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1.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466445

RESUMO

The lack of effective disease-modifying therapeutics to tackle Alzheimer's disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-ß (Aß) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.


Assuntos
Doença de Alzheimer/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Cognição/fisiologia , Metabolismo Energético/fisiologia , Hipóxia/fisiopatologia , Camundongos Transgênicos/fisiologia , Mitocôndrias/fisiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Transgênicos/metabolismo , Mitocôndrias/metabolismo
2.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322180

RESUMO

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.


Assuntos
Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Mycobacterium tuberculosis/metabolismo , Neurônios/patologia , Tuberculose Pulmonar/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/microbiologia , Sintomas Comportamentais/microbiologia , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/citologia , Encéfalo/enzimologia , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Disfunção Cognitiva/microbiologia , Depressão/metabolismo , Depressão/microbiologia , Modelos Animais de Doenças , Regulação para Baixo , Hipocampo/citologia , Hipocampo/imunologia , Hipocampo/metabolismo , Hipocampo/patologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/patogenicidade , Neurônios/citologia , Neurotransmissores/metabolismo , Tuberculose Pulmonar/enzimologia , Tuberculose Pulmonar/patologia , Tuberculose Pulmonar/psicologia , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-33031994

RESUMO

As the infected cases of COVID-19 reach more than 20 million with more than 778,000 deaths globally, an increase in psychiatric disorders including anxiety and depression has been reported. Scientists globally have been searching for novel therapies and vaccines to fight against COVID-19. Improving innate immunity has been suggested to block progression of COVID-19 at early stages, while omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have immunomodulation effects. Moreover, n-3 PUFAs have also been shown to improve mood disorders, thus, future research is warranted to test if n-3 PUFAs may have the potential to improve our immunity to counteract both physical and mental impact of COVID-19.


Assuntos
Ansiedade/prevenção & controle , Infecções por Coronavirus/prevenção & controle , Depressão/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Ansiedade/imunologia , Ansiedade/metabolismo , Ansiedade/virologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Depressão/imunologia , Depressão/metabolismo , Depressão/virologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/virologia , Ácidos Graxos Ômega-3/imunologia , Ácidos Graxos Ômega-3/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia
4.
Subst Use Misuse ; 55(14): 2438-2442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32957797

RESUMO

BACKGROUND: The overwhelming fatalities of the global COVID-19 Pandemic will have daunting epigenetic sequala that can translate into an array of mental health issues, including panic, phobia, health anxiety, sleep disturbances to dissociative like symptoms including suicide. Method: We searched PUBMED for articles listed using the search terms "COVID 19 Pandemic", COVID19 and genes," "stress and COVID 19", Stress and Social distancing: Results: Long-term social distancing may be neurologically harmful, the consequence of epigenetic insults to the gene encoding the primary receptor for SARS-CoV2, and COVID 19. The gene is Angiotensin I Converting-Enzyme 2 (ACE2). According to the multi-experiment matrix (MEM), the gene exhibiting the most statistically significant co-expression link to ACE2 is Dopa Decarboxylase (DDC). DDC is a crucial enzyme that participates in the synthesis of both dopamine and serotonin. SARS-CoV2-induced downregulation of ACE2 expression might reduce dopamine and serotonin synthesis, causing hypodopaminergia. Discussion: Indeed, added to the known reduced dopamine function during periods of stress, including social distancing the consequence being both genetic and epigenetic vulnerability to all Reward Deficiency Syndrome (RDS) addictive behaviors. Stress seen in PTSD can generate downstream alterations in immune functions by reducing methylation levels of immune-related genes. Conclusion: Mitigation of these effects by identifying subjects at risk and promoting dopaminergic homeostasis to help regulate stress-relative hypodopaminergia, attenuate fears, and prevent subsequent unwanted drug and non-drug RDS type addictive behaviors seems prudent.


Assuntos
Comportamento Aditivo/genética , Infecções por Coronavirus/metabolismo , Dopamina/metabolismo , Pneumonia Viral/metabolismo , Ansiedade/genética , Ansiedade/metabolismo , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Betacoronavirus , Infecções por Coronavirus/psicologia , Dopa Descarboxilase/genética , Dopa Descarboxilase/metabolismo , Regulação para Baixo , Epigênese Genética , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/psicologia , Recompensa , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Suicídio , Síndrome
5.
Nat Commun ; 11(1): 4484, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901027

RESUMO

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.


Assuntos
Aprendizagem da Esquiva/fisiologia , Hipocampo/fisiologia , Proteínas Proto-Oncogênicas c-fos/fisiologia , Animais , Ansiedade/metabolismo , Comportamento Animal/fisiologia , Técnicas de Inativação de Genes , Inativação Gênica , Hipocampo/anatomia & histologia , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/deficiência , Proteínas Proto-Oncogênicas c-fos/genética , Comportamento Social , Estresse Psicológico
6.
PLoS One ; 15(8): e0238307, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853281

RESUMO

OBJECTIVE: Auricular stimulation (AS) is a promising method in the treatment of situational anxiety. Expressive writing (EW) is an established psychological method, which reduces test anxiety and improves exam results. The aim of this crossover trial was to compare AS with EW, and with the no intervention (NI) condition, for treatment of exam anxiety. METHODS: Healthy medical students underwent 3 comparable anatomy exams with an interval of one month, either performing EW, receiving AS or NI prior to the exam; the order of interventions was randomized. AS was applied using indwelling fixed needles bilaterally at the areas innervated mostly by the auricular branch of the vagal nerve on the day before the exam. Anxiety level, measured using State-Trait-Anxiety Inventory (STAI) before and after the interventions and immediately before exam, was the primary outcome. Quality of night sleep, blood pressure, heart rate and activity of salivary alpha-amylase (sAA) were analyzed across 3 conditions. RESULTS: All 37 included participants completed the study. Anxiety level (STAI) decreased immediately after AS in comparison with baseline (P = 0.02) and remained lower in comparison with that after EW and NI (P<0.01) on the day of exam. After EW and NI anxiety increased on the day of exam in comparison with baseline (P<0.01). Quality of sleep improved after AS in comparison with both control conditions (P<0.01). The activity of sAA decreased after EW and after AS (P<0.05) but not after NI condition. CONCLUSION: Auricular stimulation, but not expressive writing, reduced exam anxiety and improved quality of sleep in medical students. These changes might be due to reduced activity of the sympathetic nervous system.


Assuntos
Desempenho Acadêmico/psicologia , Transtornos de Ansiedade/prevenção & controle , Transtornos de Ansiedade/psicologia , Ansiedade/psicologia , Estudantes de Medicina/psicologia , Adolescente , Adulto , Ansiedade/metabolismo , Transtornos de Ansiedade/metabolismo , Pressão Sanguínea/fisiologia , Estudos Cross-Over , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Redação , Adulto Jovem , alfa-Amilases/metabolismo
7.
PLoS One ; 15(7): e0236039, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702030

RESUMO

BACKGROUND: The bidirectional selection of high and low anxiety-like behavior is a valuable tool for understanding the neurocircuits that are responsible for anxiety disorders. Our group developed two breeding lines of rats, known as Carioca High- and Low-conditioned Freezing (CHF and CLF), based on defensive freezing in the contextual fear conditioning paradigm. A random selected line was employed as a control (CTL) comparison group for both CHF and CLF lines of animals. The present study performed Fos immunochemistry to investigate changes in neural activity in different brain structures among CHF and CLF rats when they were exposed to contextual cues that were previously associated with footshock. RESULTS: The study indicated that CHF rats expressed high Fos expression in the locus coeruleus, periventricular nucleus of the hypothalamus (PVN), and lateral portion of the septal area and low Fos expression in the medial portion of the septal area, dentate gyrus, and prelimbic cortex (PL) compared to CTL animals. CLF rats exhibited a decrease in Fos expression in the PVN, PL, and basolateral nucleus of the amygdala and increase in the cingulate and perirhinal cortices compared to CTL animals. CONCLUSIONS: Both CHF and CLF rats displayed Fos expression changes key regions of the anxiety brain circuitry. The two bidirectional lines exhibit different pattern of neural activation and inhibition with opposing influences on the PVN, the main structure involved in regulating the hypothalamic-pituitary-adrenal neuroendocrine responses observed in anxiety disorders.


Assuntos
Encéfalo/metabolismo , Condicionamento Psicológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/psicologia , Masculino , Ratos
8.
Nat Commun ; 11(1): 2221, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376858

RESUMO

Dysregulated prefrontal control over amygdala is engaged in the pathogenesis of psychiatric diseases including depression and anxiety disorders. Here we show that, in a rodent anxiety model induced by chronic restraint stress (CRS), the dysregulation occurs in basolateral amygdala projection neurons receiving mono-directional inputs from dorsomedial prefrontal cortex (dmPFC→BLA PNs) rather than those reciprocally connected with dmPFC (dmPFC↔BLA PNs). Specifically, CRS shifts the dmPFC-driven excitatory-inhibitory balance towards excitation in the former, but not latter population. Such specificity is preferential to connections made by dmPFC, caused by enhanced presynaptic glutamate release, and highly correlated with the increased anxiety-like behavior in stressed mice. Importantly, low-frequency optogenetic stimulation of dmPFC afferents in BLA normalizes the enhanced prefrontal glutamate release onto dmPFC→BLA PNs and lastingly attenuates CRS-induced increase of anxiety-like behavior. Our findings thus reveal a target cell-based dysregulation of mPFC-to-amygdala transmission for stress-induced anxiety.


Assuntos
Tonsila do Cerebelo/fisiologia , Ansiedade/fisiopatologia , Ácido Glutâmico/metabolismo , Vias Neurais/fisiologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico , Animais , Ansiedade/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Corticosterona/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Optogenética , Restrição Física
9.
Cardiovasc Ther ; 2020: 2478781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32426035

RESUMO

It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α 2-adrenoceptors (α 2-ARs) in skin-lightening experiments in the frog. Now α 2-ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α 2-AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α 2-ARs. In this model system and in the setting of furosemide-induced sodium excretion, α 2-AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α 2-AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α 2-ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α 2-ARs activate prohypertensive biochemical systems. While investigating the role of α 1-adrenoceptors (α 1-ARs) versus α 2-ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α 1-ARs suppress the postjunctional expression of α 2-ARs. Here, we describe how this finding relates to a broader understanding of the role of α 2-ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α 2-AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.


Assuntos
Pressão Sanguínea , Hipertensão Essencial/metabolismo , Rim/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Acidentes por Quedas , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Ansiedade/psicologia , Denervação Autônoma , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/uso terapêutico , Hipertensão Essencial/fisiopatologia , Hipertensão Essencial/terapia , Humanos , Hipotensão Ortostática/metabolismo , Hipotensão Ortostática/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Eliminação Renal , Reabsorção Renal , Transdução de Sinais , Sódio/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia
10.
J Neurosci ; 40(24): 4739-4749, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393533

RESUMO

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Emoções/fisiologia , Comportamento Exploratório/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/genética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Callithrix , Citalopram/farmacologia , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Humanos , Masculino , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia
11.
Psychopharmacology (Berl) ; 237(8): 2327-2343, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32399631

RESUMO

RATIONALE: The c-Jun N-terminal kinase (JNK) pathway and neurotrophic factor dysregulation play a critical role in the pathogenesis of neurobehavioral disorders (anxiety and depression). Targeting the JNK pathway and BDNF/VEGF signaling may signify a new avenue for the treatment of neurobehavioral disorders. OBJECTIVES: The present study investigated the effect of matrine (Mat) against anxiety- and depressive-like emotional status in an acute mouse model of burn injury and explores its underlying mechanism. METHODS: In the mouse model of thermal injury, anxiety- and depression-related behaviors were evaluated using the elevated plus-maze test, the light-dark box test, the open-field test, the forced swimming test, and the tail suspension test. The JNK/caspase-3 and BDNF/VEGF proteins were determined by immunohistochemistry. Additionally, proinflammatory cytokine, antioxidant, nitric oxide, and corticosterone levels were also measured. RESULTS: The results showed that treatment with Mat significantly improves anxiety- and depressive-like behaviors. It remarkably reduced the levels of proinflammatory cytokines, malondialdehyde, and nitric oxide in the hippocampus and prefrontal cortex of a mouse brain. It considerably improved burn-induced alteration in the antioxidant status, corticosterone, and BDNF/VEGF. It also inhibited burn-induced apoptotic signaling by downregulating the expression of JNK/caspase-3. Similarly, it prevented DNA damage and histopathological changes in the dentate gyrus of the hippocampus. Furthermore, molecular docking results showed that Mat possess better binding affinity for JNK/caspase-3 and BDNF/VEGF proteins. CONCLUSIONS: These findings provide convincing evidence that Mat improves anxiety- and depressive-like emotional status through modulation of JNK-mediated inflammatory, oxidative stress, apoptotic, and BDNF/VEGF signaling in an acute mouse model of burn injury.


Assuntos
Alcaloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Queimaduras/metabolismo , Caspase 3/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Quinolizinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Ansiolíticos/metabolismo , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Queimaduras/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Simulação de Acoplamento Molecular/métodos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Quinolizinas/farmacologia , Quinolizinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
12.
Radiat Res ; 193(5): 407-424, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134362

RESUMO

Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by ∼50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.


Assuntos
Neurologia , Radioterapia/efeitos adversos , Temozolomida/efeitos adversos , Animais , Ansiedade/diagnóstico , Ansiedade/etiologia , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/efeitos da radiação , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/efeitos da radiação , Terapia Combinada/efeitos adversos , Depressão/induzido quimicamente , Depressão/etiologia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/efeitos da radiação , Receptor 5-HT1A de Serotonina/metabolismo , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Temozolomida/uso terapêutico
13.
Behav Neurol ; 2020: 7830469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190129

RESUMO

Early-life stress affects neuronal plasticity of the brain regions participating in the implementation of social behavior. Our previous studies have shown that brief and prolonged separation of pups from their mothers leads to enhanced social behavior in adult female mice. The goal of the present study was to characterize the expression of genes (which are engaged in synaptic plasticity) Egr1, Npas4, Arc, and Homer1 in the prefrontal cortex and dorsal hippocampus of adult female mice with a history of early-life stress. In addition, we evaluated the expression of stress-related genes: glucocorticoid and mineralocorticoid receptors (Nr3c1 and Nr3c2) and Nr1d1, which encodes a transcription factor (also known as REVERBα) modulating sociability and anxiety-related behavior. C57Bl/6 mice were exposed to either maternal separation (MS, 3 h once a day) or handling (HD, 15 min once a day) on postnatal days 2 through 14. In adulthood, the behavior of female mice was analyzed by some behavioral tests, and on the day after the testing of social behavior, we measured the gene expression. We found increased Npas4 expression only in the prefrontal cortex and higher Nr1d1 expression in both the prefrontal cortex and dorsal hippocampus of adult female mice with a history of MS. The expression of the studied genes did not change in HD female mice. The expression of stress-related genes Nr3c1 and Nr3c2 was unaltered in both groups. We propose that the upregulation of Npas4 and Nr1d1 in females with a history of early-life stress and the corresponding enhancement of social behavior may be regarded as an adaptation mechanism reversing possible aberrations caused by early-life stress.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Estresse Psicológico/fisiopatologia , Animais , Animais Recém-Nascidos , Ansiedade/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Comportamento Animal , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Hipocampo/fisiologia , Privação Materna , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Córtex Pré-Frontal/fisiologia , Comportamento Social , Estresse Psicológico/genética
14.
Biol Sex Differ ; 11(1): 8, 2020 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087746

RESUMO

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.


Assuntos
Ansiedade/metabolismo , Núcleo Caudado/metabolismo , Depressão/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Caracteres Sexuais , Transdução de Sinais , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Animais , Ansiedade/fisiopatologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Núcleo Caudado/efeitos dos fármacos , Chlorocebus aethiops , Depressão/fisiopatologia , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Masculino , Núcleo Accumbens/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo
15.
Exp Neurol ; 327: 113216, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32014439

RESUMO

Neuropeptide Y (NPY) is a 36-amino acid neuropeptide that is widely expressed in the central nervous system, including the cerebral cortex, nucleus accumbens (NAc) and hypothalamus. We previously analyzed the behavior of transgenic mice exclusively expressing an unedited RNA isoform of the 5-HT2C receptor. These mice showed decreased NPY gene expression in the NAc and exhibited behavioral despair, suggesting that NAc NPY neurons may be involved in mood disorder; however, their role in this behavior remained unknown. Therefore, in the present study, we investigated the functional role of NAc NPY neurons in anxiety-like behavior by examining the impact of specific ablation or activation of NAc NPY neurons using NPY-Cre mice and Cre-dependent adeno-associated virus. Diphtheria toxin-mediated ablation of NAc NPY neurons significantly increased anxiety-like behavior in the open field and elevated plus maze tests, compared with before toxin treatment. Moreover, chemogenetic activation of NAc NPY neurons reduced anxiety-like behavior in both behavioral tests compared with control mice. These results suggest that NPY neurons in the NAc are involved in the modulation of anxiety in mice.


Assuntos
Ansiedade/metabolismo , Comportamento Animal/fisiologia , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Núcleo Accumbens/metabolismo , Animais , Ansiedade/genética , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Neuropeptídeo Y/genética , Receptores de Neuropeptídeo Y/metabolismo
16.
Adv Exp Med Biol ; 1191: 103-120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002925

RESUMO

Oxytocin, a neuropeptide synthesized by the hypothalamus, plays a central role in human social behavior, social cognition, anxiety, mood, stress modulation, and fear learning and extinction. The relationships between oxytocin and psychiatric disorders including depression, anxiety, schizophrenia, and autism spectrum disorder have been extensively studied. In this chapter, we focus on the current knowledge about oxytocin and anxiety disorder. We discuss the anxiolytic effects of oxytocin in preclinical and clinical findings, possible related neurobehavioral mechanisms (social cognition, fear learning, and extinction), related neurotransmitter and neuroendocrine systems (hypothalamus-pituitary-adrenal axis, serotoninergic, and GABAergic systems), and studies regarding plasma levels of oxytocin, genetic and epigenetic findings, and effects of intranasal oxytocin in DSM-5 anxiety disorder (primarily social anxiety disorder and separation anxiety disorder) patients.


Assuntos
Transtornos de Ansiedade/metabolismo , Ocitocina/metabolismo , Ansiedade/metabolismo , Medo , Humanos , Comportamento Social
17.
Adv Exp Med Biol ; 1191: 121-140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002926

RESUMO

Discovery of innovative anxiolytics is severely hampering. Existing anxiolytics are developed decades ago and are still the therapeutics of choice. Moreover, lack of new drug targets forecasts a severe jeopardy in the future treatment of the huge population of CNS-diseased patients. We simply lack the knowledge on what is wrong in brains of anxious people (normal and diseased). Translational research, based on interacting clinical and preclinical research, is extremely urgent. In this endeavor, genetic and genomic approaches are part of the spectrum of contributing factors. We focus on three druggable targets: serotonin transporter, 5-HT1A, and GABAA receptors. It is still uncertain whether and how these targets are involved in normal and diseased anxiety processes. For serotonergic anxiolytics, the slow onset of action points to indirect effects leading to plasticity changes in brain systems leading to reduced anxiety. For GABAA benzodiazepine drugs, acute anxiolytic effects are found indicating primary mechanisms directly influencing anxiety processes. Close translational collaboration between fundamental academic and discovery research will lead to badly needed breakthroughs in the search for new anxiolytics.


Assuntos
Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/fisiopatologia , Ansiedade/fisiopatologia , Descoberta de Drogas , Neurotransmissores/metabolismo , Pesquisa Médica Translacional , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Humanos
18.
Adv Exp Med Biol ; 1191: 523-541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002944

RESUMO

Exposure therapy, a key treatment for anxiety disorders, can be modelled in the laboratory using Pavlovian fear extinction. Understanding the hormonal and neurobiological mechanisms underlying fear extinction in females, who are twice more likely than males to present with anxiety disorders, may aid in optimising exposure therapy outcomes in this population. This chapter will begin by discussing the role of the sex hormones, estradiol and progesterone, in fear extinction in females. We will also propose potential mechanisms by which these hormones may modulate fear extinction. The second half of this chapter will discuss the long-term hormonal, neurological and behavioural changes that arise from pregnancy and motherhood and how these changes may alter the features of fear extinction in females. Finally, we will discuss implications of this research for the treatment of anxiety disorders in women with and without prior reproductive experience.


Assuntos
Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/terapia , Ansiedade/metabolismo , Ansiedade/terapia , Estradiol/metabolismo , Progesterona/metabolismo , Reprodução , Ansiedade/psicologia , Transtornos de Ansiedade/psicologia , Extinção Psicológica , Medo , Feminino , Humanos , Gravidez
19.
PLoS One ; 15(2): e0229269, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084196

RESUMO

Psychiatric disorders including depression and anxiety comprise a broad range of conditions with different symptoms. We have developed a mouse model of depression/anxiety in mice deficient in the St3gal4 gene. In this study, we performed a comparative analysis of urinary volatile organic compounds (VOCs) in St3gal4-deficient (St3gal4-KO) and wild-type mice using gas chromatography-mass spectrometry, and we screened 18 putative VOCs. Principal component analysis (PCA) based on these VOCs identified a major group of 11 VOCs, from which two groups were clarified by hierarchical clustering analysis. One group including six VOCs (pentanoic acid, 4-methyl-, ethyl ester; 3-heptanone, 6-methyl; benzaldehyde; 5,9-undecadien-2-ol, 6,10-dimethyl; and unknown compounds RI1291 and RI1237) was correlated with the startle response (r = 0.620), which is related to an unconscious defensive response. The other group including two VOCs (beta-farnesene and alpha-farnesene) comprised pheromones which increased in KO mice. Next, male mice underwent a social behavior test with female mice in the estrus stage, showing reduced access of KO male mice to female mice. Comparative analysis of urinary VOCs before and after encounters revealed that the six VOCs were not changed by these encounters. However, in WT mice, the two farnesenes increased after the encounters, reaching the level observed in KO mice, which was not altered following the encounter. Taken together, these results indicated that St3gal4 was involved in modulating urinary VOCs. Moreover, VOC clusters discovered by comparison of St3gal4-KO mice with WT mice were correlated with differential emotional behaviors.


Assuntos
Ansiedade/urina , Depressão/urina , Metabolômica , Compostos Orgânicos Voláteis/urina , Animais , Ansiedade/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Camundongos , Sialiltransferases/deficiência , Sialiltransferases/genética , Compostos Orgânicos Voláteis/metabolismo
20.
PLoS One ; 15(2): e0229084, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084223

RESUMO

BACKGROUND: The Trinity Amputation and Prosthesis Experience Scales-Revised (TAPES-R) is a self-administered questionnaire to measure multidimensional adjustment to a prosthetic limb. Our aim was to assess the validity and reliability of the French version of the TAPES-R (TAPES-R-F). MATERIALS AND METHODS: The cross-cultural adaptation was performed according to the recommendations. Factor analysis and Rasch analysis were also performed to allow comparison with the original English version. Construct validity was assessed by measuring the correlations between TAPES-R-F subscores and quality of life, pain, body image satisfaction, anxiety and depression. Internal consistency was measured with Cronbach's α. The standard error of measurement, smallest detectable change, Bland and Altman limits of agreement, and intraclass correlation were the measures of agreement and reliability. RESULTS: No major difficulties were encountered throughout the trans-cultural adaptation process. The final version of the TAPES-R-F was well accepted and understood by the patients. According to the factor analysis, the satisfaction scale should be treated as a one-dimensional construct when used by French-speaking people and should not be separated into two separate subscales, functional and aesthetic, as is the case in the original English version. Our study confirmed that there is a strong relationship between biopsychosocial factors and adjustment to amputation. Cronbach's α > 0.8 for all the subscales. Reliability was good to excellent for all the subscales (ICCs between 0.61 and 0.89). The smallest detectable changes were 0.7, 0.8, 1.3, 0.4, and 1.8 (general adjustment, social adjustment, adjustment to limitation, activity restriction, and global satisfaction with the prosthesis). CONCLUSIONS: The TAPES-R-F is a valid and reliable instrument to assess multidimensional adjustment of French-speaking lower limb amputees. This questionnaire can be used for both clinical assessment and research purposes.


Assuntos
Membros Artificiais , Amputação/métodos , Ansiedade/metabolismo , Comparação Transcultural , Depressão/metabolismo , Humanos , Qualidade de Vida , Reprodutibilidade dos Testes , Inquéritos e Questionários
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