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1.
Ann Epidemiol ; 84: 60-66, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37302674

RESUMO

PURPOSE: Aspirin (acetylsalicylic acid) has been reported to protect against certain cancers. However, patient-related risk factors may moderate protective effects, including excess weight, smoking, risky alcohol use, and diabetes. We explore the cancer-risk relationship between aspirin intake and those four factors. METHODS: Retrospective cohort study of cancers, aspirin intake, and four risk factors in persons aged ≥50 years. Participants received medication during 2007-2016, and cancers were diagnosed in 2012-2016. Adjusted hazard ratios (aHR) for 95% confidence intervals (95%CI) were calculated for aspirin intake and risk factors using Cox proportional hazard modeling. RESULTS: Of 118,548 participants, 15,793 consumed aspirin, and 4003 had cancer. Results indicated a significant protective effect of aspirin against colorectal (aHR: 0.7; 95%CI: 0.6-0.8), pancreatic (aHR: 0.5; 95%CI: 0.2-0.9), prostate (aHR: 0.6; 95%CI: 0.5-0.7) cancers and lymphomas (aHR: 0.5; 95%CI: 0.2-0.9), and also, although not significantly, against esophageal (aHR: 0.5; 95%CI: 0.2-1.8), stomach (aHR: 0.7; 95%CI: 0.4-1.3), liver (aHR: 0.7; 95%CI: 0.3-1.5), breast (aHR: 0.8; 95%CI: 0.6-1.0), and lung and bronchial (aHR: 0.9; 95%CI: 0.7-1.2) cancers. Aspirin intake was not significantly protective against leukemia (aHR: 1.0; 95%CI: 0.7-1.4) or bladder cancer (aHR: 1.0; 95%CI: 0.8-1.3). CONCLUSIONS: Our results suggest that aspirin intake is associated with a reduced incidence of colorectal, pancreatic, and prostate cancers and lymphomas.


Assuntos
Aspirina , Linfoma , Neoplasias , Humanos , Masculino , Aspirina/administração & dosagem , Estudos de Coortes , Linfoma/prevenção & controle , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias/prevenção & controle
2.
Artigo em Inglês | MEDLINE | ID: mdl-36901115

RESUMO

Excess weight, smoking and risky drinking are preventable risk factors for colorectal cancer (CRC). However, several studies have reported a protective association between aspirin and the risk of CRC. This article looks deeper into the relationships between risk factors and aspirin use with the risk of developing CRC. We performed a retrospective cohort study of CRC risk factors and aspirin use in persons aged >50 years in Lleida province. The participants were inhabitants with some medication prescribed between 2007 and 2016 that were linked to the Population-Based Cancer Registry to detect CRC diagnosed between 2012 and 2016. Risk factors and aspirin use were studied using the adjusted HR (aHR) with 95% confidence intervals (CI) using a Cox proportional hazard model. We included 154,715 inhabitants of Lleida (Spain) aged >50 years. Of patients with CRC, 62% were male (HR = 1.8; 95% CI: 1.6-2.2), 39.5% were overweight (HR = 2.8; 95% CI: 2.3-3.4) and 47.3% were obese (HR = 3.0; 95% CI: 2.6-3.6). Cox regression showed an association between aspirin and CRC (aHR = 0.7; 95% CI: 0.6-0.8), confirming a protective effect against CRC and an association between the risk of CRC and excess weight (aHR = 1.4; 95% CI: 1.2-1.7), smoking (aHR = 1.4; 95% CI: 1.3-1.7) and risky drinking (aHR = 1.6; 95% CI: 1.2-2.0). Our results show that aspirin use decreased the risk of CRC and corroborate the relationship between overweight, smoking and risky drinking and the risk of CRC.


Assuntos
Aspirina , Neoplasias Colorretais , Humanos , Masculino , Feminino , Aspirina/uso terapêutico , Sobrepeso/complicações , Estudos Retrospectivos , Neoplasias Colorretais/diagnóstico , Estudos de Coortes , Aumento de Peso , Etanol
3.
Temperature (Austin) ; 9(4): 306-309, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339094
4.
J Med Internet Res ; 24(7): e29056, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35852835

RESUMO

BACKGROUND: Previous works have shown that risk factors are associated with an increased likelihood of colorectal cancer. OBJECTIVE: The purpose of this study was to detect these associations in the region of Lleida (Catalonia) by using multiple correspondence analysis (MCA) and k-means. METHODS: This cross-sectional study was made up of 1083 colorectal cancer episodes between 2012 and 2015, extracted from the population-based cancer registry for the province of Lleida (Spain), the Primary Care Centers database, and the Catalan Health Service Register. The data set included risk factors such as smoking and BMI as well as sociodemographic information and tumor details. The relations between the risk factors and patient characteristics were identified using MCA and k-means. RESULTS: The combination of these techniques helps to detect clusters of patients with similar risk factors. Risk of death is associated with being elderly and obesity or being overweight. Stage III cancer is associated with people aged ≥65 years and rural/semiurban populations, while younger people were associated with stage 0. CONCLUSIONS: MCA and k-means were significantly useful for detecting associations between risk factors and patient characteristics. These techniques have proven to be effective tools for analyzing the incidence of some factors in colorectal cancer. The outcomes obtained help corroborate suspected trends and stimulate the use of these techniques for finding the association of risk factors with the incidence of other cancers.


Assuntos
Neoplasias Colorretais , Idoso , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Estudos Transversais , Humanos , Incidência , Fatores de Risco , Espanha/epidemiologia
5.
Cell Metab ; 34(2): 285-298.e7, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35108515

RESUMO

The central nervous system has long been thought to regulate insulin secretion, an essential process in the maintenance of blood glucose levels. However, the anatomical and functional connections between the brain and insulin-producing pancreatic ß cells remain undefined. Here, we describe a functional transneuronal circuit connecting the hypothalamus to ß cells in mice. This circuit originates from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT), and it reaches the islets of the endocrine pancreas via the sympathetic autonomic branch to innervate ß cells. Stimulation of PVNOXT neurons rapidly suppresses insulin secretion and causes hyperglycemia. Conversely, silencing of these neurons elevates insulin levels by dysregulating neuronal signaling and secretory pathways in ß cells and induces hypoglycemia. PVNOXT neuronal activity is triggered by glucoprivation. Our findings reveal that a subset of PVNOXT neurons form functional multisynaptic circuits with ß cells in mice to regulate insulin secretion, and their function is necessary for the ß cell response to hypoglycemia.


Assuntos
Células Secretoras de Insulina , Animais , Hipotálamo/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo
6.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326065

RESUMO

Bombesin receptor subtype-3 (BRS3) is an orphan receptor that regulates energy homeostasis. We compared Brs3 driver mice with constitutive or inducible Cre recombinase activity. The constitutive BRS3-Cre mice show a reporter signal (Cre-dependent tdTomato) in the adult brain because of lineage tracing in the dentate gyrus, striatal patches, and indusium griseum, in addition to sites previously identified in the inducible BRS3-Cre mice (including hypothalamic and amygdala subregions, and parabrachial nucleus). We detected Brs3 reporter expression in the dentate gyrus at day 23 but not at postnatal day 1 or 5 months of age. Hypothalamic sites expressed reporter at all three time points, and striatal patches expressed Brs3 reporter at 1 day but not 5 months. Parabrachial nucleus Brs3 neurons project to the preoptic area, hypothalamus, amygdala, and thalamus. Both Cre recombinase insertions reduced Brs3 mRNA levels and BRS3 function, causing obesity phenotypes of different severity. These results demonstrate that driver mice should be characterized phenotypically and illustrate the need for knock-in strategies with less effect on the endogenous gene.


Assuntos
Integrases , Receptores da Bombesina , Animais , Encéfalo/metabolismo , Hipotálamo/metabolismo , Integrases/genética , Integrases/metabolismo , Camundongos , Camundongos Transgênicos , Receptores da Bombesina/metabolismo
7.
Cell Metab ; 33(7): 1389-1403.e6, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34038711

RESUMO

The preoptic area (POA) is a key brain region for regulation of body temperature (Tb), dictating thermogenic, cardiovascular, and behavioral responses that control Tb. Previously characterized POA neuronal populations all reduced Tb when activated. Using mice, we now identify POA neurons expressing bombesin-like receptor 3 (POABRS3) as a population whose activation increased Tb; inversely, acute inhibition of these neurons reduced Tb. POABRS3 neurons that project to either the paraventricular nucleus of the hypothalamus or the dorsomedial hypothalamus increased Tb, heart rate, and blood pressure via the sympathetic nervous system. Long-term inactivation of POABRS3 neurons caused increased Tb variability, overshooting both increases and decreases in Tb set point, with RNA expression profiles suggesting multiple types of POABRS3 neurons. Thus, POABRS3 neuronal populations regulate Tb and heart rate, contribute to cold defense, and fine-tune feedback control of Tb. These findings advance understanding of homeothermy, a defining feature of mammalian biology.


Assuntos
Regulação da Temperatura Corporal , Frequência Cardíaca , Neurônios/fisiologia , Área Pré-Óptica/metabolismo , Receptores da Bombesina/metabolismo , Animais , Temperatura Corporal/genética , Regulação da Temperatura Corporal/genética , Frequência Cardíaca/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Área Pré-Óptica/citologia , Receptores da Bombesina/genética , Transdução de Sinais/genética , Sistema Nervoso Simpático/fisiologia , Termogênese/genética
8.
IEEE J Biomed Health Inform ; 25(9): 3659-3667, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33857006

RESUMO

BACKGROUND: Previous works have shown that risk factors for some kinds of cancer depend on people's lifestyle (e.g. rural or urban residence). This article looks into this, seeking relationships between cancer, age group, gender and population in the region of Lleida (Catalonia, Spain) using Multiple Correspondence Analysis (MCA). METHODS: The dataset analysed was made up of 3408 cancer episodes between 2012 and 2014, extracted from the Population-based Cancer Registry (PCR) for Lleida province. The cancers studied were colon and rectal (1059 cases), lung (551 cases), urinary bladder (446 cases), prostate (609 cases) and breast (743 cases). The MCA technique was applied and used to search relationships among the main qualitative features. The basic statistics were the percentage explaining (variance), the inertia and the contribution of each qualitative variable. RESULTS: General outcomes showed a low and moderate contribution of living in rural areas to colorectal and male prostate cancer. Males in urban areas were slightly and heavily affected by lung and urinary bladder cancer respectively. The analysis of each cancer provided additional information. Colorectal cancer greatly affected males aged <60, urban residents aged 70-79, and rural females aged ≥ 80. The impact of lung cancer was high among urban females <60, moderate among males aged 70-79 and high among rural females aged ≥ 80. The results for urinary bladder cancer results were similar to those for lung cancer. Prostate cancer affected both the <60 and ≥ 80 age groups significantly in rural areas. Breast cancer hit the 70-79 group significantly and, somewhat less so, rural females aged ≥ 80. CONCLUSIONS: MCA was a significant help for detecting the contributions of qualitative variables and the associations between them. MCA has proven to be an effective technique for analyzing the incidence of cancer. The outcomes obtained help to corroborate suspected trends, as well as detecting and stimulating new hypotheses about the risk factors associated with a specific area and cancer. These findings will be helpful for encouraging new studies and prevention campaigns to highlight observed singularities.


Assuntos
Neoplasias Pulmonares , Neoplasias da Próstata , Humanos , Incidência , Masculino , Fatores de Risco , População Rural
9.
PLoS One ; 15(12): e0243986, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33326493

RESUMO

Extracellular adenosine, a danger signal, can cause hypothermia. We generated mice lacking neuronal adenosine A1 receptors (A1AR, encoded by the Adora1 gene) to examine the contribution of these receptors to hypothermia. Intracerebroventricular injection of the selective A1AR agonist (Cl-ENBA, 5'-chloro-5'-deoxy-N6-endo-norbornyladenosine) produced hypothermia, which was reduced in mice with deletion of A1AR in neurons. A non-brain penetrant A1AR agonist [SPA, N6-(p-sulfophenyl) adenosine] also caused hypothermia, in wild type but not mice lacking neuronal A1AR, suggesting that peripheral neuronal A1AR can also cause hypothermia. Mice expressing Cre recombinase from the Adora1 locus were generated to investigate the role of specific cell populations in body temperature regulation. Chemogenetic activation of Adora1-Cre-expressing cells in the preoptic area did not change body temperature. In contrast, activation of Adora1-Cre-expressing dorsomedial hypothalamus cells increased core body temperature, concordant with agonism at the endogenous inhibitory A1AR causing hypothermia. These results suggest that A1AR agonism causes hypothermia via two distinct mechanisms: brain neuronal A1AR and A1AR on neurons outside the blood-brain barrier. The variety of mechanisms that adenosine can use to induce hypothermia underscores the importance of hypothermia in the mouse response to major metabolic stress or injury.


Assuntos
Hipotermia/metabolismo , Receptor A1 de Adenosina/metabolismo , Agonistas do Receptor A1 de Adenosina/farmacologia , Animais , Hipotálamo/metabolismo , Hipotálamo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nervos Periféricos/metabolismo , Nervos Periféricos/fisiopatologia
10.
Mol Metab ; 36: 100969, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32229422

RESUMO

OBJECTIVE: Bombesin-like receptor 3 (BRS3) is an orphan receptor and Brs3 knockout mice develop obesity with increased food intake and reduced resting metabolic rate and body temperature. The neuronal populations contributing to these effects were examined. METHODS: We studied energy metabolism in mice with Cre-mediated recombination causing 1) loss of BRS3 selectively in SIM1- or MC4R-expressing neurons or 2) selective re-expression of BRS3 from a null background in these neurons. RESULTS: The deletion of BRS3 in MC4R neurons increased body weight/adiposity, metabolic efficiency, and food intake, and reduced insulin sensitivity. BRS3 re-expression in these neurons caused partial or no reversal of these traits. However, these observations were confounded by an obesity phenotype caused by the Mc4r-Cre allele, independent of its recombinase activity. The deletion of BRS3 in SIM1 neurons increased body weight/adiposity and food intake, but not to the levels of the global null. The re-expression of BRS3 in SIM1 neurons reduced body weight/adiposity and food intake, but not to wild type levels. The deletion of BRS3 in either MC4R- or SIM1-expressing neurons affected body temperature, with re-expression in either population reversing the null phenotype. MK-5046, a BRS3 agonist, increases light phase body temperature in wild type, but not Brs3 null, mice and BRS3 re-expression in either population restored response to MK-5046. CONCLUSIONS: BRS3 in both MC4R- and SIM1-expressing neurons contributes to regulation of body weight/adiposity, insulin sensitivity, food intake, and body temperature.


Assuntos
Metabolismo Energético/fisiologia , Neurônios/metabolismo , Receptores da Bombesina/metabolismo , Adiposidade/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Temperatura Corporal/fisiologia , Peso Corporal , Encéfalo/metabolismo , Ingestão de Alimentos/fisiologia , Feminino , Homeostase/fisiologia , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Obesidade/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Receptores da Bombesina/genética , Proteínas Repressoras/metabolismo
11.
Cell Res ; 29(10): 785-786, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31471559
12.
Nat Neurosci ; 21(11): 1530-1540, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30349101

RESUMO

Bombesin-like receptor 3 (BRS3) is an orphan G-protein-coupled receptor that regulates energy homeostasis and heart rate. We report that acute activation of Brs3-expressing neurons in the dorsomedial hypothalamus (DMHBrs3) increased body temperature (Tb), brown adipose tissue temperature, energy expenditure, heart rate, and blood pressure, with no effect on food intake or physical activity. Conversely, activation of Brs3 neurons in the paraventricular nucleus of the hypothalamus had no effect on Tb or energy expenditure, but suppressed food intake. Inhibition of DMHBrs3 neurons decreased Tb and energy expenditure, suggesting a necessary role in Tb regulation. We found that the preoptic area provides major input (excitatory and inhibitory) to DMHBrs3 neurons. Optogenetic stimulation of DMHBrs3 projections to the raphe pallidus increased Tb. Thus, DMHBrs3→raphe pallidus neurons regulate Tb, energy expenditure, and heart rate, and Brs3 neurons in the paraventricular nucleus of the hypothalamus regulate food intake. Brs3 expression is a useful marker for delineating energy metabolism regulatory circuitry.


Assuntos
Temperatura Corporal/fisiologia , Núcleo Hipotalâmico Dorsomedial/metabolismo , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Frequência Cardíaca/fisiologia , Neurônios/metabolismo , Receptores da Bombesina/metabolismo , Animais , Masculino , Camundongos
13.
Am J Physiol Endocrinol Metab ; 315(3): E357-E366, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29812984

RESUMO

Intraperitoneal administration of the melanocortin agonist melanotan II (MTII) to mice causes a profound, transient hypometabolism/hypothermia. It is preserved in mice lacking any one of melanocortin receptors 1, 3, 4, or 5, suggesting a mechanism independent of the canonical melanocortin receptors. Here we show that MTII-induced hypothermia was abolished in KitW-sh/W-sh mice, which lack mast cells, demonstrating that mast cells are required. MRGPRB2 is a receptor that detects many cationic molecules and activates mast cells in an antigen-independent manner. In vitro, MTII stimulated mast cells by both MRGPRB2-dependent and -independent mechanisms, and MTII-induced hypothermia was intact in MRGPRB2-null mice. Confirming that MTII activated mast cells, MTII treatment increased plasma histamine levels in both wild-type and MRGPRB2-null, but not in KitW-sh/W-sh, mice. The released histamine produced hypothermia via histamine H1 receptors because either a selective antagonist, pyrilamine, or ablation of H1 receptors greatly diminished the hypothermia. Other drugs, including compound 48/80, a commonly used mast cell activator, also produced hypothermia by both mast cell-dependent and -independent mechanisms. These results suggest that mast cell activation should be considered when investigating the mechanism of drug-induced hypothermia in mice.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Hipotermia/induzido quimicamente , Mastócitos/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , alfa-MSH/análogos & derivados , Animais , Liberação de Histamina/efeitos dos fármacos , Liberação de Histamina/genética , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , alfa-MSH/farmacologia
15.
Mol Metab ; 6(11): 1540-1550, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29107299

RESUMO

OBJECTIVE: Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor. Brs3 null mice have reduced resting metabolic rate and body temperature, increased food intake, and obesity. Here we study the role of Brs3 in different neuron types. METHODS: Mice able to undergo Cre recombinase-dependent inactivation or re-expression of Brs3 were generated, respectively Brs3fl/y and Brs3loxTB/y. We then studied four groups of mice with Brs3 selectively inactivated or re-expressed in cells expressing Vglut2-Cre or Vgat-Cre. RESULTS: Deletion of Brs3 in glutamatergic neurons expressing Vglut2 reproduced the global null phenotype for regulation of food intake, metabolic rate, body temperature, adiposity, and insulin resistance. These mice also no longer responded to a BRS-3 agonist, MK-5046. In contrast, deletion of Brs3 in GABAergic neurons produced no detectable phenotype. Conversely, the wild type phenotype was restored by selective re-expression of Brs3 in glutamatergic neurons, with no normalization achieved by re-expressing Brs3 in GABAergic neurons. CONCLUSIONS: Brs3 expression in glutamatergic neurons is both necessary and sufficient for full Brs3 function in energy metabolism. In these experiments, no function was identified for Brs3 in GABAergic neurons. The data suggest that the anti-obesity pharmacologic actions of BRS-3 agonists occur via agonism of receptors on glutamatergic neurons.


Assuntos
Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Receptores da Bombesina/biossíntese , Adiposidade , Animais , Peso Corporal , Ingestão de Alimentos/fisiologia , Metabolismo Energético , Neurônios GABAérgicos/metabolismo , Expressão Gênica , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Obesidade/metabolismo , Pirazóis/farmacologia , Receptores da Bombesina/agonistas , Receptores da Bombesina/genética
16.
J Pharmacol Exp Ther ; 356(2): 474-82, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26606937

RESUMO

Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia.


Assuntos
Hipotermia/metabolismo , Receptor A3 de Adenosina/metabolismo , Receptores Histamínicos H1/metabolismo , Agonistas do Receptor A3 de Adenosina/farmacologia , Animais , Relação Dose-Resposta a Droga , Hipotermia/induzido quimicamente , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
17.
PLoS One ; 9(11): e112138, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25379676

RESUMO

Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2) expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV). We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs), neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection.


Assuntos
Tronco Encefálico/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Ocitocina/metabolismo , Animais , Tronco Encefálico/citologia , Células CHO , Cricetulus , Feminino , Hipotálamo/citologia , Masculino , Vias Neurais/citologia , Vias Neurais/metabolismo , Neurônios/citologia , Ocitocina/análise , Ratos Sprague-Dawley , Receptores de Ocitocina/análise , Receptores de Ocitocina/metabolismo
18.
Cell Metab ; 20(2): 333-45, 2014 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-24981835

RESUMO

The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r)-mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists, and MTII selectively activated arcuate nucleus dopaminergic neurons, suggesting that these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Receptores de Melanocortina/agonistas , alfa-MSH/análogos & derivados , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor Tipo 1 de Melanocortina/agonistas , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , Receptor Tipo 3 de Melanocortina/agonistas , Receptor Tipo 3 de Melanocortina/genética , Receptor Tipo 3 de Melanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismo , alfa-MSH/farmacologia
19.
Hypertension ; 64(3): 597-603, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24958501

RESUMO

Obstructive sleep apnea is associated with chronic intermittent hypoxia/hypercapnia (CIHH) episodes during sleep that heighten sympathetic and diminish parasympathetic activity to the heart. Although one population of neurons in the paraventricular nucleus of the hypothalamus strongly influences sympathetic tone and has increased activity after CIHH, little is known about the role of this pathway to parasympathetic neurons and how this network is altered in CIHH. We hypothesized that CIHH inhibits the excitatory pathway from the paraventricular nucleus of the hypothalamus to parasympathetic cardiac vagal neurons in the brain stem. To test this hypothesis, channelrhodopsin was selectively expressed, using viral vectors, in neurons in the paraventricular nucleus of the hypothalamus and channelrhodopsin-expressing fibers were photoactivated to evoke postsynaptic currents in cardiac vagal neurons in brain stem slices. Excitatory postsynaptic currents were diminished in animals exposed to CIHH. The paired-pulse and prolonged facilitation of the postsynaptic current amplitudes and frequencies evoked by paired and bursts of photoactivation of channelrhodopsin fibers, respectively, occurred in unexposed rats but were blunted in CIHH animals. In response to an acute challenge of hypoxia/hypercapnia, the amplitude of postsynaptic events was unchanged during, but increased after hypoxia/hypercapnia in unexposed animals. In contrast, postsynaptic currents were inhibited during hypoxia/hypercapnia in rats exposed to CIHH. In conclusion, the excitatory pathway to cardiac vagal neurons is diminished in response to both acute and chronic exposures to hypoxia/hypercapnia. This could elicit a reduced cardioprotective parasympathetic activity and an enhanced risk of adverse cardiovascular events in episodes of apnea and chronic obstructive sleep apnea.


Assuntos
Tronco Encefálico/fisiopatologia , Coração/inervação , Hipercapnia/fisiopatologia , Hipóxia/fisiopatologia , Sistema Nervoso Parassimpático/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Animais , Doenças Cardiovasculares/epidemiologia , Modelos Animais de Doenças , Feminino , Masculino , Proteínas do Tecido Nervoso/fisiologia , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Apneia Obstrutiva do Sono/fisiopatologia , Transmissão Sináptica/fisiologia
20.
J Neurosci ; 34(18): 6182-9, 2014 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-24790189

RESUMO

Locus ceruleus (LC) noradrenergic neurons are critical in generating alertness. In addition to inducing cortical arousal, the LC also orchestrates changes in accompanying autonomic system function that compliments increased attention, such as during stress, excitation, and/or exposure to averse or novel stimuli. Although the association between arousal and increased heart rate is well accepted, the neurobiological link between the LC and parasympathetic neurons that control heart rate has not been identified. In this study, we test directly whether activation of noradrenergic neurons in the LC influences brainstem parasympathetic cardiac vagal neurons (CVNs). CVNs were identified in transgenic mice that express channel-rhodopsin-2 (ChR2) in LC tyrosine hydroxylase neurons. Photoactivation evoked a rapid depolarization, increased firing, and excitatory inward currents in ChR2-expressing neurons in the LC. Photostimulation of LC neurons did not alter excitatory currents, but increased inhibitory neurotransmission to CVNs. Optogenetic activation of LC neurons increased the frequency of isolated glycinergic IPSCs by 27 ± 8% (p = 0.003, n = 26) and augmented GABAergic IPSCs in CVNs by 21 ± 5% (p = 0.001, n = 26). Inhibiting α1, but not α2, receptors blocked the evoked responses. Inhibiting ß1 receptors prevented the increase in glycinergic, but not GABAergic, IPSCs in CVNs. This study demonstrates LC noradrenergic neurons inhibit the brainstem CVNs that generate parasympathetic activity to the heart. This inhibition of CVNs would increase heart rate and risks associated with tachycardia. The receptors activated within this pathway, α1 and/or ß1 receptors, are targets for clinically prescribed antagonists that promote slower, cardioprotective heart rates during heightened vigilant states.


Assuntos
Tronco Encefálico/citologia , Locus Cerúleo/citologia , Neurônios/fisiologia , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Nervo Vago/fisiologia , Adrenérgicos/farmacologia , Vias Aferentes/fisiologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Channelrhodopsins , Glicina/farmacologia , Coração/inervação , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Optogenética , Técnicas de Patch-Clamp , Estimulação Luminosa , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
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