serotonina/metabolismo , Especificidad de la Especie , Hormona Liberadora de Tirotropina/análogos & derivados , Hormona Liberadora de Tirotropina/genética , Hormona Liberadora de Tirotropina/farmacología
6.
Cell Rep ; 42(8): 112935, 2023 08 29.
Artículo en Inglés | MEDLINE | ID: mdl-37540598

RESUMEN

Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT1A) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT1A from AgRP neurons causes RMR adaptation. Extracellular patch-clamp recordings identify distinct cellular responses of individual AgRP neurons from lean mice to Ang-II: no response, inhibition via AT1A and Gαi, or stimulation via Ang-II type 2 (AT2) receptors and Gαq. Following diet-induced obesity, a subset of Ang-II/AT1A-inhibited AgRP neurons undergo a spontaneous G-protein "signal switch," whereby AT1A stop inhibiting the cell via Gαi and instead begin stimulating the cell via Gαq. DREADD-mediated activation of Gαi, but not Gαq, in AT1A-expressing AgRP cells stimulates RMR in lean and obese mice. Thus, loss of AT1A-Gαi coupling within the AT1A-expressing AgRP neuron subtype represents a molecular mechanism contributing to RMR adaptation.


Asunto(s)
Neuronas , Obesidad , Receptor de Angiotensina Tipo 1 , Animales , Ratones , Proteína Relacionada con Agouti/metabolismo , Angiotensina II/metabolismo , Neuronas/metabolismo , Obesidad/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo
7.
Function (Oxf) ; 4(5): zqad043, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37609445

RESUMEN

Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.


Asunto(s)
Acetato de Desoxicorticosterona , Hipertensión , Receptor de Prorenina , Animales , Femenino , Ratones , Presión Sanguínea , Hipertensión/genética , Receptor de Prorenina/genética , Receptores de Superficie Celular , Renina/genética , Cloruro de Sodio , Vasoconstrictores
8.
J Physiol ; 590(14): 3335-47, 2012 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-22615434

RESUMEN

Brown Norway (BN) rats have a relatively specific deficit in CO2 sensitivity. This deficit could be due to an abnormally weak carotid body contribution to CO2 sensitivity. Accordingly, we tested the hypothesis that CBD would have less of an effect on eupnoeic breathing and CO2 sensitivity in the BN rats compared to other rat strains.We measured ventilation and blood gases at rest (eupnoea) and during hypoxia (FIO2 =0.12) or hypercapnia (FICO2 =0.07) before and up to 23 days after bilateral or Sham CBD in BN, Sprague­Dawley (SD) and Dahl Salt-Sensitive (SS) rats. In all three rat strains, CBD elicited eupnoeic hypoventilation (PaCO2 +8.7­11.0 mmHg) 1­2 days post-CBD (P <0.05), and attenuated ventilatory responses to hypoxia (P <0.05) and venous sodium cyanide (NaCN; P<0.05), while sham CBD had no effect on resting breathing, blood gases or chemoreflexes (P >0.05). In contrast, CBD had no effect on CO2 sensitivity (˙VE/PaCO2) in all strains (P>0.05). Eupnoeic PaCO2 returned to pre-CBD values within 15­23 days post-CBD. Thus, the effects of CBD in rats (1) further support an important role for the carotid bodies in eupnoeic blood gas regulation, (2) suggest that the carotid bodies are not a major determinant of CO2 sensitivity in rats, and (3) may not support the concept of an interaction among the peripheral and central chemoreceptors in rats.


Asunto(s)
Cuerpo Carotídeo/fisiología , Ventilación Pulmonar/fisiología , Reflejo/fisiología , Animales , Dióxido de Carbono/sangre , Cuerpo Carotídeo/cirugía , Desnervación , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Masculino , Oxígeno/sangre , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Especificidad de la Especie
9.
Front Synaptic Neurosci ; 14: 910820, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35844900

RESUMEN

Acute regulation of CO2 and pH homeostasis requires sensory feedback from peripheral (carotid body) and central (central) CO2/pH sensitive cells - so called respiratory chemoreceptors. Subsets of brainstem serotonin (5-HT) neurons in the medullary raphe are CO2 sensitive or insensitive based on differences in embryonic origin, suggesting these functionally distinct subpopulations may have unique transcriptional profiles. Here, we used Patch-to-Seq to determine if the CO2 responses in brainstem 5-HT neurons could be correlated to unique transcriptional profiles and/or unique molecular markers and pathways. First, firing rate changes with hypercapnic acidosis were measured in fluorescently labeled 5-HT neurons in acute brainstem slices from transgenic, Dahl SS (SSMcwi) rats expressing T2/ePet-eGFP transgene in Pet-1 expressing (serotonin) neurons (SS ePet1-eGFP rats). Subsequently, the transcriptomic and pathway profiles of CO2 sensitive and insensitive 5-HT neurons were determined and compared by single cell RNA (scRNAseq) and bioinformatic analyses. Low baseline firing rates were a distinguishing feature of CO2 sensitive 5-HT neurons. scRNAseq of these recorded neurons revealed 166 differentially expressed genes among CO2 sensitive and insensitive 5-HT neurons. Pathway analyses yielded novel predicted upstream regulators, including the transcription factor Egr2 and Leptin. Additional bioinformatic analyses identified 6 candidate gene markers of CO2 sensitive 5-HT neurons, and 2 selected candidate genes (CD46 and Iba57) were both expressed in 5-HT neurons determined via in situ mRNA hybridization. Together, these data provide novel insights into the transcriptional control of cellular chemoreception and provide unbiased candidate gene markers of CO2 sensitive 5-HT neurons. Methodologically, these data highlight the utility of the patch-to-seq technique in enabling the linkage of gene expression to specific functions, like CO2 chemoreception, in a single cell to identify potential mechanisms underlying functional differences in otherwise similar cell types.

10.
Front Physiol ; 13: 855054, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35283781

RESUMEN

Cardiovascular disease represents the leading cause of death in the United States, and metabolic diseases such as obesity represent the primary impediment to improving cardiovascular health. Rodent (mouse and rat) models are widely used to model cardiometabolic disease, and as a result, there is increasing interest in the development of accurate and precise methodologies with sufficiently high resolution to dissect mechanisms controlling cardiometabolic physiology in these small organisms. Further, there is great utility in the development of centralized core facilities furnished with high-throughput equipment configurations and staffed with professional content experts to guide investigators and ensure the rigor and reproducibility of experimental endeavors. Here, we outline the array of specialized equipment and approaches that are employed within the Comprehensive Rodent Metabolic Phenotyping Core (CRMPC) and our collaborating laboratories within the Departments of Physiology, Pediatrics, Microbiology & Immunology, and Biomedical Engineering at the Medical College of Wisconsin (MCW), for the detailed mechanistic dissection of cardiometabolic function in mice and rats. We highlight selected methods for the analysis of body composition and fluid compartmentalization, electrolyte accumulation and flux, energy accumulation and flux, physical activity, ingestive behaviors, ventilatory function, blood pressure, heart rate, autonomic function, and assessment and manipulation of the gut microbiota. Further, we include discussion of the advantages and disadvantages of these approaches for their use with rodent models, and considerations for experimental designs using these methods.

11.
Compr Physiol ; 11(2): 1653-1677, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33792908

RESUMEN

The development of the control of breathing begins in utero and continues postnatally. Fetal breathing movements are needed for establishing connectivity between the lungs and central mechanisms controlling breathing. Maturation of the control of breathing, including the increase of hypoxia chemosensitivity, continues postnatally. Insufficient oxygenation, or hypoxia, is a major stressor that can manifest for different reasons in the fetus and neonate. Though the fetus and neonate have different hypoxia sensing mechanisms and respond differently to acute hypoxia, both responses prevent deviations to respiratory and other developmental processes. Intermittent and chronic hypoxia pose much greater threats to the normal developmental respiratory processes. Gestational intermittent hypoxia, due to maternal sleep-disordered breathing and sleep apnea, increases eupneic breathing and decreases the hypoxic ventilatory response associated with impaired gasping and autoresuscitation postnatally. Chronic fetal hypoxia, due to biologic or environmental (i.e. high-altitude) factors, is implicated in fetal growth restriction and preterm birth causing a decrease in the postnatal hypoxic ventilatory responses with increases in irregular eupneic breathing. Mechanisms driving these changes include delayed chemoreceptor development, catecholaminergic activity, abnormal myelination, increased astrocyte proliferation in the dorsal respiratory group, among others. Long-term high-altitude residents demonstrate favorable adaptations to chronic hypoxia as do their offspring. Neonatal intermittent hypoxia is common among preterm infants due to immature respiratory systems and thus, display a reduced drive to breathe and apneas due to insufficient hypoxic sensitivity. However, ongoing intermittent hypoxia can enhance hypoxic sensitivity causing ventilatory overshoots followed by apnea; the number of apneas is positively correlated with degree of hypoxic sensitivity in preterm infants. Chronic neonatal hypoxia may arise from fetal complications like maternal smoking or from postnatal cardiovascular problems, causing blunting of the hypoxic ventilatory responses throughout at least adolescence due to attenuation of carotid body fibers responses to hypoxia with potential roles of brainstem serotonin, microglia, and inflammation, though these effects depend on the age in which chronic hypoxia initiates. Fetal and neonatal intermittent and chronic hypoxia are implicated in preterm birth and complicate the respiratory system through their direct effects on hypoxia sensing mechanisms and interruptions to the normal developmental processes. Thus, precise regulation of oxygen homeostasis is crucial for normal development of the respiratory control network. © 2021 American Physiological Society. Compr Physiol 11:1653-1677, 2021.


Asunto(s)
Nacimiento Prematuro , Síndromes de la Apnea del Sueño , Femenino , Humanos , Hipoxia , Recién Nacido , Recien Nacido Prematuro , Pulmón , Oxígeno , Embarazo
12.
Physiol Rep ; 9(13): e14946, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34228894

RESUMEN

Serotonin (5-HT) influences brain development and has predominantly excitatory neuromodulatory effects on the neural respiratory control circuitry. Infants that succumb to sudden infant death syndrome (SIDS) have reduced brainstem 5-HT levels and Tryptophan hydroxylase 2 (Tph2). Furthermore, there are age- and sex-dependent risk factors associated with SIDS. Here we utilized our established Dark Agouti transgenic rat lacking central serotonin KO to test the hypotheses that CNS 5-HT deficiency leads to: (1) high mortality in a sex-independent manner, (2) age-dependent alterations in other CNS aminergic systems, and (3) age-dependent impairment of chemoreflexes during post-natal development. KO rat pups showed high neonatal mortality but not in a sex-dependent manner and did not show altered hypoxic or hypercapnic ventilatory chemoreflexes. However, KO rat pups had increased apnea-related metrics during a specific developmental age (P12-16), which were preceded by transient increases in dopaminergic system activity (P7-8). These results support and extend the concept that 5-HT per se is a critical factor in supporting respiratory control during post-natal development.


Asunto(s)
Animales Recién Nacidos/fisiología , Fenómenos Fisiológicos Respiratorios , Serotonina/deficiencia , Factores de Edad , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Animales Recién Nacidos/metabolismo , Temperatura Corporal , Tronco Encefálico/química , Femenino , Técnicas de Silenciamiento del Gen , Hipercapnia/etiología , Hipercapnia/fisiopatología , Hipoxia/etiología , Hipoxia/fisiopatología , Masculino , Mortalidad , Ratas , Ratas Transgénicas , Serotonina/análisis , Serotonina/fisiología , Factores Sexuales
13.
Elife ; 72018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-30350782

RESUMEN

The neurotransmitter serotonin helps to co-ordinate the respiratory and cardiovascular responses of newborns to oxygen deprivation.


Asunto(s)
Serotonina , Humanos , Recién Nacido
14.
Front Synaptic Neurosci ; 15: 1225731, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37350930
15.
Exp Neurol ; 287(Pt 2): 102-112, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27132994

RESUMEN

The regulation of blood gases in mammals requires precise feedback mechanisms including chemoreceptor feedback from the carotid bodies. Carotid body denervation (CBD) leads to immediate hypoventilation (increased PaCO2) in adult rats, but over a period of days and weeks ventilation normalizes due in part to central (brain) mechanisms. Here, we tested the hypothesis that functional ventilatory recovery following CBD correlated with significant shifts in medullary raphe gene expression of molecules/pathways associated with known or novel forms of neuroplasticity. Tissue punches were obtained from snap frozen brainstems collected from rats 1-2days or 14-15days post-sham or post-bilateral CBD surgery (verified by physiologic measurements), and subjected to mRNA sequencing to identify, quantify, and statistically compare gene expression level differences among these groups of rats. We found the greatest number of gene expression changes acutely after CBD (154 genes), with fewer changes in the weeks after CBD (69-80 genes) and the fewest changes in expression among the time control groups (39 genes). Little or no changes were observed for multiple genes associated with serotonin- or glutamate receptor-dependent forms of neuroplasticity. However, an unbiased assessment of gene expression changes using a bioinformatics pathway analysis highlighted multiple changes in gene expression in signaling pathways associated with immune function. These included several growth factors and cytokines associated with peripheral and innate immune systems. Thus, these medullary raphe gene expression data support a role for immune-related signaling pathways in the functional restoration of blood gas control after CBD, but little or no role for serotonin- or glutamate receptor-mediated plasticity.


Asunto(s)
Cuerpo Carotídeo/fisiología , Desnervación , Regulación de la Expresión Génica/fisiología , Núcleos del Rafe/metabolismo , Recuperación de la Función/fisiología , Respiración , Serotonina/metabolismo , Animales , Cuerpo Carotídeo/cirugía , Modelos Animales de Enfermedad , Masculino , Plasticidad Neuronal/fisiología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Serotonina/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Factores de Tiempo
16.
Front Cell Neurosci ; 11: 34, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28270749

RESUMEN

Ventilation is continuously adjusted by a neural network to maintain blood gases and pH. Acute CO2 and/or pH regulation requires neural feedback from brainstem cells that encode CO2/pH to modulate ventilation, including but not limited to brainstem serotonin (5-HT) neurons. Brainstem 5-HT neurons modulate ventilation and are stimulated by hypercapnic acidosis, the sensitivity of which increases with increasing postnatal age. The proper function of brainstem 5-HT neurons, particularly during post-natal development is critical given that multiple abnormalities in the 5-HT system have been identified in victims of Sudden Infant Death Syndrome. Here, we tested the hypothesis that there are age-dependent increases in expression of pH-sensitive ion channels in brainstem 5-HT neurons, which may underlie their cellular CO2/pH sensitivity. Midline raphe neurons were acutely dissociated from neonatal and mature transgenic SSePet-eGFP rats [which have enhanced green fluorescent protein (eGFP) expression in all 5-HT neurons] and sorted with fluorescence-activated cell sorting (FACS) into 5-HT-enriched and non-5-HT cell pools for subsequent RNA extraction, cDNA library preparation and RNA sequencing. Overlapping differential expression analyses pointed to age-dependent shifts in multiple ion channels, including but not limited to the pH-sensitive potassium ion (K+) channel genes kcnj10 (Kir4.1), kcnj16 (Kir5.1), kcnk1 (TWIK-1), kcnk3 (TASK-1) and kcnk9 (TASK-3). Intracellular contents isolated from single adult eGFP+ 5-HT neurons confirmed gene expression of Kir4.1, Kir5.1 and other K+ channels, but also showed heterogeneity in the expression of multiple genes. 5-HT neuron-enriched cell pools from selected post-natal ages showed increases in Kir4.1, Kir5.1, and TWIK-1, fitting with age-dependent increases in Kir4.1 and Kir5.1 protein expression in raphe tissue samples. Immunofluorescence imaging confirmed Kir5.1 protein was co-localized to brainstem neurons and glia including 5-HT neurons as expected. However, Kir4.1 protein expression was restricted to glia, suggesting that it may not contribute to 5-HT neuron pH sensitivity. Although there are caveats to this approach, the data suggest that pH-sensitive Kir5.1 channels may underlie cellular CO2/pH chemosensitivity in brainstem 5-HT neurons.

17.
Respir Physiol Neurobiol ; 186(2): 221-8, 2013 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-23454023

RESUMEN

The Brown Norway (BN; BN/NHsdMcwi) rat exhibits a deficit in ventilatory CO2 sensitivity and a modest serotonin (5-HT) deficiency. Here, we tested the hypothesis that the selective serotonin reuptake inhibitor fluoxetine would augment CO2 sensitivity in BN but not Sprague Dawley (SD) rats. Ventilation during room air or 7% CO2 exposure was measured before, during and after 3 weeks of daily injections of saline or fluoxetine (10mg/(kgday)) in adult male BN and SD rats. Fluoxetine had minimal effects on room air breathing in BN and SD rats (p>0.05), although tidal volume (VT) was reduced in BN rats (p<0.05). There were also minimal effects of fluoxetine on CO2 sensitivity in SD rats, but fluoxetine increased minute ventilation, breathing frequency and VT during hypercapnia in BN rats (p<0.05). The augmented CO2 response was reversible upon withdrawal of fluoxetine. Brain levels of biogenic amines were largely unaffected, but 5-HIAA and the ratio of 5-HIAA/5-HT were reduced (p<0.05) consistent with selective and effective 5-HT reuptake inhibition. Thus, fluoxetine increases ventilatory CO2 sensitivity in BN but not SD rats, further suggesting altered 5-HT system function may contribute to the inherently low CO2 sensitivity in the BN rat.


Asunto(s)
Dióxido de Carbono/metabolismo , Fluoxetina/farmacología , Ventilación Pulmonar/efectos de los fármacos , Mecánica Respiratoria/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Hipercapnia/fisiopatología , Masculino , Ratas , Ratas Endogámicas BN , Ratas Sprague-Dawley , Serotonina/metabolismo
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