RESUMO
Stress can play a significant role in arterial hypertension and many other complications of cardiovascular diseases. Considerable attention is paid to the study of the molecular mechanisms involved in the body response to stressful influences, but there are still many blank spots in understanding the details. ISIAH rats model the stress-sensitive form of arterial hypertension. ISIAH rats are characterized by genetically determined enhanced activities of the hypothalamic-pituitary-adrenocortical and sympathetic-adrenomedullary systems, suggesting a functional state of increased stress reactivity. For the first time, the temporal expression patterns of Fos and several related genes were studied in the hypothalamus of adult male hypertensive ISIAH rats after a single exposure to restraint stress for 30, 60, or 120 min. Fos transcription was activated and peaked 1 h after the start of restraint stress. The time course of Fos activation coincided with that of blood pressure increase after stress. Activation of hypothalamic neurons also alters the transcription levels of several transcription factor genes (Jun, Nr4a3, Jdp2, and Ppargc1a), which are associated with the development of cardiovascular diseases. Because Fos induction is a marker of brain neuron activation, activation of hypothalamic neurons and an increase in blood pressure were concluded to accompany increased stress reactivity of the hypothalamic-pituitary-adrenocortical and sympathoadrenal systems in hypertensive ISIAH rats during short-term restraint.
Assuntos
Regulação da Expressão Gênica , Hipertensão , Hipotálamo , Animais , Hipertensão/metabolismo , Hipertensão/genética , Hipertensão/patologia , Ratos , Hipotálamo/metabolismo , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Restrição Física , Estresse Psicológico/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Pressão Sanguínea/genética , Estresse Fisiológico/genética , Neurônios/metabolismo , Neurônios/patologiaRESUMO
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been the focus of recent studies of neurodegenerative disorders, including Parkinson's disease (PD). However, the specific mechanism of action of growth arrest-specific 5 (GAS5) in PD has not yet been characterized. First, the GSE8030 and GSE16658 datasets were analyzed to obtain differentially expressed genes (DEGs), followed by the development of a PD mouse model. The effects of shRNA targeting fos-like antigen-1 (shFosl1) and microRNA (miR)-150 agomiR on PD mouse behavior and neuronal injury were evaluated in vitro and in vivo. After the determination of target lncRNAs using bioinformatics tools, cell models were developed in SH-SY5Y and N2a cells using MPP+ to verify the effects of GAS5, miR-150 and Fosl1 on cell viability. Knockdown of Fosl1 and GAS5 or overexpression of miR-150 alleviated neuronal injury in mice after MPTP treatment and significantly increased the activity of SH-SY5Y and N2a cells after MPP treatment. GAS5 bound to miR-150, while miR-150 targeted Fosl1. Fosl1 activated the PTEN/AKT/mTOR pathway, thus promoting apoptosis and inhibiting neuronal activity in the PD model. Overall, our findings illuminated that GAS5 accelerated PD progression by targeting the miR-150/Fosl1 axis.
Assuntos
MicroRNAs/metabolismo , Neurônios/metabolismo , Transtornos Parkinsonianos/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neurônios/patologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Ligação Proteica/fisiologia , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/genética , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genéticaRESUMO
Arginine vasopressin (AVP) is expressed in both hypothalamic and extra-hypothalamic neurons. The expression and role of AVP exhibit remarkable divergence between these two neuronal populations. Polysynaptic pathways enable these neuronal groups to regulate each other. AVP neurons in the paraventricular nucleus of the hypothalamus increase the production of adrenal stress hormones by stimulating the hypothalamic-pituitary-adrenal axis. Outside the hypothalamus, the medial amygdala also contains robust amounts of AVP. Contrary to the hypothalamic counterpart, the expression of extra-hypothalamic medial amygdala AVP is sexually dimorphic, in that it is preferentially transcribed in males in response to the continual presence of testosterone. Male gonadal hormones typically generate a negative feedback on the neuroendocrine stress axis. Here, we investigated whether testosterone-responsive medial amygdala AVP neurons provide negative feedback to hypothalamic AVP, thereby providing a feedback loop to suppress stress endocrine response during periods of high testosterone secretion. Contrary to our expectation, we found that AVP overexpression within the posterodorsal medial amygdala increased the recruitment of hypothalamic AVP neurons during stress, without affecting the total number of AVP neurons or the number of recently activated neurons following stress. These observations suggest that the effects of testosterone on extra-hypothalamic AVP facilitate stress responsiveness through permissive influence on the recruitment of hypothalamic AVP neurons.
Assuntos
Arginina Vasopressina/fisiologia , Complexo Nuclear Corticomedial/fisiologia , Neurônios/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Retroalimentação Fisiológica/fisiologia , Genes fos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Camundongos , Odorantes , Núcleo Hipotalâmico Paraventricular/citologia , Sistema Hipófise-Suprarrenal/fisiologia , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Recombinantes/metabolismo , Testosterona/fisiologiaRESUMO
BACKGROUND: Previous finding using DNA microarray and bioinformatics analysis, we have reported some key factors which regulated gene expression and signaling pathways in injured sciatic nerve during Wallerian Degeneration (WD). This research is focused on protein kinase C theta (Prkcq) participates in the regulation of the WD process. METHODS: In this study, we explored the molecular mechanism by which Prkcq in Schwann cells (SCs) affects nerve degeneration and regeneration in vivo and in vitro after rat sciatic nerve injury. RESULTS: Study of the cross-sectional model showed that Prkcq expression decreased significantly during sciatic nerve repair. Functional analysis showed that upregulation and downregulation of Prkcq could affect the proliferation, migration and apoptosis of Schwann cells and lead to the expression of related factors through the activation of the ß-catenin, c-fos, and p-c-jun/c-jun pathways. CONCLUSION: The study provides insights into the role of Prkcq in early WD during peripheral nerve degeneration and/or regeneration.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/biossíntese , Degeneração Neural/metabolismo , Regeneração Nervosa/fisiologia , Proteína Quinase C-theta/biossíntese , Proteínas Proto-Oncogênicas c-fos/biossíntese , Neuropatia Ciática/metabolismo , Animais , Células Cultivadas , Masculino , Degeneração Neural/patologia , Ratos , Células de Schwann/metabolismo , Células de Schwann/patologia , Nervo Isquiático/lesões , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia , Neuropatia Ciática/patologia , Transdução de Sinais/fisiologiaRESUMO
Chronic stress is one of the main risk factors of bone loss. While the neurons and neural circuits of the ventromedial hypothalamus (VMH) mediate bone loss induced by chronic stress, the detailed intrinsic mechanisms within the VMH nucleus still need to be explored. Astrocytes in brain regions play important roles in the regulation of metabolism and anxiety-like behavior through interactions with surrounding neurons. However, whether astrocytes in the VMH affect neuronal activity and therefore regulate chronic stress-induced anxiety and bone loss remain elusive. In this study, we found that VMH astrocytes were activated during chronic stress-induced anxiety and bone loss. Pharmacogenetic activation of the Gi and Gq pathways in VMH astrocytes reduced and increased the levels of anxiety and bone loss, respectively. Furthermore, activation of VMH astrocytes by optogenetics induced depolarization in neighboring steroidogenic factor-1 (SF-1) neurons, which was diminished by administration of N-methyl-D-aspartic acid (NMDA) receptor blocker but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker. These results suggest that there may be a functional "glial-neuron microcircuit" in VMH nuclei that mediates anxiety and bone loss induced by chronic stress. This study not only advances our understanding of glial cell function but also provides a potential intervention target for chronic stress-induced anxiety and bone loss therapy.
Assuntos
Transtornos de Ansiedade/fisiopatologia , Astrócitos/fisiologia , Reabsorção Óssea/fisiopatologia , Estresse Psicológico/complicações , Núcleo Hipotalâmico Ventromedial/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Densidade Óssea , Reabsorção Óssea/etiologia , Reabsorção Óssea/prevenção & controle , Doença Crônica , Clozapina/farmacologia , Clozapina/uso terapêutico , Teste de Labirinto em Cruz Elevado , Emoções , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/agonistas , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Genes Reporter , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Teste de Campo Aberto , Optogenética , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Distribuição Aleatória , Receptores de N-Metil-D-Aspartato/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiopatologiaRESUMO
Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.
Assuntos
Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , MAP Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-fos/biossíntese , Neoplasias de Mama Triplo Negativas/metabolismo , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 5/antagonistas & inibidores , MAP Quinase Quinase 5/genética , Células MCF-7 , Proteínas Proto-Oncogênicas c-fos/genética , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
Antipsychotics, including amisulpride (AMI), quetiapine (QUE), aripiprazole (ARI), and olanzapine (OLA), are used to treat mental illnesses associated with psychotic symptoms. The effect of these drugs on c-Fos expression in vasopressinergic (AVP) and oxytocinergic (OXY) neurons was studied in the hypothalamic paraventricular nucleus (PVN) of rats. The presence of c-Fos in AVP and OXY perikarya was investigated in seven PVN cells segregations: the anterior (Ant), dorsal cup (Dc), wing-shaped (Wi), periventricular zone (Pe), circle-shaped core (Co) and shell of core (Sh), and the posterior (pPVN) after an acute treatment with AMI-20 mg/kg, QUE-15 mg/kg, ARI-10 mg/kg, and OLA-5 mg/kg/bw in rats. Ninety min after treatments, the animals were sacrificed by transcardial perfusion with fixative and the PVN area sliced into 35 µm thick coronal sections for immunohistochemistry. The c-Fos was processed by avidin-biotin-peroxidase complex intensified with nickel-enhanced 3,3'-diaminobenzidine tetrahydrochloride. Visualization of AVP- and OXY-synthesizing neurons was achieved by a fluorescent marker Alexa Flour 568. The c-Fos-AVP and c-Fos-OXY colocalizations were evaluated from c-Fos stained sections merged with AVP or OXY ones. AMI, QUE, ARI, and OLA, single administration distinctly increased the c-Fos expression in each of the PVN cells segregations. QUE induced the highest magnitude of activation of AVP and OXY neurons, while OLA and AMI had only moderate effects. Incontestable variabilities detected in c-Fos expression in PVN AVP and OXY neurons extend the knowledge of selected antipsychotics extra-striatal actions and may also be helpful in a presumption of their possible functional impact.
Assuntos
Amissulprida/farmacologia , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Neurônios/efeitos dos fármacos , Olanzapina/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/biossíntese , Fumarato de Quetiapina/farmacologia , Amissulprida/administração & dosagem , Animais , Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Corantes Fluorescentes/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos , Masculino , Neurônios/química , Neurônios/metabolismo , Olanzapina/administração & dosagem , Ocitocina/análise , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Fumarato de Quetiapina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Coloração e Rotulagem , Vasopressinas/análiseRESUMO
The rate of cesarean section (CS) delivery has steadily increased over the past decades despite epidemiological studies reporting higher risks of neonatal morbidity and neurodevelopmental disorders. Yet, little is known about the immediate impact of CS birth on the brain, hence the need of experimental studies to evaluate brain parameters following this mode of delivery. Using the solvent clearing method iDISCO and 3D imaging technique, we report that on the day of birth, whole-brain, hippocampus, and striatum volumes are reduced in CS-delivered as compared to vaginally-born mice, with a stronger effect observed in preterm CS pups. These results stress the impact of CS delivery, at term or preterm, during parturition and at birth. In contrast, cellular activity and apoptosis are reduced in mice born by CS preterm but not term, suggesting that these early-life processes are only impacted by the combination of preterm birth and CS delivery.
Assuntos
Encéfalo/anatomia & histologia , Cesárea/efeitos adversos , Parto Obstétrico/efeitos adversos , Nascimento Prematuro , Animais , Animais Recém-Nascidos , Apoptose , Química Encefálica , Caspase 3/metabolismo , Feminino , Idade Gestacional , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Masculino , Camundongos , Neostriado/anatomia & histologia , Neostriado/metabolismo , Gravidez , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
RATIONALE: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. OBJECTIVES: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. METHODS: Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. RESULTS: While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. CONCLUSIONS: While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.
Assuntos
Comportamento Animal/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Substituição de Aminoácidos , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Genótipo , Hipercinese/genética , Hipercinese/psicologia , Indóis/farmacologia , Masculino , Camundongos , Mutação/genética , Inibição Pré-Pulso/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Filtro Sensorial/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
Social isolation is a growing public health concern across the lifespan. Specifically, isolation early in life, during critical periods of brain development, increases the risk of psychiatric disorders later in life. Previous studies of isolation models in mice have shown distinct neurological abnormalities in various regions of the brain, but the mechanism linking the experience of isolation to these phenotypes is unclear. In this study, we show that ΔFosB, a long-lived transcription factor associated with neuronal activity, chronic stress, and drug-induced neuroplasticity, is upregulated in the prelimbic/infralimbic (PL/IL) region of the cortex and hippocampus of adult C57BL/6J mice transiently isolated for two weeks post-weaning. Additionally, a related transcription factor, FosB, is also increased in the PL/IL in socially isolated females.In contrast, both ΔFosB and FosB are increased in male mice isolated for six weeks from weaning until tissue collection. These results show that short-term isolation during the critical post-weaning period has long-lasting and sex-dependent effects on gene expression in brain and that FosB/ΔFosB expression provides a potential mechanistic link between post-weaning social isolation and associated neurological abnormalities.
Assuntos
Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Sistema Límbico/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Isolamento Social/psicologia , Desmame , Animais , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Caracteres SexuaisRESUMO
Immunoreceptors expressed on osteoclast precursor cells modify osteoclast differentiation and bone resorption activity. Dectin-1 is a lectin receptor of ß-glucan and is specifically expressed in osteoclast precursor cells. In this study, we evaluated the bioactivity of ß-glucan on receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and observed that glucan from baker's yeast inhibited this process in mouse bone marrow cells and dectin-1-overexpressing RAW264.7 (d-RAW) cells. In conjunction, RANKL-induced nuclear factor of activated T cell c1 expression was suppressed, subsequently downregulating TRAP and Oc-stamp. Additionally, nuclear factor-kappa B activation and the expression of c-fos and Blimp1 were reduced in d-RAW cells. Furthermore, glucan from baker's yeast induced the degradation of Syk protein, essential factor for osteoclastogenesis. These results suggest that glucan from baker's yeast suppresses RANKL-induced osteoclastogenesis and can be applied as a new treatment strategy for bone-related diseases.
Assuntos
Lectinas Tipo C/metabolismo , Osteoclastos/citologia , Osteogênese/fisiologia , Ligante RANK/metabolismo , Saccharomyces cerevisiae/metabolismo , beta-Glucanas/metabolismo , Animais , Reabsorção Óssea/patologia , Linhagem Celular , Proteínas de Membrana/metabolismo , Camundongos , Fator 1 de Ligação ao Domínio I Regulador Positivo/biossíntese , Proteínas Proto-Oncogênicas c-fos/biossíntese , Células RAW 264.7 , Fosfatase Ácida Resistente a Tartarato/metabolismoRESUMO
Although ventrolateral preoptic (VLPO) nucleus is regarded as a center for sleep promotion, the exact mechanisms underlying the sleep regulation are unknown. Here, we used optogenetic tools to identify the key roles of VLPO astrocytes in sleep promotion. Optogenetic stimulation of VLPO astrocytes increased sleep duration in the active phase in naturally sleep-waking adult male rats (n = 6); it also increased the extracellular ATP concentration (n = 3) and c-Fos expression (n = 3-4) in neurons within the VLPO. In vivo microdialysis analyses revealed an increase in the activity of VLPO astrocytes and ATP levels during sleep states (n = 4). Moreover, metabolic inhibition of VLPO astrocytes reduced ATP levels (n = 4) and diminished sleep duration (n = 4). We further show that tissue-nonspecific alkaline phosphatase (TNAP), an ATP-degrading enzyme, plays a key role in mediating the somnogenic effects of ATP released from astrocytes (n = 5). An appropriate sample size for all experiments was based on statistical power calculations. Our results, taken together, indicate that astrocyte-derived ATP may be hydrolyzed into adenosine by TNAP, which may in turn act on VLPO neurons to promote sleep.SIGNIFICANCE STATEMENT Glia have recently been at the forefront of neuroscience research. Emerging evidence illustrates that astrocytes, the most abundant glial cell type, are the functional determinants for fates of neurons and other glial cells in the central nervous system. In this study, we newly identified the pivotal role of hypothalamic ventrolateral preoptic (VLPO) astrocytes in the sleep regulation, and provide novel insights into the mechanisms underlying the astrocyte-mediated sleep regulation.
Assuntos
Astrócitos/fisiologia , Área Pré-Óptica/fisiologia , Sono/fisiologia , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Fosfatase Alcalina/biossíntese , Fosfatase Alcalina/genética , Animais , Citocinas/metabolismo , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Neurotransmissores/metabolismo , Optogenética , Técnicas de Patch-Clamp , Estimulação Luminosa , Área Pré-Óptica/citologia , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: Accumulating evidence suggests that ayahuasca, a hallucinogenic beverage used in traditional Amazonian communities for ritualistic and curative purposes, has been associated with reduced rates of substance use disorders. However, the brain mechanisms underlying the therapeutic effects of ayahuasca have not yet been fully elucidated. OBJECTIVES: The aim of the present study was to investigate the effects of treatment with ayahuasca on the rewarding properties of the psychostimulant methylphenidate. METHODS: The rewarding properties of ayahuasca (100 mg/kg, orally) and methylphenidate (10 mg/kg, i.p.) were investigated using the conditioned place preference (CPP) model. Furthermore, we evaluated the effects of repeated treatment with ayahuasca on the reinstatement of methylphenidate-induced CPP. Fos expression was evaluated in different limbic structures (cingulate cortex-area 1, prelimbic cortex, infralimbic cortex, orbitofrontal cortex-lateral orbital area, nucleus accumbens core and shell, ventral tegmental area, dorsal striatum, and basolateral amygdala) upon each experimental phase. RESULTS: Both ayahuasca and methylphenidate induced CPP in mice. However, ayahuasca had limited effects on Fos expression, while methylphenidate altered Fos expression in several brain regions associated with the behavioral effects of drugs of abuse. Treatment with ayahuasca after conditioning with methylphenidate blocked the reinstatement of methylphenidate-induced CPP. Those behavioral effects were accompanied by changes in Fos expression patterns, with ayahuasca generally blocking the changes in Fos expression induced by conditioning with methylphenidate and/or reexposure to methylphenidate. CONCLUSIONS: Our findings suggest that ayahuasca restored normal brain function in areas associated with the long-term expression of drug wanting/seeking in animals conditioned to methylphenidate.
Assuntos
Banisteriopsis , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Metilfenidato/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/biossíntese , Administração Oral , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Condicionamento Clássico/fisiologia , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Expressão Gênica , Alucinógenos/administração & dosagem , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/genéticaRESUMO
Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus (DEPN) which has been recognized as an epileptogenic zone. We generated a forebrain-specific Ctgf knockout (FbCtgf KO) mouse line in which the expression of Ctgf in the DEPN is eliminated. In this study, we adopted a pentylenetetrazole (PTZ)-induced seizure model and found similar severity and latencies to death between FbCtgf KO and WT mice. Interestingly, there was a delay in the seizure reactions in the mutant mice. We further observed reduced c-fos expression subsequent to PTZ treatment in the KO mice, especially in the hippocampus. While the densities of astrocytes and microglia in the hippocampus were kept constant after acute PTZ treatment, microglial morphology was different between genotypes. Our present study demonstrated that in the FbCtgf KO mice, PTZ failed to increase neuronal activity and microglial response in the hippocampus. Our results suggested that inhibition of Ctgf function may have a therapeutic potential in preventing the pathophysiology of epilepsy.
Assuntos
Astrócitos/fisiologia , Fator de Crescimento do Tecido Conjuntivo/deficiência , Genes fos , Microglia/fisiologia , Prosencéfalo/metabolismo , Convulsões/fisiopatologia , Animais , Astrócitos/efeitos dos fármacos , Contagem de Células , Claustrum/efeitos dos fármacos , Claustrum/metabolismo , Fator de Crescimento do Tecido Conjuntivo/fisiologia , Convulsivantes/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Pentilenotetrazol/toxicidade , Prosencéfalo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Convulsões/induzido quimicamente , Convulsões/genética , Convulsões/patologiaRESUMO
Electroacupuncture (EA) is widely used as an effective method to treat stress-related disorders. However, its mechanisms remain largely unknown. The aim of this study was to investigate the effects and mechanisms of EA on gastric slow wave (GSW) dysrhythmia and c-Fos expression in the nucleus of the solitary tract (NTS) induced by stress in a rodent model of functional dyspepsia (FD). Rats in the neonatal stage were treated using intragastric iodoacetamide. Eight weeks later, the rats were implanted with electrodes in the stomach for the measurement of GSW and electrodes into accupoints ST36 for EA. Autonomic functions were assessed by spectral analysis of heart rate variability. Rats were placed for 30 min in a cylindrical plastic tube for acute restraint stress. The involvement of a central afferent pathway was assessed by measuring c-Fos-immunoreactive cells in the NTS. 1) EA normalized restraint stress-induced impairment of GSW in FD rats. 2) EA significantly increased vagal activity (P = 0.002) and improved sympathovagal balance (P = 0.004) under stress in FD rats. 3) In FD rats under restraint stress, plasma norepinephrine concentration was increased substantially (P < 0.01), which was suppressed with EA. 4) The EA group showed increased c-Fos-positive cell counts in the NTS compared with the sham EA group (P < 0.05) in FD rats. Acute restraint stress induces gastric dysrhythmia in a rodent model of FD. EA at ST36 improves GSW under stress in FD rats mediated via the central and autonomic pathways, involving the NTS and vagal efferent pathway.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Dispepsia/fisiopatologia , Dispepsia/terapia , Eletroacupuntura , Gastropatias/terapia , Estresse Psicológico/complicações , Vias Aferentes/fisiopatologia , Animais , Animais Recém-Nascidos , Esvaziamento Gástrico , Iodoacetamida , Masculino , Norepinefrina/sangue , Proteínas Proto-Oncogênicas c-fos/biossíntese , Ratos , Ratos Sprague-Dawley , Restrição Física , Núcleo Solitário/metabolismo , Gastropatias/induzido quimicamente , Nervo Vago/fisiopatologiaRESUMO
The purpose of this study was to investigate the therapeutic effects of focused ultrasound on the expression of notch1, c-fos and transforming growth factor-ß3 (TGF-ß3) in genital skin of SD rats with vulvar lichen simplex chronicus (LSC). Fifty-six female SD rats with LSC were randomly divided into therapy and sham groups. The therapy group was exposed to focused ultrasound. The sham group received the same therapy with an instrument that had no power output. Four wk after a singly focused ultrasound therapy, histologic analyses revealed that recovered SD rats accounted for 75% of SD rats in the therapy group and 10.7% in the sham group. Total collagen fiber density in the superficial layer of dermis in the therapy group was significantly lower than that in the sham group. Notch1 and c-fos protein expression in the therapy group was significantly lower than that in the sham group, with the opposite effect present for TGF-ß3. Focused ultrasound therapy may inhibit superficial collagen fibrosis in the dermis by affecting expression of notch1, c-fos and TGF-ß3 in vulvar skin tissue and consequently reduce the recurrence rate of LSC.
Assuntos
Ablação por Ultrassom Focalizado de Alta Intensidade , Neurodermatite/metabolismo , Neurodermatite/terapia , Proteínas Proto-Oncogênicas c-fos/biossíntese , Receptor Notch1/biossíntese , Pele/metabolismo , Fator de Crescimento Transformador beta3/biossíntese , Vulva/metabolismo , Animais , Feminino , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
Toll-like receptor 2 (TLR2) recognizes a wide range of microbial molecules and plays critical roles in the initiation of innate immune responses. In the present study, we aimed to investigate whether the depletion of microglia and macrophages with clodronate liposomes (Clod-Lips) attenuates the activation of mouse brain circuits for TLR2-mediated inflammation and hypothermia. The peripheral administration of the TLR2 agonist zymosan induced nuclear factor-κB activation in microglia and macrophages and Fos expression in astrocytes/tanycytes and neurons in the circumventricular organs (CVOs). The depletion of microglia and macrophages with Clod-Lips markedly decreased zymosan-induced Fos expression in astrocytes/tanycytes and neurons in the CVOs. The treatment with Clod-Lips significantly attenuated zymosan-induced hypothermia. These results indicate that microglia and macrophages in the CVOs participate in the initiation and transmission of inflammatory responses after the peripheral administration of zymosan.
Assuntos
Ácido Clodrônico/administração & dosagem , Hipotermia/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Zimosan/toxicidade , Fatores Etários , Animais , Conservadores da Densidade Óssea/administração & dosagem , Portadores de Fármacos/administração & dosagem , Expressão Gênica , Hipotermia/induzido quimicamente , Hipotermia/prevenção & controle , Lipossomos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/metabolismoRESUMO
Aging represents the largest risk factor for developing Parkinson's disease (PD); another salient feature of this disorder is a decreased brain levels of somatostatin. Recently, in aged Wistar rats, we simulated the central somatostatinergic deficiency by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin (cSST). The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease; young animals were insensitive to cSST. The neuroanatomical substrates responsible for the increased cataleptogenic activity of cSST in aged animals, are currently unknown. To study this issue, we assessed the cSST effect on brain c-Fos-protein expression in aged and young rats; thirty three brain regions were examined. cSST was employed at the dose cataleptogenic for aged animals and non-cataleptogenic for young ones. c-Fos expression patterns in the 'cataleptic' and 'non-cataleptic' animals were very similar, with the only distinction being a decrease in the c-Fos expression in the aged lateral entorhinal cortex (LEntCx). This decrease was not observed when the cSST-induced cataleptic response was inhibited by administration of diphenhydramine and nicotine. Thus, the development of catalepsy in the aged Wistar rats appeared to be associated with a hypoactivation of the LEntCx; possibly, there exists a mechanistic link between the LEntCx hypoactivation and increased susceptibility of aged rats to catalepsy. Apparently, these findings may provide novel insight into the link between mechanisms of parkinsonian motor disorders and aging.
Assuntos
Envelhecimento/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/metabolismo , Córtex Entorrinal/metabolismo , Peptídeos Cíclicos/toxicidade , Proteínas Proto-Oncogênicas c-fos/biossíntese , Envelhecimento/efeitos dos fármacos , Animais , Córtex Entorrinal/efeitos dos fármacos , Expressão Gênica , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos WistarRESUMO
Objectives: FOSL1 is overexpressed in multiple cancers including malignant glioma and contributes to different cellular processes. However, little attention has been paid to the lower grade glioma (LGG).Methods: Cox coefficients were examined to compare FOSL1 expression among different tumors types using OncoLnc. The UCSC Xena browser was used to generate Kaplan-Meier survival curves and explore the association between FOSL1 expression and overall survival (OS) in TCGA-LGG and subgroups.Results: FOSL1 expression in LGG was ranked first among 21 different cancers. LGG with lower FOSL1 expression had longer OS (P < 0.001). The astrocytoma group had the highest FOSL1 expression and shortest OS, followed by oligoastrocytoma and oligodendroglioma (P < 0.05). The 1p19q co-deletion or IDH mutation subgroups had lower FOSL1 expression and longer OS (P < 0.001). Compared with the corresponding groups, LGG with lower FOSL1 expression had longer OS than the following groups: astrocytoma, oligodendroglioma, with/without 1p19q co-deletion, with IDH mutation, with radiation, and with pharmaceutical therapy (P < 0.05).Discussion: FOSL1 is a prognostic marker in LGG and subgroups.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Glioma/patologia , Proteínas Proto-Oncogênicas c-fos/biossíntese , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Glioma/metabolismo , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Tolerância a Radiação/fisiologiaRESUMO
Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits.