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1.
JAMA Netw Open ; 3(1): e1919940, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31995213

RESUMO

Importance: Prenatal maternal stress is increasingly associated with adverse outcomes in pregnant women and their offspring. However, the association between maternal stress and human fetal brain growth and metabolism is unknown. Objective: To identify the association between prenatal maternal psychological distress and fetal brain growth, cortical maturation, and biochemical development using advanced 3-dimensional volumetric magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS). Design, Setting, and Participants: This cohort study prospectively recruited pregnant women from low-risk obstetric clinics in Washington, DC, from January 1, 2016, to April 17, 2019. Participants were healthy volunteers with a normal prenatal medical history, no chronic or pregnancy-induced physical or mental illnesses, and normal results on fetal ultrasonography and biometry studies. Fetal brain MRI studies were performed at 2 time points between 24 and 40 weeks' gestation. Exposures: Prenatal maternal stress, anxiety, and depression. Main Outcomes and Measures: Volumes of fetal total brain, cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampus were measured from 3-dimensional reconstructed T2-weighted MRI scans. Cortical folding measurements included local gyrification index, sulcal depth, and curvedness. Fetal brain N-acetylaspartate, creatine, and choline levels were quantified using 1H-MRS. Maternal stress, depression, and anxiety were measured with the Perceived Stress Scale (PSS), Edinburgh Postnatal Depression Scale (EPDS), Spielberger State Anxiety Inventory (SSAI), and Spielberger Trait Anxiety Inventory (STAI). Results: A total of 193 MRI studies were performed in 119 pregnant women (67 [56%] carrying male fetuses and 52 [44%], female fetuses; maternal mean [SD] age, 34.46 [5.95] years) between 24 and 40 gestational weeks. All women were high school graduates, 99 (83%) were college graduates, and 100 (84%) reported professional employment. Thirty-two women (27%) had positive scores for stress, 31 (26%) for anxiety, and 13 (11%) for depression. Maternal trait anxiety was associated with smaller fetal left hippocampal volume (STAI score: -0.002 cm3; 95% CI, -0.003 to -0.0008 cm3; P = .004). Maternal anxiety and stress were associated with increased fetal cortical gyrification in the frontal lobe (ß for SSAI score: 0.004 [95% CI, 0.001-0.006; P = .002]; ß for STAI score: 0.004 [95% CI, 0.002-0.006; P < .001]; ß for PSS score: 0.005 [95% CI, 0.001-0.008; P = .005]) and temporal lobe (ß for SSAI score: 0.004 [95% CI, 0.001-0.007; P = .004]; ß for STAI score: 0.004 [95% CI, 0.0008-0.006; P = .01]). Elevated maternal depression was associated with decreased creatine (EPDS score: -0.04; 95% CI, -0.06 to -0.02; P = .005) and choline (EPDS score: -0.03; 95% CI, -0.05 to -0.01; P = .02) levels in the fetal brain. Conclusions and Relevance: This study found that the prevalence of maternal psychological distress in healthy, well-educated, and employed pregnant women was high, underappreciated, and associated with impaired fetal brain biochemistry and hippocampal growth as well as accelerated cortical folding. These findings appear to support the need for routine mental health surveillance for all pregnant women and targeted interventions in women with elevated psychological distress.


Assuntos
Encéfalo/crescimento & desenvolvimento , Córtex Cerebral/diagnóstico por imagem , Desenvolvimento Fetal/fisiologia , Substância Cinzenta/diagnóstico por imagem , Complicações na Gravidez/diagnóstico por imagem , Estresse Psicológico/patologia , Adulto , Estudos de Coortes , Feminino , Humanos , Imageamento Tridimensional/métodos , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Gravidez , Complicações na Gravidez/psicologia , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Estresse Psicológico/diagnóstico por imagem
2.
Nature ; 577(7792): 676-681, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31969699

RESUMO

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs)1,2, but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics3,4, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.


Assuntos
Vias Autônomas/fisiopatologia , Cor de Cabelo/fisiologia , Melanócitos/patologia , Nicho de Células-Tronco/fisiologia , Células-Tronco/patologia , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Glândulas Suprarrenais/metabolismo , Adrenalectomia , Animais , Vias Autônomas/patologia , Proliferação de Células , Células Cultivadas , Denervação , Feminino , Humanos , Masculino , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Norepinefrina/metabolismo , Trauma Psicológico/patologia , Trauma Psicológico/fisiopatologia , Receptores Adrenérgicos beta 2/deficiência , Receptores Adrenérgicos beta 2/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Estresse Psicológico/patologia , Sistema Nervoso Simpático/patologia
3.
Endocr Regul ; 53(2): 83-92, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517626

RESUMO

OBJECTIVE: Prolonged treatment with neuroleptics has been shown to induce FosB/ΔFosB expression in several brain regions including the medial prefrontal cortex, dorsomedial and dorsolateral striatum, ventrolateral and dorsolateral septum, nucleus accumbens shell and core, and the hypothalamic paraventricular nucleus (PVN). Some of these regions are known to be also stress responsive. This study was designed to determine whether repeated clozapine (CLZ) administration for 7 consecutive days to Wistar rats may modify FosB/ΔFosB expression in the above-mentioned brain areas induced by acute stress or novel stressor that followed 13-day chronic mild stress preconditioning. METHODS: Following experimental groups were used: unstressed animals treated with vehicle/ CLZ for 7 days; 7-day vehicle/CLZ-treated animals on the last day exposed to acute stress - forced swimming (FSW); and animals preconditioned with stress for 13 days treated from the 8th day with vehicle/CLZ and on the 14th day exposed to novel stress - FSW. RESULTS: In the unstressed animals CLZ markedly increased FosB/ΔFosB immunoreactivity in the ventrolateral septum and PVN. FSW elevated FosB/ΔFosB expression in the medial prefrontal cortex, striatum, and septum. CLZ markedly potentiated the effect of the FSW on FosB/ΔFosB expression in the PVN, but suppressed it in the dorsomedial striatum. Novel stress with stress preconditioning increased FosB/ΔFosB immunoreactivity in the prefrontal cortex, striatum, ventrolateral septum, and the PVN. In the nucleus accumbens the effect of the novel stressor was potentiated by CLZ. CONCLUSION: Our data indicate that CLZ may modulate the acute as well as novel stress effects on FosB/ΔFosB expression but its effect differs within the individual brain regions.


Assuntos
Clozapina/farmacologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estresse Psicológico/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Masculino , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Ratos , Ratos Wistar , Estresse Psicológico/complicações , Estresse Psicológico/patologia , Natação/psicologia
4.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540539

RESUMO

Treatment of the unpredictable chronic mild stress (UCMS) mice with the ethanol extract of Dipterocarpus alatus leaf attenuated anhedonia (increased sucrose preference) and behavioral despair (decreased immobility time in tail suspension test (TST) and forced swimming test (FST)). The extract not only decreased the elevation of serum corticosterone level and the index of over-activation of the hypothalamic-pituitary-adrenal (HPA) axis, caused by UCMS, but also ameliorated UCMS-induced up-regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) mRNA expression and down-regulation of cyclic AMP-responsive element binding (CREB) and brain-derived neurotrophic factor (BDNF) mRNAs in frontal cortex and hippocampus. In vitro monoamine oxidase (MAO) inhibition assays showed that the extract exhibited the partial selective inhibition on MAO-A. HPLC analysis of the extract showed the presence of flavonoids (luteolin-7-O-glucoside, kaempferol-3-glucoside, rutin) and phenolic acids (gallic acid, ferulic acid, and caffeic acid) as major constituents.


Assuntos
Depressão , Dipterocarpaceae/química , Etanol/química , Extratos Vegetais , Folhas de Planta/química , Estresse Psicológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Proteínas Imediatamente Precoces/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteínas Serina-Treonina Quinases/biossíntese , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
5.
Int J Mol Sci ; 20(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319604

RESUMO

Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4+ and CD8+ T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (Treg) and decreased gene expression levels of TGF-ß. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4+ cells (CD4-PPARγKO), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγWT controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses Treg cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.


Assuntos
Diferenciação Celular/imunologia , Estresse Psicológico/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Suscetibilidade a Doenças , Masculino , Camundongos , Estresse Psicológico/patologia , Linfócitos T Reguladores/patologia , Células Th17/patologia
6.
World J Gastroenterol ; 25(23): 2911-2923, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31249449

RESUMO

BACKGROUND: Stress-induced gastric ulcer (SGU) is one of the most common visceral complications after trauma. Restraint water-immersion stress (RWIS) can cause serious gastrointestinal dysfunction and has been widely used to study the pathogenesis of SGU to identify medications that can cure the disease. The mediodorsal thalamic nucleus (MD) is the centre integrating visceral and physical activity and contributes to SGU induced by RWIS. Hence, the role of the MD during RWIS needs to be studied. AIM: To screen for differentially expressed proteins in the MD of the RWIS rats to further elucidate molecular mechanisms of SGU. METHODS: Male Wistar rats were selected randomly and divided into two groups, namely, a control group and an RWIS group. Gastric mucosal lesions of the sacrificed rats were measured using the erosion index and the proteomic profiles of the MD were generated through isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography and tandem mass spectrometry. Additionally, iTRAQ results were verified by Western blot analysis. RESULTS: A total of 2853 proteins were identified, and these included 65 dysregulated (31 upregulated and 34 downregulated) proteins (fold change ratio ≥ 1.2). Gene Ontology (GO) analysis showed that most of the upregulated proteins are primarily related to cell division, whereas most of the downregulated proteins are related to neuron morphogenesis and neurotransmitter regulation. Ingenuity Pathway Analysis revealed that the dysregulated proteins are mainly involved in the neurological disease signalling pathways. Furthermore, our results indicated that glycogen synthase kinase-3 beta might be related to the central mechanism through which RWIS gives rise to SGU. CONCLUSION: Quantitative proteomic analysis elucidated the molecular targets associated with the production of SGU and provides insights into the role of the MD. The underlying molecular mechanisms need to be further dissected.


Assuntos
Núcleo Mediodorsal do Tálamo/patologia , Proteoma/metabolismo , Úlcera Gástrica/etiologia , Estresse Psicológico/patologia , Animais , Modelos Animais de Doenças , Humanos , Masculino , Proteômica , Ratos , Ratos Wistar , Estresse Psicológico/complicações , Estresse Psicológico/etiologia , Regulação para Cima
7.
Int J Mol Sci ; 20(7)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965559

RESUMO

Ketamine is an N-methyl-d-aspartate receptor antagonist that has gained wide attention as a potent antidepressant. It has also been recently reported to have prophylactic effects in animal models of depression and anxiety. Alterations of neuroplasticity in different brain regions; such as the hippocampus; prefrontal cortex; and amygdala; are a hallmark of stress-related disorders; and such changes may endure beyond the treatment of symptoms. The present study investigated whether a prophylactic injection of ketamine has effects on structural plasticity in the brain in mice that are subjected to chronic unpredictable stress followed by an 8-day recovery period. Ketamine administration (3 mg/kg body weight) 1 h before stress exposure increased the number of resilient animals immediately after the cessation of stress exposure and positively influenced the recovery of susceptible animals to hedonic deficits. At the end of the recovery period; ketamine-treated animals exhibited significant differences in dendritic spine density and dendritic spine morphology in brain regions associated with depression compared with saline-treated animals. These results confirm previous findings of the prophylactic effects of ketamine and provide further evidence of an association between the antidepressant-like effect of ketamine and alterations of structural plasticity in the brain.


Assuntos
Antidepressivos/uso terapêutico , Região CA3 Hipocampal/efeitos dos fármacos , Depressão/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Ketamina/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Animais , Comportamento Animal , Depressão/patologia , Modelos Animais de Doenças , Elevação dos Membros Posteriores/fisiologia , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Restrição Física/fisiologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia
8.
Mol Brain ; 12(1): 37, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971312

RESUMO

Genetic and pharmacological manipulations targeting metabotropic glutamate receptor 5 (mGluR5) affect performance in behavioural paradigms that depend on cognitive flexibility. Many of these studies involved exposing mice to highly stressful conditions including electric foot shocks or water immersion and forced swimming. Because mGluR5 is also implicated in resilience and stress responses, however, apparent impairments in inhibitory learning may have been an artifact of manipulation-induced changes in affective state. To address this, we present here a characterization of cognitive flexibility in mGluR5 knockout (KO) mice conducted with a rodent touchscreen cognitive assessment apparatus in which the animals experience significantly less stress.Our results indicate a significant reversal learning impairment relative to wild-type (WT) controls in the two-choice Visual Discrimination-Reversal (VDR) paradigm. Upon further analysis, we found that this deficit is primarily driven by a prolonged period of perseveration in the early phase of reversal. We also observed a similar perseveration phenotype in the KO mice in the Extinction (EXT) paradigm. In addition, mGluR5 KO mice show higher breakpoints in the touchscreen Progressive Ratio (PR) and altered decision making in the Effort-related Choice (ERC) tasks. Interestingly, this impairment in PR is an additional manifestation of an increased propensity to perseverate on the emission of relatively simplistic behavioural outputs.Together, these findings suggest that under conditions of low stress, mGluR5 KO mice exhibit a pronounced perseverative phenotype that blunts cognitive flexibility.


Assuntos
Comportamento Animal , Receptor de Glutamato Metabotrópico 5/deficiência , Estresse Psicológico/patologia , Animais , Comportamento de Escolha , Tomada de Decisões , Extinção Psicológica , Comportamento Alimentar , Deleção de Genes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Análise e Desempenho de Tarefas , Percepção Visual
9.
Biomed Res Int ; 2019: 2649281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30956976

RESUMO

Centella asiatica ameliorates memory impairment and induces expression of hippocampal brain-derived neurotropic factor (BDNF) in chronically stressed rats. The relationship between the anti-inflammatory effect of Centella asiatica on hippocampal BDNF and the involvement of sirtuin-1, a BDNF expression regulator, in neuroprotective mechanisms of Centella asiatica warrants an investigation. We investigated the effect of Centella asiatica ethanolic extracts (CA) on TNF-α, IL-10, and SIRT1 levels and whether these predicted BDNF expression in rat hippocampus after chronic stress. For the experiments, thirty male rats (Sprague Dawley) were divided into six groups: nonstressed-control, stressed-control, nonstressed +CA 300mg/kg/d, stressed +CA 150 mg/kg/d, stressed +CA 300 mg/kg/d, and stressed +CA 600 mg/kg/d. On day 28, rats were sacrificed and hippocampus was dissected out. Hippocampal TNF-α, IL-10, SIRT1, and BDNF were measured by enzyme-linked immunosorbent assay. Hippocampal TNF-α level was significantly higher in the stressed-control compared to nonstressed-control groups. Across all stress conditions, rats receiving the highest dose of CA had the lowest mean TNF-α and highest mean BDNF. There were no significant differences in IL-10 and SIRT1 levels between groups. Hippocampal TNF-α did not predict hippocampal BDNF in a regression analysis. In conclusion, lower TNF-α and higher BDNF in the hippocampus support the hypothesis that these factors independently contribute to Centella asiatica's neuroprotective effect in chronically stressed rats.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Centella/química , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Psicológico , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Doença Crônica , Hipocampo/patologia , Masculino , Fármacos Neuroprotetores/química , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/prevenção & controle , Triterpenos/química
10.
Eur J Pharmacol ; 853: 236-246, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928632

RESUMO

Hesperidin, a kind of citrus bioflavonoid distributed in foods including grapefruits, oranges and lemons, has many pharmacological activities. This study was aimed to evaluate the anti-depressant-like effect of hesperidin on chronic unpredictable mild stress (CUMS)-induced mice. Depressive-like behavior was detected by the sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST). A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to assess the cell viability of corticosterone-induced PC12 cells. The serum, hippocampal and cell supernatant concentrations of interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α were determined using enzyme-linked immunosorbent assay (ELISA) commercial kits. Furthermore, the protein expression levels of high-mobility group box 1 protein (HMGB1), receptor for advanced glycation end-products (RAGE)/NF-κB and brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway in the hippocampus and corticosterone-induced PC12 cells were detected by Western blot. Our results showed that hesperidin (100, 200 mg/kg) significantly relieved depressive-like behaviors, including decreased sucrose consumption in sucrose preference test (SPT), immobility in the forced swimming test (FST), tail suspension test, and locomotor activity in the open field test (OFT). Hesperidin reduced inflammatory cytokine levels by attenuating the HMGB1/RAGE/NF-κB signaling pathway and BDNF/TrkB pathway both in vivo and in vitro. In conclusion, hesperidin possessed efficient neuroprotective effects on depression, which was associated with neuroinflammation mediated by the HMGB1/RAGE/NF-κB and BDNF/TrkB pathways.


Assuntos
Antidepressivos/farmacologia , Hesperidina/farmacologia , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Depressão/psicologia , Proteína HMGB1/metabolismo , Hesperidina/uso terapêutico , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , NF-kappa B/metabolismo , Células PC12 , Proteínas Tirosina Quinases/metabolismo , Ratos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/psicologia
11.
PLoS One ; 14(3): e0214093, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30908509

RESUMO

The repeated use of a drug frequently leads to alterations in the response to that drug. We undertook this study to determine whether multiple exposures to the general anesthetic produced alterations in subsequent exposures to this anesthetic. For this study, adult male rats were anesthetized with 2.5% isoflurane for one hour. The rats were divided into 4 groups of 8 rats each. Groups 1-3 were transported between their homeroom and the anesthesia testing room and were handled in an identical manner weekly for a period of 12 weeks, but were anesthetized on different schedules. Group 1 was anesthetized weekly for 12 weeks, Group 2 on either a 3 or 4 week schedule and Group 3 was anesthetized a single time, at the end of the 12 week period. To receive anesthesia multiple times, animals were transported from their homeroom to the anesthesia location and handled repeatedly. We took into consideration of the frequency of anesthesia exposure and the stress involved. Rats in groups 2 and 3 were placed in the anesthesia chamber, with O2 but with no anesthetic, every week when they were not scheduled to receive anesthesia. In Group 4, rats were not transported or handled in any way and stayed in the home room for a period of 12 weeks. Rats in this group were anesthetized once, at the very end of the study. Recovery of the rat's righting reflex was used to assess the acceleration of recovery time from general anesthesia. Group 1 rats showed dramatically faster emergence from anesthesia after several rounds of anesthesia. Surprisingly, Groups 2 and 3 rats, treated in an identical manner as Group 1, but which were anesthetized on different schedules, also exhibited more rapid emergence from anesthesia, when compared to Group 4 rats, which were never handled or transported prior to a single anesthesia. These results suggest that the stress of transportation and handling altered responsiveness to anesthesia. Our results show that responsiveness to anesthetic agents can change over time outside of the normal developmental changes taking place in rats as they age.


Assuntos
Anestesia Geral , Anestésicos Inalatórios/efeitos adversos , Isoflurano/efeitos adversos , Estresse Psicológico/fisiopatologia , Anestésicos Inalatórios/farmacologia , Animais , Isoflurano/farmacologia , Projetos Piloto , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/patologia
12.
Psychopathology ; 52(1): 18-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30844818

RESUMO

BACKGROUND: Post-traumatic embitterment disorder (PTED) has recently been introduced as a subgroup of adjustment disorders related to stressful life events. Embitterment is defined as persistent feelings of inadequacy or hoping for revenge after being insulted but feeling helpless after experiencing a life stressor. This study aims to investigate the cumulative and differential effects of negative life events on the risk of developing embitterment among young adults in South Korea. METHODS: Data for the present study were collected from a web-based survey of 1,000 young adults aged 18-35 years. All participants completed a list of negative life events, the PTED Self-Rating Scale. Logistic regression analysis was conducted to evaluate the relationships between the number of negative life events and reactive embitterment. Analyses of the relationships between each negative life event and reactive embitterment were performed using covariates, including childhood trauma, depression, and anxiety symptoms. RESULTS: The total number of participants with reactive embitterment (cut-off scores > 2.5) was 452 (45.2%). Greater exposure to negative life events increased the risk of reactive embitterment compared to no negative events. Negative life events, including financial problems, family problems, and being excluded by friends, had significant associations with the risk of reactive embitterment. CONCLUSIONS: The present study revealed a substantial number of young adults with a high level of embitterment. Furthermore, cumulative and differential effects of negative events increased the risk for reactive embitterment. Our findings underlined the crucial role of adverse life events in the development of reactive embitterment.


Assuntos
Transtornos de Estresse Pós-Traumáticos/diagnóstico , Estresse Psicológico/psicologia , Adolescente , Adulto , Feminino , Humanos , Masculino , República da Coreia , Transtornos de Estresse Pós-Traumáticos/patologia , Estresse Psicológico/patologia , Inquéritos e Questionários , Adulto Jovem
13.
Int J Neuropsychopharmacol ; 22(5): 349-357, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30911751

RESUMO

BACKGROUND: Suicide and major depression are prevalent in individuals reporting early-life adversity. Prefrontal cortex volume is reduced by stress acutely and progressively, and changes in neuron and glia density are reported in depressed suicide decedents. We previously found reduced neurotrophic factor brain-derived neurotrophic factor in suicide decedents and with early-life adversity, and we sought to determine whether cortex thickness or neuron or glia density in the dorsolateral prefrontal and anterior cingulate cortex are associated with early-life adversity or suicide. METHODS: A total of 52 brains, constituting 13 quadruplets of nonpsychiatric controls and major depressive disorder suicide decedents with and without early-life adversity, were matched for age, sex, race, and postmortem interval. Brains were collected at autopsy and frozen, and dorsolateral prefrontal cortex and anterior cingulate cortex were later dissected, postfixed, and sectioned. Sections were immunostained for neuron-specific nuclear protein (NeuN) to label neurons and counterstained with thionin to stain glial cell nuclei. Cortex thickness, neuron and glial density, and neuron volume were measured by stereology. RESULTS: Cortical thickness was 6% less with early-life adversity in dorsolateral prefrontal cortex and 12% less in anterior cingulate cortex (P < .05), but not in depressed suicide decedents in either region. Neuron density was not different in early-life adversity or with suicide, but glial density was 17% greater with early-life adversity in dorsolateral prefrontal cortex and 15% greater in anterior cingulate cortex, but not in suicides. Neuron volume was not different with early-life adversity or suicide. CONCLUSIONS: Reported early-life adversity, but not the stress associated with suicide, is associated with thinner prefrontal cortex and greater glia density in adulthood. Early-life adversity may alter normal neurodevelopment and contribute to suicide risk.


Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância , Substância Cinzenta/patologia , Córtex Pré-Frontal/patologia , Estresse Psicológico/patologia , Suicídio , Adulto , Transtorno Depressivo/patologia , Feminino , Giro do Cíngulo/patologia , Humanos , Masculino , Neuroglia/patologia , Neurônios/patologia , Tamanho do Órgão
14.
Horm Behav ; 112: 20-31, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30917909

RESUMO

Chronic exposure to stress during adolescent period has been demonstrated to impair cognitive functions and the dendritic morphology of pyramidal neurons in the rat hippocampal CA3 area. The present study investigated the combined protective effects of Spirulina platensis (SP), a supplement made from blue-green algae with neuroprotective properties, voluntary exercise (EX) and environmental enrichment (EE) against cognitive deficits, alternations in hippocampal BDNF levels, and abnormal neuronal remodeling in adult female rats (PND 60) induced by exposure to chronic restraint stress during adolescent period (PND 30-40). Rats were exposed to restraint stress (2 h/day for 10 days, PND 30-40). Then, the animals were subjected to treatment with SP (200 mg/kg/day), EX, EE and the combined treatments (SP + EX, and SP + EE) between PND 41 and 55 of age. Following the interventions, spatial learning and memory, passive avoidance performance, hippocampal dendritic morphology and BDNF levels were assessed. Results showed that plasma corticosterone levels increased at PND 40 and remained elevated at PND 55 and 70 in the stressed rats. Stressed rats showed deficits in spatial learning and memory and passive avoidance performance, decreased BDNF levels in the hippocampus, and reduced apical dendritic length and branch points of the CA3 pyramidal neurons. These deficits were alleviated by the SP, EX and EE, and the combined treatments, which accompanied with a decline in serum corticosterone in stressed animals. Some treatments even enhanced cognitive functions, and BDNF levels and neuroanatomical remodeling in the hippocampus of non-stressed animals. Our findings provide important evidences that physical activity, exposure to EE, and the SP treatment during adolescent period can protect against adolescent stress induced behavioral, biochemical and neuroanatomical impairments in adulthood.


Assuntos
Extratos Celulares/farmacologia , Transtornos Cognitivos/prevenção & controle , Plasticidade Neuronal , Condicionamento Físico Animal/fisiologia , Meio Social , Spirulina/química , Estresse Psicológico/complicações , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , /fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Memória/efeitos dos fármacos , Memória/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar , Restrição Física/fisiologia , Restrição Física/psicologia , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/fisiologia , Aprendizagem Espacial/efeitos dos fármacos , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/psicologia
15.
Neurol Res ; 41(5): 446-455, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30759063

RESUMO

BACKGROUND: Post-stroke depression (PSD) is one of the most prevalent emotional disorders after stroke and often results in poor outcomes. However, the underlying physiopathologic mechanism and effective treatment of PSD remain poorly elucidated. OBJECTIVE: To investigate whether paeoniflorin has antidepressant-like activity in a rat model of PSD. METHODS: Rats were randomly divided into four groups: sham-operated control (Sham), PSD, paeoniflorin (with PSD) and fluoxetine group(with PSD). PSD was developed by the right middle cerebral artery occlusion followed 21 days chronic unpredictable mild stress combined (CUMS) with raised alone. Tests of sucrose preference and open field were used to assess the depression-like behavior. Neurological function was evaluated by neurological deficit score and beam balance test. Expression of phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF) in the CA1 region of the hippocampal complex was evaluated by western blot and immunofluorescence. RESULTS: Te depressive-like behaviors markedly improved after paeoniflorin and fluoxetine treatment. Furthermore, paeoniflorin treatment significantly increased BDNF and p-CREB expression in the CA1 region. CONCLUSIONS: Observed results suggested that paeoniflorin could ameliorate the symptoms and improve the functional capability of PSD rats, similar to the effect of fluoxetine. ABBREVIATIONS: PSD: post-stroke depression; CUMS: chronic unpredictable mild stress stimulation; MCAO: middle cerebral artery occlusion; OFT: open field test; SPT: sucrose preference test, NDS: neurological deficit score, BBT: beam balance test; BDNF: brain-derived neurotrophic factor protein; p-CREB: phosphorylated Cyclic-AMP responsive element binding protein.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/etiologia , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Acidente Vascular Cerebral/complicações , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Transtorno Depressivo/patologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Fluoxetina/farmacologia , Masculino , Distribuição Aleatória , Ratos Sprague-Dawley , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
16.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30783612

RESUMO

Stress causes divergent patterns of structural and physiological plasticity in the hippocampus versus amygdala. However, a majority of earlier studies focused primarily on neurons. Despite growing evidence for the importance of glia in health and disease, relatively little is known about how stress affects astrocytes. Further, previous work focused on hippocampal astrocytes. Hence, we examined the impact of chronic immobilization stress (2 h/d, 10 d), on the number and structure of astrocytes in the rat hippocampus and amygdala. We observed a reduction in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the basal amygdala (BA), 1 d after the end of 10 d of chronic stress. Detailed morphometric analysis of individual dye-filled astrocytes also revealed a decrease in the neuropil volume occupied by these astrocytes in the BA, alongside a reduction in the volume fraction of fine astrocytic protrusions rather than larger dendrite-like processes. By contrast, the same chronic stress had no effect on the number or morphology of astrocytes in hippocampal area CA3. We also confirmed previous reports that chronic stress triggers dendritic hypertrophy in dye-filled BA principal neurons that were located adjacent to astrocytes that had undergone atrophy. Thus, building on earlier evidence for contrasting patterns of stress-induced plasticity in neurons across brain areas, our findings offer new evidence that the same stress can also elicit divergent morphological effects in astrocytes in the hippocampus versus the amygdala.


Assuntos
Tonsila do Cerebelo/patologia , Astrócitos/patologia , Região CA3 Hipocampal/patologia , Estresse Psicológico/patologia , Tonsila do Cerebelo/metabolismo , Animais , Astrócitos/metabolismo , Região CA3 Hipocampal/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo
17.
J Pharmacol Exp Ther ; 369(1): 163-172, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30635472

RESUMO

N-Palmitoylethanolamide (PEA), an endocannabinoid-like molecule, participates in controlling behaviors associated with mental disorders as an endogenous neuroprotective factor. On the basis of accumulating evidence and our previous data, we tested the hypothesis that the antidepressant-like effects of PEA observed during chronic unpredictable mild stress (CUMS) are mediated by possible targets in the peroxisome proliferator-activated receptor alpha (PPARα) pathway. In this study, rats were subjected to 35 days of CUMS and treated with drugs such as PEA (2.5, 5.0, or 10 mg/kg, by mouth), fluoxetine (10 mg/kg, by mouth), or the combination of PEA and MK886 (1-[(4-chlorophenyl) methyl]-3-[(1,1-dimethylethyl) thio]-α,α-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid). After behavioral tests, the animals were sacrificed and their hippocampi were dissected for subsequent studies. PEA normalized weight gain, sucrose preferences, locomotor activity in an open-field test, and levels of the PPARα mRNA and protein in the hippocampus, and it reduced serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels in rats subjected to CUMS. PEA reversed the abnormal levels of several oxidative stress biomarkers and increased the concentrations of two neurotrophic factors in the hippocampus of CUMS-induced rats. In addition, PEA alleviated the decrease in hippocampal weight. However, the aforementioned effects of PEA were completely or partially abolished by MK886, a selective PPARα antagonist. On the basis of these findings, the PPARα pathway in the hippocampus is a possible target of the antidepressant effects of PEA, and the maintenance of a stable hypothalamic-pituitary-adrenal axis, the antioxidant defenses, and normalization of neurotrophic factor levels in the hippocampus are involved in this process.


Assuntos
Antidepressivos/farmacologia , Etanolaminas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , PPAR alfa/metabolismo , Ácidos Palmíticos/farmacologia , Hormônio Adrenocorticotrópico/sangue , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/sangue , Etanolaminas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Glutationa/metabolismo , Hipocampo/patologia , Masculino , Malondialdeído/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ácidos Palmíticos/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/sangue , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Superóxido Dismutase/metabolismo
18.
Mol Med Rep ; 19(3): 2386-2396, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664210

RESUMO

Brain metabolism is closely associated with neuronal activity and enables the accurate synthesis and function of neurotransmitters. Although previous studies have demonstrated that chronic stress is associated with the overproduction of reactive oxygen species (ROS), which leads to oxidative stress and the disruption of glucose metabolism, the molecular mechanisms and cerebral gluconeogenesis in depression have not yet been completely elucidated. In order to examine this subject, the present study evaluated changes in the expression of selected genes involved in the glycolytic pathway and the levels of glucogenic and neuroactive amino acids in the brain of rats exposed to chronic variable stress. Male Wistar rats (50­55 days old, weighing 200­250 g) were divided into two groups: control and stressed, and the rats in the stressed group were exposed to stress conditions for 40 days. Depressive­like states were observed and recorded by measuring the body weight and forced swim test (FST). The mRNA levels of Slc2a3 (coding GLUT3) and Tfam (activator of mitochondrial transcription and a participant in mitochondrial genome replication) were markedly increased, while a decrease in the expression of Ldhb and GAPDH was also observed. These modifications were associated with the redirection of glucose metabolism to appropriate defensive pathways under chronic stress conditions, and an increased ability to maintain mitochondrial function as potential adaptive responses. A marked reduction of glucogenic and neuroactive amino acids levels indicate the support of energy metabolism by stimulation of the gluconeogenesis pathway. The findings of the present study provide a novel insight into the molecular and biochemical events that impact the development of depression under chronic stress conditions, and they may identify novel targets for therapeutic intervention.


Assuntos
Encéfalo/metabolismo , Depressão/genética , Metabolismo Energético/genética , Estresse Psicológico/genética , Aminoácidos/genética , Animais , Peso Corporal/genética , Encéfalo/patologia , Depressão/fisiopatologia , Regulação da Expressão Gênica/genética , Glucose/metabolismo , Transportador de Glucose Tipo 3/genética , Humanos , Isoenzimas/genética , L-Lactato Desidrogenase/genética , Mitocôndrias , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/biossíntese , Neurotransmissores/metabolismo , Estresse Oxidativo/genética , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Fatores de Transcrição/genética
19.
Neurochem Res ; 44(4): 917-929, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30656594

RESUMO

Increasing evidence suggests that exposure to chronic stress during adolescent period may lead to behavioral and neuronal morphology deficits in adulthood. This study examined whether crocin, the main active saffron constituent, and voluntary exercise, alone or combined, could prevent the detrimental influences of chronic restraint stress during adolescent (postnatal days, PND, 30-40) on behavioral and morphological deficits in adult (PND60) male rats. Results showed that plasma corticosterone levels increased at PND40, but not PND60 in stressed rats. Moreover, stressed rats demonstrated enhanced anxiety levels and depression like behaviors in adulthood. These behavioral abnormalities were accompanied by a decline in apical dendritic length in both infralimbic and prelimbic regions and dendritic branches in infralimbic region of the prefrontal cortex. Treatment with crocin, exposure to wheel running activity, and the combined interventions alleviated both behavioral and morphological deficits induced by adolescent stress. Moreover, these treatments exerted positive neuronal morphological effects in the prefrontal cortex in non-stressed animals. Our findings provide important evidences that exercise as a non-pharmacological intervention and crocin treatment during pre-pubertal period can protect against adolescent stress induced behavioral and morphological abnormalities in adulthood.


Assuntos
Ansiedade/terapia , Carotenoides/administração & dosagem , Dendritos/efeitos dos fármacos , Depressão/terapia , Condicionamento Físico Animal/métodos , Estresse Psicológico/terapia , Animais , Ansiedade/sangue , Terapia Combinada/métodos , Corticosterona/sangue , Dendritos/patologia , Dendritos/fisiologia , Depressão/sangue , Depressão/patologia , Masculino , Condicionamento Físico Animal/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar , Restrição Física , Estresse Psicológico/sangue , Estresse Psicológico/patologia , Resultado do Tratamento
20.
J Clin Invest ; 129(3): 1030-1046, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30688660

RESUMO

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress-induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Epinefrina/metabolismo , L-Lactato Desidrogenase/metabolismo , Células-Tronco Neoplásicas/enzimologia , Estresse Psicológico/metabolismo , Animais , Ácido Ascórbico/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/patologia
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