Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Mol Psychiatry ; 25(5): 1006-1021, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31485012

RESUMO

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.


Assuntos
Anedonia , Depressão/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Vias Neurais , Pró-Opiomelanocortina/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia
2.
Infect Immun ; 88(4)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32014896

RESUMO

Rickettsiae are cytosolically replicating, obligately intracellular bacteria causing human infections worldwide with potentially fatal outcomes. We previously showed that Rickettsia australis activates ASC inflammasome in macrophages. In the present study, host susceptibility of ASC inflammasome-deficient mice to R. australis was significantly greater than that of C57BL/6 (B6) controls and was accompanied by increased rickettsial loads in various organs. Impaired host control of R. australis in vivo in ASC-/- mice was associated with dramatically reduced levels of interleukin 1ß (IL-1ß), IL-18, and gamma interferon (IFN-γ) in sera. The intracellular concentrations of R. australis in bone marrow-derived macrophages (BMMs) of TLR4-/- and ASC-/- mice were significantly greater than those in BMMs of B6 controls, highlighting the important role of inflammasome and these molecules in controlling rickettsiae in macrophages. Compared to B6 BMMs, TLR4-/- BMMs failed to secrete a significant level of IL-1ß and had reduced expression levels of pro-IL-1ß in response to infection with R. australis, suggesting that rickettsiae activate ASC inflammasome via a Toll-like receptor 4 (TLR4)-dependent mechanism. Further mechanistic studies suggest that the lipopolysaccharide (LPS) purified from R. australis together with ATP stimulation led to cleavage of pro-caspase-1 and pro-IL-1ß, resulting in TLR4-dependent secretion of IL-1ß. Taken together, these observations indicate that activation of ASC inflammasome, most likely driven by interaction of TLR4 with rickettsial LPS, contributes to host protective immunity against R. australis These findings provide key insights into defining the interactions of rickettsiae with the host innate immune system.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Imunidade Inata , Inflamassomos/metabolismo , Rickettsia/imunologia , Rickettsiose do Grupo da Febre Maculosa/imunologia , Receptor 4 Toll-Like/metabolismo , Animais , Carga Bacteriana , Proteínas Adaptadoras de Sinalização CARD/deficiência , Células Cultivadas , Modelos Animais de Doenças , Suscetibilidade a Doenças , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/deficiência
3.
Sci Adv ; 8(3): eabk0185, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35044814

RESUMO

Estrogen receptor­α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERαvlVMH) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERαvlVMH neurons. We found that selective activation of ERαvlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERαvlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERαvlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HTDRN neurons mediate the stimulatory effects of ERαvlVMH neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERαvlVMH neurons is required for the maintenance of energy balance. Together, these findings support a model that ERαvlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HTDRN neurons.

4.
Front Endocrinol (Lausanne) ; 13: 889122, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120438

RESUMO

Pro-opiomelanocortin (POMC) neurons are important for the regulation of body weight and glucose balance. The inhibitory tone to POMC neurons is mediated primarily by the GABA receptors. However, the detailed mechanisms and functions of GABA receptors are not well understood. The α5 subunit of GABAA receptor, Gabra5, is reported to regulate feeding, and we found that Gabra5 is highly expressed in POMC neurons. To explore the function of Gabra5 in POMC neurons, we knocked down Gabra5 specifically from mature hypothalamic POMC neurons using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 strategy. This POMC-specific knock-down of Gabra5 did not affect body weight or food intake in either male or female mice. Interestingly, the loss of Gabra5 caused significant increases in the firing frequency and resting membrane potential, and a decrease in the amplitude of the miniature inhibitory postsynaptic current (mIPSC) in male POMC neurons. However, the loss of Gabra5 only modestly decreased the frequency of mIPSC in female POMC neurons. Consistently, POMC-specific knock-down of Gabra5 significantly improved glucose tolerance in male mice but not in female mice. These results revealed a sexually dimorphic role of Gabra5 in POMC neuron activity and glucose balance, independent of body weight control.


Assuntos
Glucose , Pró-Opiomelanocortina , Animais , Peso Corporal , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Pró-Opiomelanocortina/genética , Receptores de GABA-A
5.
Pathogens ; 10(7)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208806

RESUMO

Although rickettsiae can cause life-threatening infections in humans worldwide, no licensed vaccine is currently available. To evaluate the suitability of live-attenuated vaccine candidates against rickettsioses, we generated a Rickettsia parkeri mutant RPATATE_0245::pLoxHimar (named 3A2) by insertion of a modified pLoxHimar transposon into the gene encoding a phage integrase protein. For visualization and selection, R. parkeri 3A2 expressed mCherry fluorescence and resistance to spectinomycin. Compared to the parent wild type (WT) R. parkeri, the virulence of R. parkeri 3A2 was significantly attenuated as demonstrated by significantly smaller size of plaque, failure to grow in human macrophage-like cells, rapid elimination of Rickettsia and ameliorated histopathological changes in tissues in intravenously infected mice. A single dose intradermal (i.d.) immunization of R. parkeri 3A2 conferred complete protection against both fatal R. parkeri and R. conorii rickettsioses in mice, in association with a robust and durable rickettsiae-specific IgG antibody response. In summary, the disruption of RPATATE_0245 in R. parkeri resulted in a mutant with a significantly attenuated phenotype, potent immunogenicity and protective efficacy against two spotted fever group rickettsioses. Overall, this proof-of-concept study highlights the potential of R. parkeri mutants as a live-attenuated and multivalent vaccine platform in response to emergence of life-threatening spotted fever rickettsioses.

6.
Cell Rep ; 37(10): 110075, 2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34879284

RESUMO

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage.


Assuntos
Metabolismo Energético , Jejum/metabolismo , Comportamento Alimentar , Hipotálamo/metabolismo , Neurônios/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , Obesidade/metabolismo , Hipernutrição/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Ansiedade/psicologia , Modelos Animais de Doenças , Jejum/psicologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células HEK293 , Humanos , Hipotálamo/fisiopatologia , Masculino , Camundongos Knockout , Coativador 2 de Receptor Nuclear/genética , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/psicologia , Hipernutrição/genética , Hipernutrição/fisiopatologia , Hipernutrição/psicologia , Pró-Opiomelanocortina/genética , Resposta de Saciedade , Transdução de Sinais , Aumento de Peso
7.
Front Neurol ; 12: 734055, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35002913

RESUMO

Plasticity is often implicated as a reparative mechanism when addressing structural and functional brain development in young children following traumatic brain injury (TBI); however, conventional imaging methods may not capture the complexities of post-trauma development. The present study examined the cingulum bundles and perforant pathways using diffusion tensor imaging (DTI) in 21 children and adolescents (ages 10-18 years) 5-15 years after sustaining early childhood TBI in comparison with 19 demographically-matched typically-developing children. Verbal memory and executive functioning were also evaluated and analyzed in relation to DTI metrics. Beyond the expected direction of quantitative DTI metrics in the TBI group, we also found qualitative differences in the streamline density of both pathways generated from DTI tractography in over half of those with early TBI. These children exhibited hypertrophic cingulum bundles relative to the comparison group, and the number of tract streamlines negatively correlated with age at injury, particularly in the late-developing anterior regions of the cingulum; however, streamline density did not relate to executive functioning. Although streamline density of the perforant pathway was not related to age at injury, streamline density of the left perforant pathway was significantly and positively related to verbal memory scores in those with TBI, and a moderate effect size was found in the right hemisphere. DTI tractography may provide insight into developmental plasticity in children post-injury. While traditional DTI metrics demonstrate expected relations to cognitive performance in group-based analyses, altered growth is reflected in the white matter structures themselves in some children several years post-injury. Whether this plasticity is adaptive or maladaptive, and whether the alterations are structure-specific, warrants further investigation.

8.
Mol Metab ; 42: 101053, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32712433

RESUMO

OBJECTIVE: Estrogen protects animals from obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, the effects of estrogen on feeding behavior in hungry animals remain unclear. In this study, we examined the roles of 17ß-estradiol (E2) and ERα in the regulation of feeding in hungry female animals and explored the underlying mechanisms. METHODS: Wild-type female mice with surgical depletion of endogenous estrogens were used to examine the effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF20 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying acute feeding triggered by either fasting or central glucopenia (induced by intracerebroventricular injections of 2-deoxy-D-glucose). We also used electrophysiology to explore the impact of these ERα mutations on the neural activities of ERα neurons in the hypothalamus. RESULTS: In the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF20 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERα-C451A mutation consistently impaired the neural responses of hypothalamic ERα neurons to hypoglycemia. CONCLUSION: In addition to previous evidence that estrogen reduces deviations in energy balance by inhibiting eating at a satiated state, our findings demonstrate the unexpected role of E2 that promotes eating in hungry mice, also contributing to the stability of energy homeostasis. This latter effect specifically requires membrane-bound ERα activity.


Assuntos
Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Animais , Estradiol/fisiologia , Receptor alfa de Estrogênio/genética , Comportamento Alimentar/fisiologia , Feminino , Homeostase/efeitos dos fármacos , Fome/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade , Ovariectomia , Transdução de Sinais
9.
Nat Commun ; 11(1): 2165, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358493

RESUMO

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH to mpARH circuit and inhibition of ERαvlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERαvlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Glucose/metabolismo , Neurônios/metabolismo , Animais , Eletrofisiologia , Endocrinologia , Feminino , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real
10.
Metabolism ; 70: 152-159, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28403939

RESUMO

BACKGROUND: Brain estrogen receptor-α (ERα) is essential for estrogenic regulation of energy homeostasis and reproduction. We previously showed that ERα expressed by pro-opiomelanocortin (POMC) neurons mediates estrogen's effects on food intake, body weight, negative regulation of hypothalamic-pituitary-gonadal axis (HPG axis) and fertility. RESULTS AND CONCLUSIONS: We report here that global deletion of a key downstream receptor for POMC peptide, the melanocortin 4 receptor (MC4R), did not affect normal negative feedback regulation of estrogen on the HPG axis, estrous cyclicity and female fertility. Furthermore, loss of the MC4R did not influence estrogenic regulation on food intake and body weight. These results indicate that the MC4R is not required for estrogen's effects on metabolic and reproductive functions.


Assuntos
Estrogênios , Homeostase , Receptor Tipo 4 de Melanocortina/fisiologia , Reprodução , Animais , Peso Corporal , Ingestão de Alimentos , Metabolismo Energético , Retroalimentação Fisiológica , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Pró-Opiomelanocortina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA