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Many experts have extensively studied the potential of exercise as a treatment option for psychiatric conditions, including depression and autism spectrum disorder (ASD). Despite their core symptoms, these conditions exhibits comparable component traits, an anxiety. In this study, we explored the effect of exercise on behavioral abnormalities in psychiatric conditions, focusing on its intensity and emotional resilience. Shank3B knockout (KOSED) mice displaying self-injurious repetitive behavior and C57BL/6J mice, susceptible to stress as ASD and depression model, respectively, were subjected to moderate-intensity exercise (ME) for 2 weeks. ME mitigated the core symptoms (excessive grooming traits and behavioral despair) but did not exert a significant anxiolytic effect. Notably, exercise intensity has emerged as a critical determinant of its efficacy, as evidenced by a lower ventilation threshold and anxiolytic effect mediated by low-intensity exercise. The findings substantiate the notion that exercise is promising as a disease-modifying treatment, but intensity matters for emotional resilience.
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Ansiedade , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Animais , Ansiedade/terapia , Condicionamento Físico Animal/fisiologia , Camundongos , Masculino , Transtorno do Espectro Autista/terapia , Transtorno do Espectro Autista/psicologia , Comportamento Animal/fisiologia , Camundongos Knockout , Depressão/terapia , Depressão/psicologia , Modelos Animais de Doenças , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismoRESUMO
Glucocorticoids (GCs) have a wide spectrum of effects on animal behavior. A recently suggested effect involves determining the structure of individual differences, that is how the behavioral traits of an individual covary, forming the so-called behavioral syndromes. As GCs can exert their action in multiple ways, e.g., via rapid non-genomic effects or via the activation of two highly homologous members of the steroid receptor family acting as transcription factors, it is unclear how the GC modulation of behavioral syndromes takes place. We exploited a zebrafish line with a frameshift mutation in the gene encoding the GC receptor (Gr), to investigate this question. We found that lack of Gr altered the average score of several behavioral traits in the mutant line, determining reduced boldness, and increased activity and sociability. Critically, the pattern of covariation between these traits was also substantially affected by the loss of Gr. The most evident effect was an association of traits involved in boldness in the gr mutant line. This study reveals that, in zebrafish, Gr is not only involved in the modulation of the average value of behavioral traits, but also in how the behavioral traits of an individual are interrelated and determine the behavioral syndromes.
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Deficiencies in maternal nutrition have long-term consequences affecting brain development of the progeny and its behavior. In the present work, female mice were exposed to a normal-protein or a low-protein diet during gestation and lactation. We analyzed behavioral and molecular consequences of malnutrition in dams and how it affects female offspring at weaning. We have observed that a low-protein diet during pregnancy and lactation leads to anxiety-like behavior and anhedonia in dams. Protein malnutrition during the perinatal period delays physical and neurological development of female pups. Glucocorticoid levels increased in the plasma of malnourished female offspring but not in dams when compared to the control group. Interestingly, the expression of glucocorticoid receptor (GR) was reduced in hippocampus and amygdala on both malnourished dams and female pups. In addition, malnourished pups exhibited a significant increase in the expression of Dnmt3b, Gadd45b, and Fkbp5 and a reduction in Bdnf VI variant mRNA in hippocampus. In contrast, a reduction on Dnmt3b has been observed on the amygdala of weaned mice. No changes have been observed on global methylation levels (5-methylcytosine) in hippocampal genomic DNA neither in dams nor female offspring. In conclusion, deregulated behaviors observed in malnourished dams might be mediated by a low expression of GR in brain regions associated with emotive behaviors. Additionally, low-protein diet differentially deregulates the expression of genes involved in DNA methylation/demethylation machinery in female offspring but not in dams, providing an insight into regional- and age-specific mechanisms due to protein malnutrition.
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Chronic treatment with clomipramine, a tricyclic antidepressant drug, reduces symptoms of obsessive-compulsive disorder (OCD) and can influence the activity of the hypothalamic-pituitary-adrenal axis. However, little is known regarding the effects of acute clomipramine on the immediate expression of stress responses. Serotonergic drugs can elicit surfacing, a behavioral profile potentially related to toxicity in fish, although surfacing has not yet been observed after clomipramine exposure. The present study investigated the impact of acute exposure to clomipramine on basal and stress-induced behaviors in the novel tank test and cortisol levels in mixed-sex, wild-type, adult zebrafish (Danio rerio). The findings show clomipramine-exposed groups (regardless of stress exposure) spent much more time in the top of the novel tank and had significantly less overall motor activity in the behavioral task compared to the fish not exposed to the drug. Then, the dose-dependent effects of acute clomipramine on activity in the surface of the novel tank (top third of the top half) were investigated further. Clomipramine dose-dependently increased surface-dwelling and elicited a dose-dependent hypoactivity in overall motor behavior. There were no statistically significant differences in whole-body cortisol levels in either experiment. Like other serotonin-acting drugs, clomipramine strongly elicited surface-dwelling and depressed motor behavior in adult zebrafish. Additional testing is needed to elucidate whether surfacing represents a toxic state and how serotonin regulates surfacing.
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Comportamento Animal , Clomipramina , Relação Dose-Resposta a Droga , Hidrocortisona , Peixe-Zebra , Animais , Clomipramina/farmacologia , Clomipramina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Hidrocortisona/metabolismo , Masculino , Feminino , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagemRESUMO
Bisphenol S (BPS) and Bisphenol F (BPF), the analogues of the legacy endocrine disrupting chemical, Bisphenol A (BPA) are ubiquitous in the environment and present in various consumer goods, and potentially neurotoxic. Here, we studied sex-specific responses of bisphenols on behavioural phenotypes, including their association with pro-inflammatory biomarkers and altered neurotransmitters levels, and the key gut microbial abundances. Neurobehavioural changes, using standard test battery, biochemical and molecular estimations for inflammatory cytokines, neurotransmitters, and oxido-nitrosative stress markers, gene expression analysis using qRT-PCR, H&E based histological investigations, gut permeability assays and Oxford Nanopore-based 16S-rRNA metagenomics sequencing for the gut microbial abundance estimations were performed. Bisphenol(s) exposure induces anxiety and depression-like behaviours, particularly in the male mice, with heightened pro-inflammatory cytokines levels and systemic endotoxemia, altered monoamine neurotransmitters levels/turnovers and hippocampal neuronal degeneration and inflammatory responses in the brain. They also increased gut permeability and altered microbial diversity, particularly in males. Present study provides evidence for sex-specific discrepancies in neurobehavioural phenotypes and gut microbiota, which necessitate a nuanced understanding of sex-dependent responses to bisphenols. The study contributes to ongoing discussions on the multifaceted implications of bisphenols exposure and underscores the need for tailored regulatory measures to mitigate potential health risks associated with them.
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Comportamento Animal , Compostos Benzidrílicos , Disruptores Endócrinos , Microbioma Gastrointestinal , Fenóis , Caracteres Sexuais , Sulfonas , Animais , Fenóis/toxicidade , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Feminino , Compostos Benzidrílicos/toxicidade , Sulfonas/toxicidade , Disruptores Endócrinos/toxicidade , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Fenótipo , Camundongos , Camundongos Endogâmicos C57BL , Ansiedade/induzido quimicamente , Depressão/induzido quimicamente , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Neurotransmissores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismoRESUMO
Binge drinking causes a range of problems especially damage to the nervous system, and the specific neural mechanism of brain loss and behavioral abnormalities caused by which is still unclear. Extracellular regulated protein kinases (ERK) maintain neuronal survival, growth, and regulation of synaptic plasticity by phosphorylating specific transcription factors to regulate expression of brain-derived neurotrophic factor (BDNF). Dual-specific phosphatase 1 (DUSP1) and DUSP6 dephosphorylate tyrosine and serine/threonine residues in ERK1/2 to inactivate them. To investigate the molecular mechanism by which alcohol affects memory and emotion, a chronic intermittent alcohol exposure (CIAE) model was established. The results demonstrated that mice in the CIAE group developed short-term recognition memory impairment and anxiety-like behavior; meanwhile, the expression of DUSP1 and DUSP66 in the mPFC was increased, while the levels of p-ERK and BDNF were decreased. Micro-injection of DUSP1/6 inhibitor BCI into the medial prefrontal cortex (mPFC) restored the dendritic morphology by reversing the activity of ERK-BDNF and ultimately improved cognitive and emotional impairment caused by CIAE. These findings indicate that CIAE inhibits ERK-BDNF by increasing DUSP1/6 in the mPFC that may be associated with cognitive and emotional deficits. Consequently, DUSP1 and DUSP6 appear to be potential targets for the treatment of alcoholic brain disorders.
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Fator Neurotrófico Derivado do Encéfalo , Fosfatase 1 de Especificidade Dupla , Etanol , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Camundongos , Masculino , Fosfatase 1 de Especificidade Dupla/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Etanol/toxicidade , Etanol/farmacologia , Fosfatase 6 de Especificidade Dupla/metabolismo , Fosfatase 6 de Especificidade Dupla/genética , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/farmacologia , Aminoacetonitrila/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Sistema de Sinalização das MAP QuinasesRESUMO
Ulcerative colitis (UC) is a common inflammatory bowel disease with a complex origin in clinical settings. It is frequently accompanied by negative emotional responses, including anxiety and depression. Enteric glial cells (EGCs) are important components of the gut-brain axis and are involved in the development of the enteric nervous system (ENS), intestinal neuroimmune, and regulation of intestinal motor functions. Since there is limited research encompassing the regulatory function of EGCs in anxiety- and depression-like behaviors induced by UC, this study aims to reveal their regulatory role in such behaviors and associated intestinal inflammation. This study applied morphological, molecular biological, and behavioral methods to observe the morphological and functional changes of EGCs in UC mice. The results indicated a significant activation of EGCs in the ENS of dextran sodium sulfate -induced UC mice. This activation was evidenced by morphological alterations, such as elongation or terminal swelling of processes. Besides EGCs activation, UC mice exhibited significantly elevated expression levels of pro-inflammatory cytokines in the peripheral blood, accompanied by anxiety- and depression-like behaviors. The inhibition of EGCs activity within the ENS can ameliorate the anxiety- and depression-like behaviors caused by UC. Our data suggest that UC and its resulting behaviors may be related to the activation of EGCs within the ENS. Moreover, the modulation of intestinal inflammation through inhibition of EGCs activation emerges as a promising clinical approach for alleviating UC-induced anxiety- and depression-like behaviors.
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Ansiedade , Colite Ulcerativa , Depressão , Neuroglia , Animais , Colite Ulcerativa/psicologia , Colite Ulcerativa/patologia , Colite Ulcerativa/metabolismo , Ansiedade/psicologia , Ansiedade/metabolismo , Depressão/metabolismo , Depressão/psicologia , Neuroglia/metabolismo , Neuroglia/patologia , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Sulfato de Dextrana/toxicidade , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/patologia , Inflamação/metabolismo , Inflamação/patologia , Comportamento AnimalRESUMO
Aggressiveness, expressed by fighting, is a frequent problem in group-housed laboratory male mice and results in increased stress, injury, and death. One way to prevent fighting is by pairing the male mice with ovariectomized female mice to provide a compatible companion. However, the effect of these housing conditions remains unclear. Therefore, we aimed to evaluate behavior and stress levels in two different housing conditions, pair-housed with an ovariectomized female and group-housed with other males. Behavioral tests were performed to assess stress and anxiety-like behavior. Moreover, the corticosterone levels in plasma were measured by ELISA. Based on home cage behavior assessment, pair-housed male mice showed no signs of fighting, not even after isolation and regrouping. Our results also showed that the pair-housed males had a better memory and demonstrated less anxiety-like behavior. Subsequently, the pair-housed male mice had a larger reduction in corticosterone levels compared to group-housed males. Overall, pair-housing reduced anxiety-like behavior and stress levels in male mice compared to standard group-housing.
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BACKGROUND: Anxiety is an adaptive response to potentially threatening conditions. Excessive and uncontrolled anxiety responses become nonadaptive and cause anxiety disorders. To better understand the anxiety-modulating effects of Mg sulfate, behavioral test batteries in the assessment of anxiety and learning and memory functions were performed simultaneously over a time period. This study also examines the effects of Mg sulfate compared to diazepam, an anxiolytic drug with amnestic effects on anxiety-like behavior, as well as possible oxidative-nitrosative stress and hippocampal changes in male rats exposed to predator odor. METHODS: Young adult Sprague-Dawley male rats were used. The rats were assessed using a comprehensive neurobehavioral test battery consisting of novel object recognition, open field, and successive alleys tasks. Anxiety was induced by cat odor, and diazepam and Mg were used as study drugs. Of the frontal cortex and hippocampus, the state of total oxidant and antioxidant and NO levels and histological examination of hippocampal CA1, CA2, CA3, and DG regions were performed. RESULTS: Diazepam- and Mg-treated rats showed an improvement in anxiety-related behavior to predator odors. Furthermore, Mg treatment alleviated some of the increasing oxidative stress in the frontal cortex and hippocampus of rats, while diazepam treatment in particular enhanced hippocampal oxidant and antioxidant activity. In addition, brain NO increase induced by animal odor exposure or diazepam treatment was ameliorated by Mg administration. CONCLUSIONS: Overall, our work suggests that Mg had a partial anxiolytic effect on anxiety-like behaviors, although not as much as diazepam, and this effect varied depending on the dose. Mg treatment might counteract increased oxidative stress and elevated NO levels in the brain.
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Ansiolíticos , Ansiedade , Diazepam , Modelos Animais de Doenças , Sulfato de Magnésio , Ratos Sprague-Dawley , Animais , Masculino , Ansiedade/tratamento farmacológico , Diazepam/farmacologia , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Sulfato de Magnésio/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Memória/efeitos dos fármacos , Óxido Nítrico/metabolismo , OdorantesRESUMO
Pregnancy is associated with neural and behavioral plasticity, systemic inflammation, and oxidative stress, yet the impact of inflammation and oxidative stress on maternal neural and behavioral plasticity during pregnancy is unclear. We hypothesized that healthy pregnancy transiently reduces learning and memory and these deficits are associated with pregnancy-induced elevations in inflammation and oxidative stress. Cognitive performance was tested with novel object recognition (recollective memory), Morris water maze (spatial memory), and open field (anxiety-like) behavior tasks in female Sprague-Dawley rats of varying reproductive states [nonpregnant (nulliparous), pregnant (near term), and 1-2 mo after pregnancy (primiparous); n = 7 or 8/group]. Plasma and CA1 proinflammatory cytokines were measured with a MILLIPLEX magnetic bead assay. Plasma oxidative stress was measured via advanced oxidation protein products (AOPP) assay. CA1 markers of oxidative stress, neuronal activity, and apoptosis were quantified via Western blot analysis. Our results demonstrate that CA1 oxidative stress-associated markers were elevated in pregnant compared with nulliparous rats (P ≤ 0.017) but there were equivalent levels in pregnant and primiparous rats. In contrast, reproductive state did not impact CA1 inflammatory cytokines, neuronal activity, or apoptosis. Likewise, there was no effect of reproductive state on recollective or spatial memory. Even so, spatial learning was impaired (P ≤ 0.007) whereas anxiety-like behavior (P ≤ 0.034) was reduced in primiparous rats. Overall, our data suggest that maternal hippocampal CA1 is protected from systemic inflammation but vulnerable to peripartum oxidative stress. Peripartum oxidative stress elevations, such as in pregnancy complications, may contribute to peripartum neural and behavioral plasticity.NEW & NOTEWORTHY Healthy pregnancy is associated with elevated maternal systemic and brain oxidative stress. During postpregnancy, brain oxidative stress remains elevated whereas systemic oxidative stress is resolved. This sustained maternal brain oxidative stress is associated with learning impairments and decreased anxiety-like behavior during the postpregnancy period.
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Estresse Oxidativo , Ratos Sprague-Dawley , Animais , Feminino , Gravidez , Ratos , Inflamação/metabolismo , Inflamação/fisiopatologia , Memória , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Memória Espacial , Citocinas/metabolismo , Citocinas/sangue , Ansiedade/metabolismo , Neurônios/metabolismo , Aprendizagem em Labirinto , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/sangueRESUMO
Repetitive transcranial magnetic stimulation (rTMS) emerged as a non-invasive brain stimulation technique in the treatment of psychiatric disorders. Both preclinical and clinical studies as well as systematic reviews provide a heterogeneous picture, particularly concerning the stimulation protocols used in rTMS. Here, we present a review of rTMS effects in rodent models of depressive-like symptoms with the aim to identify the most relevant factors that lead to an increased therapeutic success. The influence of different factors, such as the stimulation parameters (stimulus frequency and intensity, duration of stimulation, shape and positioning of the coil), symptom severity and individual characteristics (age, species and genetic background of the rodents), on the therapeutic success are discussed. Accumulating evidence indicates that rTMS ameliorates a multitude of depressive-like symptoms in rodent models, most effectively at high stimulation frequencies (≥5â¯Hz) especially in adult rodents with a pronounced pathological phenotype. The therapeutic success of rTMS might be increased in the future by considering these factors and using more standardized stimulation protocols.
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Depressão , Modelos Animais de Doenças , Estimulação Magnética Transcraniana , Animais , Depressão/terapia , Depressão/fisiopatologia , Roedores , Estimulação Magnética Transcraniana/métodosRESUMO
AIMS: This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. METHODS: Anxiety-like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open-field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll-like receptor 4 (TLR4) inhibitor TAK-242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. RESULTS: DSS-induced colitis increased anxiety-like behaviors, which was reduced by TAK-242. Spatial transcriptome analysis of the hippocampus showed an excitatory-inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. CONCLUSION: Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over-excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety-like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC-associated anxiety.
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Ansiedade , Hipocampo , Inflamação , Receptores de Glutamato Metabotrópico , Animais , Masculino , Camundongos , Ansiedade/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana , Hipocampo/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/genéticaRESUMO
As wireless communication devices gain popularity, concerns about the potential risks of environmental exposure to complex frequency electromagnetic radiation (EMR) on mental health have become a public health issue. Historically, EMR research has predominantly focused on single- frequency electromagnetic waves, neglecting the study of multi-frequency electromagnetic waves, which more accurately represent everyday life. To address these concerns, our study compared the emotional effects of single-frequency and dual-frequency EMR while exploring potential molecular mechanisms and intervention targets. Our results revealed that single-frequency EMR at 2.65 or 0.8 GHz did not induce anxiety-like behavior in mice. However, exposure to dual-frequency EMR at 2.65/0.8 GHz significantly led to anxiety-like behavior in mice. Further analysis of mouse sera revealed substantial increases in corticosterone and corticotrophin releasing hormone levels following exposure to 2.65/0.8 GHz EMR. Transcriptome sequencing indicated a significant decrease in the expression of Cnr1, encoding cannabinoid receptor 1 Type (CB1R), in the cerebral. This finding was consistently verified through western blot analysis, revealing a substantial reduction in CB1R content. Additionally, a significant decrease in the endocannabinoid 2-arachidonoylglycerol was observed in the cerebral cortex. Remarkably, administering the cannabinoid receptor agonist Win55-212-2 significantly alleviated the anxiety-like behavior, and the cannabinoid receptor antagonist AM251 effectively counteracted the anti-anxiety effects of Win55-212-2. In summary, our research confirmed that dual-frequency EMR is more likely to induce anxiety-like behavior in mice than single-frequency EMR, with implications for the hypothalamic-pituitary-adrenal axis and the endocannabinoid system. Furthermore, our findings suggest that Win55-212-2 may represent a novel avenue for researching and developing anti-EMR drugs.
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Fluorene-9-bisphenol (BHPF) is widely used in the manufacture of plastic products and potentially disrupts several physiological processes, but its biological effects on social behavior remain unknown. In this study, we investigated the effects of BHPF exposure on anxiety-like and social behavior in female mice and the potential mechanisms, thereby proposing a potential therapy strategy. We exposed female Balb/c mice to BHPF by oral gavage at different doses (0.5, 50 mg/kg bw/2-day) for 28 days, which were found BHPF (50 mg/kg) exposure affected motor activity in the open field test (OFT) and elevated cross maze (EPM), resulting in anxiety-like behaviors, as well as abnormal social behavioral deficits in the Social Interaction Test (SIT). Analysis of histopathological staining results showed that BHPF exposure caused damage to hippocampal neurons in the CA1/CA3/DG region and decreased Nissl pyramidal neurons in the CA1/CA3 regions of the hippocampus, as well as a decrease in parvalbumin neuron expression. In addition, BHPF exposure upregulated the expression of excitatory and inhibitory (E/I) vesicle transporter genes (Vglut1, Vglut2, VGAT, GAD67, Gabra) and axon growth gene (Dcc) in the mouse hippocampus. Interestingly, behavioral disturbances and E/I balance could be alleviated by exogenous melatonin (15 mg/kg bw/2-day) therapy. Our findings suggest that exogenous melatonin may be a potential therapy with protective potential for ameliorating or preventing BHPF-induced hippocampal neuronal damage and behavioral disturbances. This study provided new insight into the neurotoxicological effects on organisms exposed to endocrine-disrupting chemicals and aroused our vigilance in current environmental safety about chemical use.
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Ansiedade , Fluorenos , Melatonina , Camundongos Endogâmicos BALB C , Comportamento Social , Animais , Camundongos , Ansiedade/induzido quimicamente , Feminino , Fluorenos/toxicidade , Melatonina/farmacologia , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Fenóis/toxicidadeRESUMO
The vagus nerve, a pivotal link within the gut-brain axis, plays a critical role in maintaining homeostasis and mediating communication between the gastrointestinal tract and the brain. It has been reported that gastrointestinal infection by Salmonella typhimurium (S. typhimurium) triggers gut inflammation and manifests as anxiety-like behaviors, yet the mechanistic involvement of the vagus nerve remains to be elucidated. In this study, we demonstrated that unilateral cervical vagotomy markedly attenuated anxiety-like behaviors induced by S. typhimurium SL1344 infection in C57BL/6 mice, as evidenced by the open field test and marble burying experiment. Furthermore, vagotomy significantly diminished neuronal activation within the nucleus of the solitary tract and amygdala, alongside mitigating aberrant glial cell activation in the hippocampus and amygdala. Additionally, vagotomy notably decreases serum endotoxin levels, counters the increase in splenic Salmonella concentration, and modulates the expression of inflammatory cytokines-including IL-6, IL-1ß, and TNF-α-in both the gastrointestinal tract and brain, with a concurrent reduction in IL-22 and CXCL1 expression. This intervention also fostered the enrichment of beneficial gut microbiota, including Alistipes and Lactobacillus species, and augmented the production of gamma-aminobutyric acid (GABA) in the gut. Administration of GABA replicated the vagotomy's beneficial effects on reducing gut inflammation and anxiety-like behavior in infected mice. However, blockade of GABA receptors with picrotoxin abrogated the vagotomy's protective effects against gut inflammation, without influencing its impact on anxiety-like behaviors. Collectively, these findings suggest that vagotomy exerts a protective effect against infection by promoting GABA synthesis in the colon and alleviating anxiety-like behavior. This study underscores the critical role of the vagus nerve in relaying signals of gut infection to the brain and posits that targeting the gut-brain axis may offer a novel and efficacious approach to preventing gastrointestinal infections and associated behavioral abnormalities.
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Ansiedade , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Vagotomia , Nervo Vago , Ácido gama-Aminobutírico , Animais , Ansiedade/metabolismo , Camundongos , Nervo Vago/metabolismo , Masculino , Ácido gama-Aminobutírico/metabolismo , Salmonella typhimurium , Citocinas/metabolismo , Eixo Encéfalo-Intestino , Encéfalo/metabolismo , Infecções por Salmonella/metabolismo , Comportamento Animal , Hipocampo/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Inflamação/metabolismo , Tonsila do Cerebelo/metabolismoRESUMO
Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, but only reduced in the DG subregion during the chronic phase. Furthermore, mRNA levels of proinflammatory cytokines ( Il1ß, Tnfα, and Ifnγ) and glial cell markers ( Gfap and Cd68) were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Doenças dos Roedores , Camundongos , Animais , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/veterinária , Hipocampo/metabolismo , Neurônios/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/veterinária , Citocinas/metabolismo , Doenças dos Roedores/metabolismo , Doenças dos Roedores/patologiaRESUMO
BACKGROUND: Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to infection or injury. Recent studies have uncovered their intriguing functions as moonlighting proteins involved in various biological processes, including development, learning, and memory. However, the specific functions of individual TLRs are still largely unknown. AIMS: We investigated the effects of TLR3 and TLR9 receptor deficiency on motor, cognitive, and behavioral functions during development using genetically modified male mice of different ages. METHODS: We evaluated the motor coordination, anxiety-like behavior, spatial learning, and working memory of male mice lacking the TLR3 and TLR9 genes at different ages (two, four, six, and eight months) using the rotarod, open field, water maze, and T-maze tests. RESULTS: We observed that the deletion of either TLR3 or TLR9 resulted in impaired motor performance. Furthermore, young TLR3-deficient mice exhibited reduced anxiety-like behavior and spatial learning deficits; however, their working memory was unaffected. In contrast, young TLR9-knockout mice showed hyperactivity and a tendency toward decreased working memory. CONCLUSIONS: These findings provide valuable insights into the broader roles of the TLR system beyond the innate immune response, revealing its involvement in pathways associated with the central nervous system. Importantly, our results establish a strong association between the endosomal receptors TLR3 and TLR9 and the performance of motor, cognitive, and behavioral tasks that change over time. This study contributes to the growing body of research on the multifaceted functions of TLRs and enhances our understanding of their participation in non-immune-related processes.
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Receptor 3 Toll-Like , Receptor Toll-Like 9 , Animais , Masculino , Camundongos , Cognição , Camundongos Knockout , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/metabolismo , Receptor Toll-Like 9/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMO
Probiotic supplementation has been identified as a potential target to reduce inflammatory mediators associated with obesity. Therefore, this study assessed the effect of probiotic Lacticaseibacillus rhamnosus LB1.5 on anxiety-like behavior, gene expression in the prefrontal cortex, and neuroinflammation in the cerebral cortex and hippocampus of male mice fed a high-fat diet. Mice aged 21 days were divided into four groups: control (CONT), control plus probiotic (CONT + PROB), high-fat diet (HFD), and high-fat diet plus probiotic (HFD + PROB), and fed for 13 weeks. The probiotic Lact. rhamnosus 1.5 (3.1 × 108 CFU/mL, derived from raw buffalo milk) was administered by gavage three times a week. Probiotic supplementation provided an anxiolytic effect in CONT and HFD. The IL-6 showed lower levels after probiotic supplementation in the HFD. Regarding immunoreactivity for GFAP in the cerebral cortex, we demonstrated that animals HFD-fed had a reduction in cells number compared to CONT. In the hippocampus, we found an interaction between diet and supplementation, as well as an effect of probiotic supplementation. A higher number of Th positive cells was observed in the cerebral cortex in mice fed HFD. Lact. rhamnosus LB1.5 supplementation decreased serum IL-6 levels in HFD-fed mice and promoted a reduction in anxiety-like behavior.
Assuntos
Lacticaseibacillus rhamnosus , Probióticos , Camundongos , Masculino , Animais , Dieta Hiperlipídica/efeitos adversos , Doenças Neuroinflamatórias , Interleucina-6 , Neuroproteção , Ansiedade/prevenção & controle , Camundongos Endogâmicos C57BLRESUMO
As one of the most environmental concerns, inhaled particulate matter (PM10) causes numerous health problems. However, the associations between anxiety behavior and toxicity caused by PM10 have rarely been reported so far. To investigate the changes of behavior after PM10 exposure and to identify the potential mechanisms of toxicity, PM10 samples (with doses of 15 mg/kg and 30 mg/kg) were intratracheally instilled into rats to simulate inhalation of polluted air by the lungs. After instillation for eight weeks, anxiety-like behavior was evaluated, levels of oxidative stress and morphological changes of hippocampus were measured. The behavioral results indicated that PM10 exposure induced obvious anxiety-like behavior in the open field and elevated plus maze tests. Both PM10 concentrations tested could increase whole blood viscosity and trigger hippocampal neuronal damage and oxidative stress by increasing superoxide dismutase (SOD) activities and malondialdehyde levels, and decreasing the expressions of antioxidant-related proteins (e.g., nuclear factor erythroid 2-related factor 2 (Nrf2), SOD1 and heme oxygenase 1). Furthermore, through collecting and analyzing questionnaires, the data showed that the participants experienced obvious anxiety-related emotions and negative somatic responses under heavily polluted environments, especially PM10 being the main pollutant. These results show that PM10 exposure induces anxiety-like behavior, which may be related to suppressing the Nrf2/Keap1-SOD1 pathway.
Assuntos
Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Humanos , Ratos , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Superóxido Dismutase-1/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ansiedade/induzido quimicamente , Hipocampo/metabolismoRESUMO
Adolescent binge alcohol drinking is a serious health concern contributing to adult alcohol abuse often associated with anxiety disorders. We have used adolescent intermittent ethanol (AIE) administration as a model of binge drinking in rats in order to explore its long-term effect on the basolateral amygdala (BLA) responsiveness to alcohol and anxiety-like behavior. AIE increased the number of BLA c-Fos positive cells in adult Wistar rats and anxiety-like behavior assessed by the open field test (OFT). Additionally, in adult female rats receiving AIE BLA over expression of miR-182 was found. Therefore, our results indicate that alcohol consumption during adolescence can lead to enduring changes in anxiety-like behavior and BLA susceptibility to alcohol that may be mediated by sex-dependent epigenetic changes. These results contribute to understanding the mechanisms involved in the development of alcohol use disorders (AUD) and anxiety-related disorders.