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1.
Gene ; 745: 144651, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32259633

RESUMO

Sexual differentiation and ovotestis development are closely associated with cortisol levels, the principal indicator of stress, via the glucocorticoid receptor (GR) in teleosts. Thus, GR is regarded as a mediator to expound the relationship between social stress and gonad development. In the present study, two gr genes (gr1 and gr2) were cloned and analyzed from a protandrous hermaphroditic teleost, the yellowtail clownfish (Amphiprion clarkii). GR1 was found to display a conserved nine-amino-acid insert, WRARQNTDG, between two zinc finger domains. The phylogenetic tree of GR showed that yellowtail clownfish GR1 and GR2 are clustered to teleost GR1 and teleost GR2 separately, and differ from tetrapod GR. The result of real-time PCR revealed that high-level gr1 was mainly distributed in the cerebellum, hypothalamus and heart. The gr2 gene was abundant in the pituitary and liver of females and nonbreeders, while gr2 was mainly detected in the medulla oblongata and middle kidney of males. Moreover, GRs can be expressed in cultured eukaryotic cells and functionally interact with dexamethasone (exogenous glucocorticoid), thereby triggering downstream signaling pathways of different potentials. GR1 and GR2 can be activated by 10 nM dexamethasone treatment in HEK-293T cells. Notably, real-time PCR analysis among three social status groups demonstrated that gr2 expression was the highest in the hypothalamus of nonbreeders, but gr1 was no difference. We speculate that social stress would increase the expression of gr2 gene expression in the hypothalamus to inhibit sexual development. These data provide evidence of social stress involving reproductive regulation, which may help to elucidate the underlying mechanism of sex differentiation and change.


Assuntos
Proteínas de Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento , Perciformes/genética , Receptores de Glucocorticoides/genética , Diferenciação Sexual/genética , Animais , Dexametasona/farmacologia , Feminino , Proteínas de Peixes/metabolismo , Células HEK293 , Humanos , Masculino , Família Multigênica , Perciformes/metabolismo , Filogenia , Receptores de Glucocorticoides/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reprodução/genética , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/genética , Dedos de Zinco/genética
2.
BMC Med Genet ; 21(1): 53, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171272

RESUMO

BACKGROUND: Adolescence is a distinctive stage of various changes and is noted as peak age for onset of many psychiatric disorders, especially linked to stress and depression. Several genetic variations are being increasingly known to be linked with stress and depression. The polymorphisms in two such genes, the BDNF and SLC1A3, have been reported to be linked with either depression/stress or with suicidal behaviour. These genes have not been validated in Indian population, and therefore there is a need to investigate these genes in Indian population. The present study was undertaken to test whether the known polymorphisms SLC1A3 C3590T, SLC1A3 C869G and BDNF G196A are associated or not with stress or depression in an eastern Indian population. METHODS: A case-control association study was performed with 108 cases having variable levels of stress and depression and 205 matched controls. Detection of stress and depression was done by using standard instruments as PSS and CES-D, respectively and demographic profile was obtained for each individual on the basis of personal data sheet. Genotyping for the selected polymorphisms was performed by PCR followed by restriction digestion. RESULTS: The SNP SLC1A3 C3590T was found to be associated with stress and depression (p = 0.0042, OR = 2.072). Therefore, the T allele increases the risk by more than two folds for stress and depression in the present population. The other allele of SLC1A3, G869C, as well as BDNF G196A were not associated with stress or depression in the population studied. CONCLUSION: SLC1A3 C3590T is a predisposition factor for stress and depression in an eastern Indian population, whereas SLC1A3 G869C and BDNF G196A were not found to be a risk factor. Therefore, presence of T allele of SLC1A3 C3590T, may predict the development of stress and depression in an individual. This may also help in the understanding of pathophysiology of the disease. However, these findings warrant a wider study in Indian populations and would be of significance in understanding the predisposition of stress and depression in this population.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/genética , Transportador 1 de Aminoácido Excitatório/genética , Polimorfismo de Nucleotídeo Único , Estresse Psicológico/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Depressão/epidemiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Índia/epidemiologia , Masculino , Psicologia do Adolescente , Fatores de Risco , Estresse Psicológico/epidemiologia , Adulto Jovem
3.
PLoS One ; 15(1): e0227909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31986193

RESUMO

Vitiligo is a T-cell mediated skin disorder characterized by progressive loss of skin color. In individuals genetically predisposed to the disease, various triggers contribute to the initiation of vitiligo. Precipitating factors can stress the skin, leading to T-cell activation and recruitment. Though hereditary factors are implicated in the pathogenesis of vitiligo, it is unknown whether precipitating, stressful events play a role in vitiligo. To understand this, we utilized a validated perceived stress scale (PSS) to measure this parameter in vitiligo patients compared to persons without vitiligo. Additionally, we probed a clinical database, using a knowledge linking software called ROCKET, to gauge stress-related conditions in the vitiligo patient population. From a pool of patients in an existing database, a hundred individuals with vitiligo and twenty-five age- and sex-matched comparison group of individuals without vitiligo completed an online survey to quantify their levels of perceived stress. In parallel, patients described specifics of their disease condition, including the affected body sites, the extent, duration and activity of their vitiligo. Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo. ROCKET analyses suggested signs of metabolic-related disease (i.e., 'stress') preceding vitiligo development. No correlation was found between perceived stress and the stage or the extent of disease, suggesting that elevated stress may not be a consequence of pigment loss alone. The data provide further support for stress as a precipitating factor in vitiligo development.


Assuntos
Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Vitiligo/fisiopatologia , Vitiligo/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Resposta ao Choque Térmico/genética , Humanos , Lactente , Recém-Nascido , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Pessoa de Meia-Idade , Pacientes/psicologia , Estresse Psicológico/complicações , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Inquéritos e Questionários , Linfócitos T/metabolismo , Linfócitos T/patologia , Vitiligo/complicações , Vitiligo/metabolismo , Adulto Jovem
4.
Biomed Res Int ; 2019: 5705232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612144

RESUMO

Postmenopausal depression is closely associated with depletion of estrogen which modulates transmission of 5-HT, a key neurotransmitter that regulates stress-managing circuits in the brain. In this study, antidepressive efficacy of white ginseng (Panax gingseng Meyer, WG) was evaluated in stressed ovariectomized rats. Female Sprague Dawley rats were ovariectomized and repeatedly restraint stressed for 2 weeks (2h/day). Thirty minutes before restraint stress, rats were administered saline (control), WG 200 mg/kg (p.o.), WG 400 mg/kg (p.o.), or fluoxetine (PC, 10 mg/kg, i.p.). Tail suspension test (TST) and forced swimming test (FST) were performed to assess antidepressant effect of WG. After behavioral tests, levels of serum corticosterone (CORT) and hippocampal 5-HT were measured. Significant decrease of immobility time in TST and FST was shown in rats administered with PC or WG 400 compared to the control. WG200-treated rats showed remarkable reduction in immobility time of TST. PC, WG 200, or WG 400-administred group exhibited significant reduction of CORT compared to the control. PC or WG-treated rats exhibited remarkable increase in hippocampal 5-HT concentration compared to the control. Hippocampal 5-HT levels in WG groups were higher than those in the PC group. The present study demonstrated that WG had antidepressant efficacy in an animal model of menopausal depression. Treatment with WG enhanced hippocampal 5-HT level while suppressing depressive symptom and serum CORT level. These results provide evidence that WG plays an important role in activating serotonergic neurons in stressful situation, suggesting that WG might be a reliable natural alternative of antidepressant drugs to treat menopausal depression.


Assuntos
Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Panax/química , Serotonina/metabolismo , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Depressão/genética , Depressão/fisiopatologia , Transtorno Depressivo/genética , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Elevação dos Membros Posteriores/métodos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Ratos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Natação
5.
Endocr Regul ; 53(2): 100-109, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517627

RESUMO

OBJECTIVES: Despite extensive research efforts, mechanisms participating on development of Alzheimer's disease (AD) are covered only partially. Data from the last decades indicate that various stressors, as etiological factors, may play a role of in the AD. Therefore, we investigated the effect of two acute stressors, immobilization (IMO) and lipopolysaccharide (LPS), on the AD-related neuropathology. METHODS: Adult C57BL/6J mice males were exposed to a single IMO stress or a single intraperitoneal injection of LPS (250 µg/kg body weight). After terminating the experiments, the brains were removed and their cortices isolated. Gene expression of pro-inflammatory cytokines, as well as expression of genes implicated in the AD neuropathology were determined. In addition, mediators related to the activation of the microglia, monocytes, and perivascular macrophages were determined in brain cortices, as well. RESULTS: In comparison with the control animals, we found increased gene expression of proinflammatory mediators in mice brain cortex in both IMO and LPS groups. In stressed animals, we also showed an increased expression of genes related to the AD neuropathology, as well as positive correlations between genes implicated in AD development and associated neuroinflammation. CONCLUSIONS: Our data indicate that acute exposure to a strong IMO stressor, composed of the combined physical and psychological challenges, induces similar inflammatory and other ADrelated neuropathological changes as the immune LPS treatment. Our data also indicate that cytokines are most likely released from the peripheral immune cells, as we detected myeloid cells activity, without any microglia response. We hypothesize that stress induces innate immune response in the brain that consequently potentiate the expression of genes implicated in the AD-related neuropathology.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Inflamação , Lipopolissacarídeos , Restrição Física/efeitos adversos , Estresse Psicológico/genética , Doença Aguda , Doença de Alzheimer/metabolismo , Animais , Encéfalo/patologia , Citocinas/genética , Inflamação/induzido quimicamente , Inflamação/genética , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Restrição Física/psicologia , Estresse Psicológico/etiologia , Regulação para Cima/genética
6.
Nat Med ; 25(9): 1428-1441, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501614

RESUMO

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ+ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.


Assuntos
Imunidade Celular , Neoplasias/imunologia , Estresse Psicológico/imunologia , Fatores de Transcrição/genética , Animais , Ansiedade/sangue , Ansiedade/induzido quimicamente , Ansiedade/imunologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Carcinógenos/toxicidade , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/psicologia , Corticosterona/sangue , Células Dendríticas/transplante , Regulação Neoplásica da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/psicologia , Ativação Linfocitária/genética , Camundongos , Monitorização Imunológica/métodos , Neoplasias/induzido quimicamente , Neoplasias/genética , Neoplasias/psicologia , Receptores de Glucocorticoides/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/psicologia , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/genética , Estresse Psicológico/terapia , Fatores de Transcrição/imunologia
7.
Trans Am Clin Climatol Assoc ; 130: 235-245, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31516188

RESUMO

Significant adverse impact of various forms of psychological stress on susceptibility to infection, altered wound healing, increased prevalence and severity of hypersensitivity diseases, and even increased mortality in cancer patients has been well described. Yet these observations are limited by often unpredictable individual responses to various stressful situations. These associations are further clouded by natural variability among diverse forms of and responses to chronic life stressors and associated comorbid conditions. This is particularly true for inflammatory diseases where gene/external environmental interactions are well-described. What is much less understood is gene-internal environmental (i.e., psychological) interactions that commonly affect disease activity and possible susceptibility. We have used selected single nucleotide polymorphisms of stress hormone and regulatory cytokine receptors to categorize both baseline and stress-associated immune parameters for the a priori classification of individuals with the most stress susceptible immune systems to identify those most responsive to a stress reduction/management-based intervention.


Assuntos
Hipersensibilidade/genética , Estresse Psicológico/genética , Suscetibilidade a Doenças , Predisposição Genética para Doença , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/psicologia , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/imunologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/imunologia , Estresse Psicológico/imunologia , Estresse Psicológico/psicologia
8.
Nat Neurosci ; 22(9): 1413-1423, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31427770

RESUMO

Understanding the transcriptional changes that are engaged in stress resilience may reveal novel antidepressant targets. Here we use gene co-expression analysis of RNA-sequencing data from brains of resilient mice to identify a gene network that is unique to resilience. Zfp189, which encodes a previously unstudied zinc finger protein, is the highest-ranked key driver gene in the network, and overexpression of Zfp189 in prefrontal cortical neurons preferentially activates this network and promotes behavioral resilience. The transcription factor CREB is a predicted upstream regulator of this network and binds to the Zfp189 promoter. To probe CREB-Zfp189 interactions, we employ CRISPR-mediated locus-specific transcriptional reprogramming to direct CREB or G9a (a repressive histone methyltransferase) to the Zfp189 promoter in prefrontal cortex neurons. Induction of Zfp189 with site-specific CREB is pro-resilient, whereas suppressing Zfp189 expression with G9a increases susceptibility. These findings reveal an essential role for Zfp189 and CREB-Zfp189 interactions in mediating a central transcriptional network of resilience.


Assuntos
Adaptação Psicológica/fisiologia , Estresse Psicológico/genética , Dedos de Zinco/genética , Animais , Redes Reguladoras de Genes/genética , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Transcrição Genética
9.
Drug Des Devel Ther ; 13: 2127-2134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308626

RESUMO

Purpose: Episodes of acute emotional or physical stress can have significant adverse effects on the hippocampus. Ginsenoside Rb1, the most predominant ginsenoside present in Panax species, has been reported to show a neuroprotective effect. The purpose of this study was to investigate the influence of ginsenoside Rb1 on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in rats subjected to acute immobilization stress. Methods: Wistar rats were divided into controls treated with saline only (N), rats exposed to stress only (M), and rats pretreated with Rb1 (40 mg.kg (-1)) thirty minutes prior to stress exposure (R). In the model, animals were restrained in a plastic immobilizer for 2 h of acute immobilization stress at room temperature. ELISA was used to determine plasma levels of CORT and ACTH. The effect of Rb1 pretreatment on the expression of BDNF and TrkB was determined by immunofluorescence, real-time PCR, and Western blotting analysis. Results: The R group showed significantly increased plasma CORT and ACTH levels compared to the N and M groups. Acute stress stimulation suppressed BDNF and TrkB protein and mRNA expression in the hippocampus; otherwise, Rb1 pretreatment reversed the decreases. Conclusion: The results from this study demonstrate that Rb1 pretreatment reverses the decreases in hippocampal BDNF/TrkB and increases the plasma levels of CORT and ACTH, indicating a potential neuroprotective effect of Rb1 against acute stress.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Imobilização , Fármacos Neuroprotetores/farmacologia , RNA Mensageiro/genética , Receptor trkB/genética , Estresse Psicológico , Hormônio Adrenocorticotrópico/sangue , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Corticosterona/sangue , Ginsenosídeos/administração & dosagem , Hipocampo/metabolismo , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/genética , Estresse Psicológico/metabolismo
10.
Rev Assoc Med Bras (1992) ; 65(6): 830-833, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31340312

RESUMO

OBJECTIVE: Even though stress has been long known as a provocative factor for Graves' disease, its relationship with Hashimoto's thyroiditis is more controversial. Studies on this topic are scanty. This paper aims to report a case of stress-induced Hashitoxicosis. RESULTS: Here we report a case of Hashitoxicosis induced by a psychological stressful event in a 28-year-old woman with Hashimoto's thyroiditis. She had remained stably euthyroid for 12 years. She was first observed in April 2016, while euthyroid. She came back after 11 months because of fatigue and palpitations, in the absence of neck pain. Thyroid function tests revealed moderate thyrotoxicosis (undetectable TSH; FT4 36.94 pmol/L, normal values 9.0-24.46; FT3 13.50 pmol/L, normal values 3.07-6.14) with negative TSH-receptor antibodies. In the previous three months, she had experienced a psychological stressful event. Inflammatory markers were negative, and the white cell count was normal. Thyroid ultrasound revealed a modest increase in vascularization. Transient subclinical hypothyroidism ensued after seven weeks and spontaneously recovered. On the last visit, the patient was still on euthyroidism. (TSH 1.01 mU/L; FT4 9.22 pmol/L; FT3 3.98 pmol/L). We also performed HLA serotyping and genotyping. CONCLUSION: This case demonstrates that, similarly to Graves' disease, Hashitoxicosis can also be triggered by stressful life events.


Assuntos
Antígenos HLA/genética , Doença de Hashimoto/psicologia , Estresse Psicológico/complicações , Adolescente , Feminino , Genótipo , Doença de Hashimoto/genética , Humanos , Sorogrupo , Estresse Psicológico/genética , Tireotropina/sangue , Tiroxina/sangue
11.
Psych J ; 8(3): 363-377, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264389

RESUMO

The short (s) allele of a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is related to reduced serotonin transporter efficiency and an increased vulnerability to stress and mental disorders. In the present study, we investigated how 5-HTTLPR impacts on memory retrieval under stress and related neural activity by reanalyzing a small genetic neuroimaging data set. Twenty-seven healthy male volunteers participated in both the Trier Social Stress Test (TSST) and a respective control procedure and then their brain activity was measured with functional MRI (fMRI) while they performed an emotional-face-recognition task. Sixteen participants were carriers of the short allele (ss/sl carriers) and 11 were homozygous for the long allele (ll carriers). Genotype groups were compared with respect to stress-related physiological changes, memory performance, and brain activity. No significant genotype-dependent effects on memory performance or cortisol levels were found. The ss/sl carriers showed significantly higher systolic and diastolic blood pressure than the ll carriers, independent of stress. The ss/sl carriers reported stronger stress-induced nervous mood than the ll carriers. Our fMRI data revealed that the ss/sl carriers showed significantly weaker left hippocampus activation and stronger dorsomedial prefrontal cortex (dmPFC) deactivation when retrieving memories under stress as compared with the ll carriers. Subsequent analyses revealed that the distinct hippocampal activation pattern in both genotypes was associated with stress-induced cortisol elevation, while the distinct dmPFC activation pattern in both genotypes was associated with stress-induced changes in reaction times. Our results thus add new evidence that serotonin signaling modulates neural activity in the hippocampus and dmPFC during memory retrieval under acute psychosocial stress.


Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/psicologia , Adulto , Alelos , Humanos , Imagem por Ressonância Magnética , Masculino , Polimorfismo Genético , Estresse Psicológico/genética
12.
Psychopharmacology (Berl) ; 236(8): 2485-2500, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201478

RESUMO

BACKGROUND: Borderline personality disorder (BPD) is a pervasive psychiatric disorder characterized by emotion dysregulation, impulsivity, impaired self-perceptions, and interpersonal relationships and currently affects 1-3% of the US population as reported by Torgersen et al. (Arch Gen Psychiatry 58:590-596, Torgersen et al. 2001), Lenzenweger et al. (Biol Psychiatry 62:553-564, Lenzenweger et al. 2007), and Tomko et al. (J Personal Disord 28:734-750, Tomko et al. 2014). One major obstacle to our understanding of the neural underpinnings of BPD is a lack of valid animal models that translate the key known features of the disorder to a system that is amenable to study. OBJECTIVE: To summarize the etiology, major symptoms, and symptom triggers of BPD and then propose a blueprint for building an animal model of BPD by choosing key components of the disorder that can be implemented in rodents. RESULTS: We identify the role of early life stress and subsequent mild stress in adulthood as contributing etiological factors and the potential use of altered communication between frontal cortices and the amygdala in extinction and habituation, increased impulsivity, dysregulation of the hypothalamic pituitary axis (HPA), and increased neuroinflammation as biological markers of BPD. Building upon these features of BPD, we propose a two-hit animal model that uses maternal abandonment to alter maturation of the HPA axis and mild secondary adult stress to evoke behavioral symptoms such as increased impulsivity and impaired extinction, habituation, and social interactions. CONCLUSION: Through exploration of the etiology, symptom presentation, and altered neurological function, we propose an animal model of BPD. We believe that a number of existing animal paradigms that model other mental health disorders should be combined in a unique way to reflect the etiology, symptom presentation, and altered neurological function that is evident in BPD. These model, when compared with available human data, will inform research and treatment in humans for better understanding of systems from the micro-molecular level to more global physiology underlying BPD.


Assuntos
Transtorno da Personalidade Borderline/psicologia , Modelos Animais de Doenças , Comportamento Impulsivo/fisiologia , Relações Interpessoais , Tonsila do Cerebelo/metabolismo , Animais , Transtorno da Personalidade Borderline/genética , Transtorno da Personalidade Borderline/metabolismo , Emoções/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , 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
13.
Environ Toxicol Pharmacol ; 70: 103202, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173966

RESUMO

Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmacokinetics. We treated ICR mice with CBD administered orally and intravenously and then determined the kinetic constants. A single bolus intravenous injection of CBD resulted in a half-life of 3.9 h, mean residence time of 3.3 h, and oral bioavailability of about 8.6%. The antidepressant-like effects of periodically administered CBD on the chronic mild stress mouse model are evaluated. Results demonstrated that such treatment at a high dose of 100 mg/kg CBD (p.o.) or a low dose of 10 mg/kg CBD (i.v.), elicited significant antidepressant-like behavioral effects in forced swim test, following increased mRNA expression of brain-derived neurotrophic factor (BDNF) and synaptophysin in the prefrontal cortex and the hippocampus. Our findings are expected to provide a reference for the development of intravenous antidepressant formulations of CBD.


Assuntos
Antidepressivos/administração & dosagem , Antidepressivos/farmacocinética , Canabidiol/administração & dosagem , Canabidiol/farmacocinética , Estresse Psicológico/tratamento farmacológico , Administração Intravenosa , Administração Oral , Animais , Antidepressivos/sangue , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas de Ligação ao Cálcio/genética , Canabidiol/sangue , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/genética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/genética , Sinaptofisina/genética
14.
PLoS One ; 14(6): e0216035, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31233509

RESUMO

Early life stress has been shown to contribute to alterations in biobehavioral regulation. Genetic make-up, especially related to social sensitivity, might affect the child's vulnerability to these alterations. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in changing resting cardiovascular outcomes at age 5-6. In the Amsterdam-Born-Children-and-their-Development-(ABCD)-study, a large prospective, observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week (range 11-25 weeks, SD 2 weeks) by a questionnaire (maternal self-report). Indicators of resting cardiac autonomic nervous system activity (sympathetic drive by pre-ejection period, parasympathetic drive by respiratory sinus arrhythmia), heart rate, and blood pressure were measured at age 5-6 years. Data on oxytocin receptor gene polymorphisms rs53576, rs2268498 and oxytocin polymorphisms rs2740210, rs4813627, were collected (N = 966 included). If the child was carrier of the rs53576 GG variant, exposure to maternal verbally aggressive behavior (10.6%) was associated with increased systolic blood pressure at age 5-6 (B = 4.9 mmHg,95% CI[2.2;7.7]). If the child was carrier of the rs2268498 TT/TC variant, exposure to maternal verbally aggressive behavior was associated with increased systolic blood pressure at age 5-6 (B = 3.0 mmHg,95%CI[1.0:5.0]). No significant interactions of maternal verbally aggressive behavior with oxytocin gene polymorphisms on heart rate or cardiac autonomic nervous system activity were found. In conclusion, oxytocin receptor gene polymorphisms may partly determine a child's vulnerability to develop increased systolic blood pressure after being exposed to maternal verbally aggressive behavior in early infancy.


Assuntos
Maus-Tratos Infantis/psicologia , Comportamento Materno/psicologia , Ocitocina/genética , Polimorfismo de Nucleotídeo Único , Receptores de Ocitocina/genética , Estresse Psicológico/genética , Pressão Sanguínea , Determinação da Pressão Arterial , Criança , Maus-Tratos Infantis/etnologia , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genótipo , Frequência Cardíaca , Humanos , Masculino , Comportamento Materno/etnologia , Estudos Prospectivos , Autorrelato , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia
15.
Eur J Endocrinol ; 181(2): 129-137, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146258

RESUMO

Objective: Previous finding suggests that children growing up under chronic stress tend to experience earlier sexual maturity. The present study aims to examine polygenic risk by experience interaction in predicting pubertal timing, as well as provide insight regarding the relevance of two G × E paradigms. Design and methods: Data were analyzed from a 3-year prospective puberty cohort in Anhui Province, China. Breast Tanner stage and testicular volume (TV) of 997 children were annually assessed. The polygenic risk score (PRS) was computed based on 17 SNPs for early pubertal timing. Hair cortisol concentrations (HCC) were assessed in the first 3 cm hair segment as a biological marker of chronic stress. Results: Comparing with participants under moderate levels of stress as measured by HCC, the puberty-accelerating effects of chronic stress were only observed among girls with moderate (1.7 months earlier, P = 0.007) and low genetic susceptibility (2.2 months earlier, P < 0.001) and among boys with high genetic susceptibility (2.0 months earlier, P = 0.005). Polygenic differences (PRSs) in age at thelarche was most prominent in those with low levels of stress by HCC (9.06, 9.36 and 9.53 years for high, moderate and low PRS, respectively; F = 105.06, P < 0.0001), while polygenic differences in age at TV ≥4 mL was strongest in those under chronic stress (10.91, 11.06 and 11.17 years for high, moderate and low PRS, respectively; F = 100.48, P < 0.0001). Conclusion: Chronic stress predicts earlier age at pubertal onset in a sex-specific and genetic background-dependent manner. The bioecological G × E model for girls and diathesis stress model for boys in pubertal timing warrants further investigation.


Assuntos
Interação Gene-Ambiente , Herança Multifatorial/genética , Puberdade Precoce/genética , Puberdade Precoce/psicologia , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Criança , China/epidemiologia , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Puberdade/fisiologia , Puberdade/psicologia , Puberdade Precoce/epidemiologia , Fatores de Risco , Maturidade Sexual/fisiologia , Estresse Psicológico/epidemiologia
16.
Nutrients ; 11(5)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121870

RESUMO

Gene-environment (G × E) interactions involving job stress and mental health on risk factors of cardiovascular disease (CVD) are minimally explored. This study examined the association and G × E interaction effects of vascular endothelial growth factor receptor-2 (VEGFR-2) gene polymorphisms (rs1870377, rs2071559) on cardiometabolic risk in Chinese Malaysian adults. Questionnaires: Job Stress Scale (JSS); Depression, Anxiety, and Stress Scale (DASS-21); and Rhode Island Stress and Coping Inventory (RISCI) were used to measure job stress, mental health, and coping with perceived stress. Cardiometabolic risk parameters were evaluated in plasma and genotyping analysis was performed by real-time polymerase chain reaction. The subjects were 127 Chinese Malaysian adults. The allele frequencies for rs1870377 (A allele and T allele) and rs2071557 (A allele and T allele) polymorphisms were 0.48 and 0.52, and 0.37 and 0.63, respectively. Significant correlations include scores from JSS dimensions with blood glucose (BG) (p = 0.025-0.045), DASS-21 dimensions with blood pressure, BMI, and uric acid (p = 0.029-0.047), and RISCI with blood pressure and BG (p = 0.016-0.049). Significant G × E interactions were obtained for: rs1870377 with stress on total cholesterol (p = 0.035), low density lipoprotein cholesterol (p = 0.019), and apolipoprotein B100 (p = 0.004); and rs2071559 with anxiety on blood pressure (p = 0.006-0.045). The significant G × E interactions prompt actions for managing stress and anxiety for the prevention of CVD.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doenças Cardiovasculares/genética , Saúde Mental/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único/genética , Estresse Psicológico/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Malásia , Masculino , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Pessoa de Meia-Idade , Fatores de Risco , Estresse Psicológico/epidemiologia
17.
Acta Neuropsychiatr ; 31(4): 186-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31106715

RESUMO

OBJECTIVE: Depression is a disorder caused by genetics and environmental factors. The aim of this study was to perform a review investigating the interaction between genetic variations located in genes involved in hypothalamus-pituitary-adrenal axis (HPA-axis) and stressful life events (SLEs) in depression. METHODS: In this systematic review, we selected articles investigating the interaction between genes involved in the HPA-axis, such as Arginine Vasopressin (AVP), Angiotensin Converting Enzyme (ACE), Corticotrophin Releasing Hormone (CRH), Corticotrophin Releasing Hormone Receptor 1 (CRHR1), Corticotrophin Releasing Hormone Receptor 2 (CRHR2), FK506 binding protein (FKBP5), Nuclear Receptor subfamily 3 group C member 1 (NR3C1), Nuclear Receptor subfamily 3 group C member 2 (NR3C2), and SLE. The literature search was conducted using the Pubmed, Embase, and PsychINFO databases in adherence with the PRISMA guidelines. RESULTS: The search yielded 48 potentially relevant studies, of which 40 were excluded following screening. Eight studies were included in the final review. A total of 97 single nucleotide polymorphisms (SNPs) were examined in the eight included studies. The most prevalent gene was FKBP5, and the best studied polymorphism was FKBP5:rs1360780. Two of the five studies reported significant gene-environment (G × E) interactions between rs1360780 and SLE. Overall, four studies reported significant G × E interactions between FKBP5, CRH, or CRHR1 and SLE, respectively. No significant G × E interactions were found for the remaining genes. CONCLUSIONS: Our results suggest that genetic variation in three genes in the HPA-axis possibly moderate the effects of SLEs in depression.


Assuntos
Transtorno Depressivo/genética , Interação Gene-Ambiente , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/genética , Transtorno Depressivo/complicações , Humanos , Polimorfismo de Nucleotídeo Único , Estresse Psicológico/complicações , Proteínas de Ligação a Tacrolimo/genética
18.
Neuroscience ; 410: 274-292, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31071414

RESUMO

Prescription opioid abuse is a serious public health issue. Recently, we showed that female and male Sprague-Dawley rats acquire conditioned place preference (CPP) to the mu opioid receptor agonist oxycodone. Anatomical analysis of the hippocampus from these rats unveiled sex differences in the opioid system in a way that would support excitation and opiate associative learning processes especially in females. In this study, we examined the expression and protein densities of opioid, plasticity, stress and related kinase and signaling molecules in the hippocampus of female and male rats following oxycodone CPP. Oxycodone CPP females have: a) increases in ARC (activity regulated cytoskeletal-associated protein)-immunoreactivity (ir) in CA3 pyramidal cells; b) decreases in Npy (neuropeptide Y) gene expression in the medial hippocampus but higher numbers of NPY-containing hilar interneurons compared to males; c) increases in Crhr2 (corticotropin releasing factor receptor 2) expression in CA2/3; d) increases in Akt1 (AKT serine/threonine kinase 1) expression in medial hippocampus; and e) decreases in phosphorylated MAPK (mitogen activated protein kinase)-ir in CA1 and dentate gyrus. Oxycodone CPP males have: a) increases in Bdnf (brain derived-neurotrophic factor) expression, which is known to be produced in granule cells, relative to females; b) elevated Mapk1 expression and pMAPK-ir in the dentate hilus which harbors newly generated granule cells; and c) increases in CRHR1-ir in CA3 pyramidal cell soma. These sex-specific changes in plasticity, stress and kinase markers in hippocampal circuitry parallel previously observed sex differences in the opioid system after oxycodone CPP.


Assuntos
Analgésicos Opioides/farmacologia , Plasticidade Neuronal/fisiologia , Oxicodona/farmacologia , Caracteres Sexuais , Estresse Psicológico/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/genética
19.
Biomed Res Int ; 2019: 7505260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31032362

RESUMO

Background: Repeated or continuous chronic psychological stress may induce diverse neuropsychiatric disorders; however, the underlying mechanisms remain unclear. In this study, we explored the expression profiles of long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, in mice after repeated social defeat (RSD) stress to explore their potential involvement in the development of anxiety-like behaviors. Main Methods: RNA-sequencing was used to screen all differentially expressed (DE) lncRNAs and mRNAs between the RSD and control groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for confirmation of the RNA-sequencing results. The function of DE lncRNAs was predicted by Gene Ontology (GO) enrichment and pathway analyses of target mRNAs. In addition, the functional regulatory network of the target mRNAs was constructed to reveal potential relationships between lncRNAs and their target genes with bioinformatics approaches. Key Findings: In mice experiencing RSD, 373 and 454 lncRNAs, along with 1142 and 654, mRNAs were significantly upregulated and downregulated, respectively. The detailed regulatory network included 126 eligible lncRNA-mRNA pairs. Among them, 14 genes such as Arhgef1, Chchd2, Fam107a, Dlg1, Nova2, Dpf1, and Shank3 involved in neurite growth, neural development, and synaptic plasticity were direct targets of the DE lncRNAs. qRT-PCR of four of the DE lncRNAs and mRNAs confirmed the reliability of RNA-sequencing. GO clustering analyses showed that the top enriched biological process, cellular component, and molecular function terms were synaptic transmission, neuron spine, and glutamate receptor binding, respectively. Further, the top three significant enriched pathways were synaptic adhesion-like molecule (SALM) protein interactions at the synapses, trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as glutamate binding, activation of AMPA receptors, and synaptic plasticity. Significance: Hundreds of lncRNAs and mRNAs are dysregulated after RSD, and many of these lncRNAs might participate in the development of anxiety-like behaviors via multiple complex mechanisms such as target regulation. Available informatics evidence highlighted the likely role of synapse dysfunction and abnormal synaptic neurotransmission in these behaviors. Thus, our findings provide potential candidate biomarkers or intervention targets for chronic psychological stress-induced neuropsychiatric disorders.


Assuntos
Córtex Pré-Frontal/metabolismo , RNA Longo não Codificante/genética , Estresse Psicológico/genética , Animais , Biologia Computacional , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Córtex Pré-Frontal/fisiopatologia , RNA Mensageiro/genética , Análise de Sequência de RNA , Estresse Psicológico/fisiopatologia
20.
Neuropsychobiology ; 78(2): 86-94, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943524

RESUMO

BACKGROUND: The serotonergic and noradrenergic systems have a strong impact on several affective disorders and are key targets for psychopharmacological therapy. With respect to pathogenesis, there is a growing body of evidence showing an influence of a promoter repeat polymorphism (MAOA-uVNTR) altering the expression rate of monoamine oxidase A. However, only a few studies investigate its influence on depression with only 2 of them considering the moderating effects of life stress. For burnout, there are no studies so far investigating the genetic basis. OBJECTIVES: The aim of the present study was to replicate an interaction effect of MAOA-uVNTR and life stress on depression, and extend these possible findings to the burnout syndrome. Especially, the latter one might help in understanding the underlying mechanisms of burnout and its association to depression. METHOD: A total of n = 1,541 participants (n = 1,099 healthy controls, n = 442 inpatients with affective disorders) provided genetic samples and filled in self-report questionnaires measuring depression, burnout, and the extent of experienced stressful life events (SLEs). RESULTS: A life stress x MAOA-uVNTR interaction on depression and burnout was observed in women suggesting that carriers of the high expressing allele (MAO-H) with many SLEs had the highest scores in both burnout and depression. In men, there was only a weak effect of MAOA-uVNTR on depression. CONCLUSIONS: The results suggest a more pronounced reactivity to adverse environmental factors in carriers of the MAO-H allele. Especially the effect of life stress and MAOA-uVNTR on burnout should be independently replicated in the future as this is the first study showing this association.


Assuntos
Esgotamento Psicológico/genética , Depressão/genética , Repetições Minissatélites/genética , Monoaminoxidase/genética , Estresse Psicológico/genética , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Fatores Sexuais , Adulto Jovem
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