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1.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808655

RESUMO

Chronic stress is encountered in our everyday life and is thought to contribute to a number of diseases. Many of these stress-related disorders display a sex bias. Because glucocorticoid hormones are the main biological mediator of chronic stress, researchers have been interested in understanding the sexual dimorphism in glucocorticoid stress response to better explain the sex bias in stress-related diseases. Although not yet demonstrated for glucocorticoid regulation, sex chromosomes do influence sex-specific biology as soon as conception. Then a transient rise in testosterone start to shape the male brain during the prenatal period differently to the female brain. These organizational effects are completed just before puberty. The cerebral regions implicated in glucocorticoid regulation at rest and after stress are thereby impacted in a sex-specific manner. After puberty, the high levels of all gonadal hormones will interact with glucocorticoid hormones in specific crosstalk through their respective nuclear receptors. In addition, stress occurring early in life, in particular during the prenatal period and in adolescence will prime in the long-term glucocorticoid stress response through epigenetic mechanisms, again in a sex-specific manner. Altogether, various molecular mechanisms explain sex-specific glucocorticoid stress responses that do not exclude important gender effects in humans.


Assuntos
Glucocorticoides/metabolismo , Caracteres Sexuais , Estresse Fisiológico , Estresse Psicológico , Adolescente , Animais , Criança , Desenvolvimento Infantil , Desenvolvimento Embrionário/genética , Estudos de Associação Genética , Hormônios Gonadais/metabolismo , Humanos , Hidrocortisona/metabolismo , Puberdade/genética , Puberdade/metabolismo , Fatores Sexuais , Esteroides/metabolismo , Estresse Fisiológico/genética , Estresse Psicológico/genética
2.
Adv Exp Med Biol ; 1305: 117-128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33834398

RESUMO

Exposure to early life stress (ELS) represents a major risk factor for the development of psychiatric disorders, including depression. The susceptibility associated with ELS may result from persistent changes in gene transcription, which can occur through epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNA expression. Animal models and reports in humans described that negative stimuli can alter the neurodevelopment of an individual, affecting their behavior and cognitive development. It is currently hypothesized that levels of environmental adversity in this early developmental period are able to shape the experience-dependent maturation of stress-regulating pathways leading to long-lasting alterations in stress responsivity during adulthood. Here, we review key findings from animal and clinical studies examining the effects of prenatal and postnatal environment in shaping development of the neuroendocrine regulation of stress and the role of epigenetic mechanisms in the predisposition of depression.


Assuntos
Experiências Adversas da Infância , Transtornos Mentais , Adulto , Animais , Metilação de DNA , Depressão/genética , Epigênese Genética , Feminino , Humanos , Gravidez , Estresse Psicológico/genética
3.
J Affect Disord ; 286: 204-212, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33740637

RESUMO

INTRODUCTION: Attenuated adult hippocampal neurogenesis may manifest in affective symptomatology and/or resistance to antidepressant treatment. While early-life adversity and the short variant ('s') of the serotonin transporter gene's long polymorphic region (5-HTTLPR) are suggested as interacting risk factors for affective disorders, no studies have examined whether their superposed risk effectuates neurogenic changes into adulthood. Similarly, it is not established whether reduced hippocampal volume in adolescence, variously identified as a marker and antecedent of affective disorders, anticipates diminished adult neurogenesis. We investigate these potential developmental precursors of neurogenic alterations using a bonnet macaque model. METHODS: Twenty-five male infant bonnet macaques were randomized to stressed [variable foraging demand (VFD)] or normative [low foraging demand (LFD)] rearing protocols and genotyped for 5-HTTLPR polymorphisms. Adolescent MRI brain scans (mean age 4.2y) were available for 14 subjects. Adult-born neurons were detected post-mortem (mean age 8.6y) via immunohistochemistry targeting the microtubule protein doublecortin (DCX). Models were adjusted for age and weight. RESULTS: A putative vulnerability group (VG) of VFD-reared 's'-carriers (all 's/l') exhibited reduced neurogenesis compared to non-VG subjects. Neurogenesis levels were positively predicted by ipsilateral hippocampal volume normalized for total brain volume, but not by contralateral or raw hippocampal volume. LIMITATIONS: No 's'-carriers were identified in LFD-reared subjects, precluding a 2×2 factorial analysis. CONCLUSION: The 's' allele (with adverse rearing) and low adolescent hippocampal volume portend a neurogenic deficit in adult macaques, suggesting persistent alterations in hippocampal plasticity may contribute to these developmental factors' affective risk in humans.


Assuntos
Experiências Adversas da Infância , Proteínas da Membrana Plasmática de Transporte de Serotonina , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Macaca/metabolismo , Masculino , Neurogênese/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estresse Psicológico/genética
4.
J Int Med Res ; 49(3): 3000605211002695, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33745336

RESUMO

Over the past several decades, studies have demonstrated the existence of bi-directional relationships between periodontal disease and systemic conditions. Periodontitis is a polymicrobial and multifactorial disease involving both host and environmental factors. Tissue destruction is primarily associated with hyperresponsiveness of the host resulting in release of inflammatory mediators. Pro-inflammatory cytokines play a major role in bacterial stimulation and tissue destruction. In addition, these cytokines are thought to underlie the associations between periodontitis and systemic conditions. Current research suggests that increased release of cytokines from host cells, referred to as the cytokine storm, is associated with disease progression in patients with coronavirus disease 2019 (COVID-19). An intersection between periodontitis and pulmonary disease is biologically plausible. Hence, we reviewed the evidence linking COVID-19, cytokines, and periodontal disease. Plaque control is essential to prevent exchange of bacteria between the mouth and the lungs, reducing the risk of lung disease. Understanding these associations may help identify individuals at high risk and deliver appropriate care at early stages.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/imunologia , Placa Dentária/imunologia , Interações Hospedeiro-Patógeno/imunologia , Periodontite/imunologia , Estresse Psicológico/imunologia , /complicações , /virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/virologia , Placa Dentária/complicações , Placa Dentária/genética , Placa Dentária/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Periodontite/complicações , Periodontite/genética , Periodontite/virologia , Transdução de Sinais , Estresse Psicológico/complicações , Estresse Psicológico/genética , Estresse Psicológico/virologia , Dente/imunologia , Dente/patologia , Dente/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
Environ Health Prev Med ; 26(1): 8, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33451279

RESUMO

BACKGROUND: Prenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring. METHODS: Rats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting. RESULTS: There was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress's offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment. CONCLUSIONS: The learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.


Assuntos
Proteínas do Citoesqueleto/genética , Regulação da Expressão Gênica , Fator de Crescimento Insulin-Like II/genética , Deficiências da Aprendizagem/genética , Transtornos da Memória/genética , Proteínas do Tecido Nervoso/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Meio Social , Estresse Psicológico/genética , Animais , Proteínas do Citoesqueleto/metabolismo , Feminino , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Aprendizagem , Deficiências da Aprendizagem/psicologia , Masculino , Transtornos da Memória/psicologia , Proteínas do Tecido Nervoso/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Distribuição Aleatória , Ratos , Ratos Wistar
6.
Biol Psychiatry ; 89(9): 911-919, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33384174

RESUMO

BACKGROUND: Adolescence is a period of increased vulnerability to psychiatric disorders, including depression. Discovering novel biomarkers to identify individuals who are at high risk is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood by targeting the netrin-1 guidance cue receptor gene Dcc in the medial prefrontal cortex (mPFC). METHODS: Here, we investigated whether miR-218 regulates Dcc expression in adolescence and could serve as an early predictor of lifetime stress vulnerability in male mice. RESULTS: miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively with Dcc levels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood. CONCLUSIONS: miR-218 expression in adolescence may serve both as a marker of risk and as a target for early interventions.


Assuntos
MicroRNAs , Córtex Pré-Frontal , Animais , Regulação para Baixo , Masculino , Camundongos , MicroRNAs/genética , Comportamento Social , Estresse Psicológico/genética
7.
Nat Neurosci ; 24(2): 204-213, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33361822

RESUMO

Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.


Assuntos
Encéfalo/imunologia , Feto/imunologia , Imunidade Inata/genética , Proteostase/genética , Animais , Comportamento Animal , Deficiências do Desenvolvimento/genética , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Biossíntese de Proteínas/genética , Proteoma/biossíntese , RNA/biossíntese , RNA/genética , RNA Interferente Pequeno , Caracteres Sexuais , Transdução de Sinais , Estresse Psicológico/genética , Estresse Psicológico/psicologia
8.
Sci Rep ; 10(1): 22082, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328497

RESUMO

Brain inflammation is one of hypotheses explaining complex pathomechanisms of depression. Angiotensin II (ANGII), which is associated with hypertension, also induces brain inflammation. However, there is no animal study showing the direct relationship between ANGII and depression. To address this issue, ANGII-containing osmotic pumps were implanted into adult male C57BL/6 mice subcutaneously for subacute (7 days) and chronic (at least 21 days) periods and behavioral and molecular analyses were conducted. Chronic infusion of ANGII into mice induced depressive-like behaviors, including the tail suspension test and forced swimming test, which were reversed by imipramine. Chronic infusion of ANGII also induced microglial activation in the hippocampus with increase of Il-1ß mRNA and decrease of Arg1 mRNA. In addition, chronic ANGII infusion activated the hypothalamic-pituitary-adrenal axis (HPA axis) and resulted in decreased hippocampal glucocorticoid receptor level. However, subacute ANGII infusion did not induce significant molecular and behavioral changes in mice compared to that of control. The molecular and behavioral changes by chronic ANGII infusion were reversed by co-treatment of minocycline or telmisartan. In addition, ANGII treatment also induced the pro-inflammatory changes in BV-2 microglial cells. Our results indicate that ANGII can induce depressive-like behaviors via microglial activation in the hippocampus and HPA axis hyperactivation in mice. These might suggest possible mechanism on depressive symptom in chronic hypertensive state.


Assuntos
Angiotensina II/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Depressivo/genética , Interleucina-1beta/genética , Estresse Psicológico/genética , Angiotensina II/efeitos adversos , Animais , Transtorno Depressivo/induzido quimicamente , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Elevação dos Membros Posteriores , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/fisiopatologia
9.
Subst Use Misuse ; 55(14): 2438-2442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32957797

RESUMO

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


Assuntos
Comportamento Aditivo/genética , Infecções por Coronavirus/metabolismo , Dopamina/metabolismo , Pneumonia Viral/metabolismo , Ansiedade/genética , Ansiedade/metabolismo , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Betacoronavirus , Infecções por Coronavirus/psicologia , Dopa Descarboxilase/genética , Dopa Descarboxilase/metabolismo , Regulação para Baixo , Epigênese Genética , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/psicologia , Recompensa , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Suicídio , Síndrome
10.
PLoS One ; 15(8): e0237001, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790782

RESUMO

Why people differ in their susceptibility to external events is essential to our understanding of personality, human development, and mental disorders. Genes explain a substantial portion of these differences. Specifically, genes influencing the serotonin system are hypothesized to be differential susceptibility factors, determining a person's reactivity to both positive and negative environments. We tested whether genetic variation in the serotonin transporter (5-HTTLPR) is a differential susceptibility factor for daily events. Participants (N = 326, 77% female, mean age = 25, range = 17-36) completed smartphone questionnaires four times a day over four to five days, measuring stressors, uplifts, positive and negative affect. Affect was predicted from environment valence in the previous hour on a within-person level using three-level autoregressive linear mixed models. The 5-HTTLPR fulfilled all criteria of a differential susceptibility factor: Positive affect in carriers of the short allele (S) was less reactive to both uplifts and stressors, compared to homozygous carriers of the long allele (L/L). This pattern might reflect relative affective inflexibility in S-allele carriers. Our study provides insight into the serotonin system's general role in susceptibility and highlights the need to assess the whole spectrum of naturalistic experiences.


Assuntos
Predisposição Genética para Doença , Acontecimentos que Mudam a Vida , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/genética , Adolescente , Adulto , Afeto , Alelos , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Transtornos Mentais/genética , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Psicológicos , Inquéritos e Questionários , Adulto Jovem
11.
Gene ; 763: 145071, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827682

RESUMO

The previous study indicated that transport stress resulted in oxidative damage and autophagy/mitophagy elevation, companied by NOX1 over- expression in the jejunal tissues of pigs. However, the transportation-related gene expression profile and NOX1 function in intestine remain to be explicated. In the current study, differentially expressed genes involved in PI3K-Akt and NF-κB pathways, oxidative stress and autophagy process have been identified in pig jejunal tissues after transcriptome analysis following transportation. The physiological functions of NOX1 down-regulation were explored against oxidative damage and excessive autophagy in porcine intestinal epithelial cells (IPEC-1) following NOX1 inhibitor ML171 and H2O2 treatments. NOX1 down-regulation could decrease the content of Malondialdehyde (MDA), Lactic dehydrogenase (LDH) activity and reactive oxygen species (ROS) level, and up-regulate superoxide dismutase (SOD) activity. Furthermore, mitochondrial membrane potential and content were restored, and the expressions of tight junction proteins (Claudin-1 and ZO-1) were also increased. Additionally, NOX1 inhibitior could down-regulate the expression of autophagy-associated proteins (ATG5, LC3, p62), accompanied by activating SIRT1/PGC-1α pathway. NOX1 down-regulation might alleviate oxidative stress-induced mitochondria damage and intestinal mucosal injury via modulating excessive autophagy and SIRT1/PGC-1α signaling pathway. The data will shed light on the molecular mechanism of NOX1 on intestine oxidative damage following pig transportation.


Assuntos
Autofagia , Enterócitos/metabolismo , NADPH Oxidase 1/metabolismo , Estresse Oxidativo , Estresse Psicológico/metabolismo , Transcriptoma , Animais , Linhagem Celular , Feminino , Masculino , Mitocôndrias/metabolismo , NADPH Oxidase 1/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Estresse Psicológico/genética , Suínos
12.
Biodemography Soc Biol ; 65(3): 245-256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32727277

RESUMO

Hand grip strength (GS) is a valid and reliable predictor of future morbidity and mortality and is considered a useful indicator of aging. In this paper, we use results from the genetic analysis in animal studies to evaluate associations for GS, frailty, and subsequent mortality among humans. Specifically, we use data from the Health and Retirement Survey (HRS) to investigate the association between three polymorphisms in a candidate frailty gene (Tiam1) and GS. Results suggest that the A allele in rs724561 significantly reduces GS among older adults in the US (b = -0.340; p < .006) and is significantly associated with self-reported weakness (b = 0.221; p = .036). This same polymorphism was weakly associated (one-tailed) with an increased risk of mortality (b = 1.091; p < .093) and adjustments for GS rendered this association statistically non-significant (b = 1.048; p < .361). Overall, our results provide tentative evidence that the Tiam1 gene may be associated with frailty development, but we encourage further studies.


Assuntos
Força da Mão/fisiologia , Mutação/genética , Mutação/fisiologia , Estresse Psicológico/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mortalidade , Dinamômetro de Força Muscular , Modelos de Riscos Proporcionais , Estresse Psicológico/fisiopatologia
13.
Adv Exp Med Biol ; 1195: 59-71, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468460

RESUMO

Herein, we deploy an in silico pipeline of structural bioinformatics, thermodynamics, and molecular dynamics to investigate the role of cortisol in circadian rhythms, biorhythms, stress response, and even sleep disorders. Our study shows that high concentrations of cortisol intercalate in the minor groove of DNA. This phenomenon widens the adjacent major grooves and provides the Clock/Bmal1 complex with more space to dock and interact with DNA. Then, the strong charges of cortisol pull the alpha helices of the Clock/Bmal1 complex and bend it inward, thus establishing stronger interactions and prolonged signaling. Our results indicate that elevated cortisol levels play an important role in stress, inflammation, and sleep disorders as a result of prolonged and stronger dsDNA - Clock/Bmal1 interactions.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Proteínas CLOCK/metabolismo , DNA/química , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Transtornos do Sono-Vigília/fisiopatologia , Estresse Psicológico/prevenção & controle , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Simulação por Computador , DNA/metabolismo , Humanos , Hidrocortisona/química , Inflamação/genética , Inflamação/metabolismo , Substâncias Intercalantes/química , Substâncias Intercalantes/metabolismo , Receptores de Glucocorticoides/metabolismo , Transtornos do Sono-Vigília/genética , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia
14.
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
15.
Neuron ; 106(6): 912-926.e5, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32304628

RESUMO

Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression.


Assuntos
Transtorno Depressivo Maior/genética , Córtex Pré-Frontal/metabolismo , RNA Longo não Codificante/genética , Resiliência Psicológica , Estresse Psicológico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Comportamento Animal , Depressão/genética , Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Regulação para Baixo , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , RNA-Seq , Fatores Sexuais , Estresse Psicológico/metabolismo , Adulto Jovem
16.
PLoS One ; 15(4): e0221310, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32243432

RESUMO

OBJECTIVE: Exposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel experimental design to test how young adults' exposure to ELA influences neuroendocrine and inflammatory responses to acute stress. MATERIALS AND METHODS: Participants were 12 males (mean age = 21.25), half of whom endorsed at least three significant adverse events up to age 18 years ('ELA group'), and half who confirmed zero ('controls'). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of the glucocorticoid receptor (NR3C1), and plasma levels of pro-inflammatory cytokines (IL-1ß, IL-6, IL-8 and TNFα) over a 4-hour window post-test. RESULTS: In this pilot study, the ELA group evinced higher cortisol response and blunted NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups. CONCLUSION: Overall, this pilot feasibility study provides a framework to investigate the biological embedding of early-adversity via dysregulation across physiological and genomic systems in response to acute psychosocial stress. ELA may program such systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate and expand upon these preliminary findings.


Assuntos
Estresse Psicológico/etiologia , Adolescente , Adulto , Citocinas/sangue , Citocinas/imunologia , Estudos de Viabilidade , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade , Masculino , Projetos Piloto , Receptores de Glucocorticoides/genética , Estresse Psicológico/sangue , Estresse Psicológico/genética , Estresse Psicológico/imunologia , Adulto Jovem
17.
Psychopharmacology (Berl) ; 237(6): 1783-1793, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32296859

RESUMO

RATIONALE: Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive. OBJECTIVE: Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia. METHODS: We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4. RESULTS: Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus. CONCLUSIONS: Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.


Assuntos
Antipsicóticos/administração & dosagem , Encéfalo/efeitos dos fármacos , Genes Precoces/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Estresse Psicológico/tratamento farmacológico , Animais , Encéfalo/fisiologia , Esquema de Medicação , Genes Precoces/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Estresse Psicológico/genética , Estresse Psicológico/psicologia
18.
Behav Neurol ; 2020: 7830469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190129

RESUMO

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


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Estresse Psicológico/fisiopatologia , Animais , Animais Recém-Nascidos , Ansiedade/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Comportamento Animal , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Hipocampo/fisiologia , Privação Materna , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Córtex Pré-Frontal/fisiologia , Comportamento Social , Estresse Psicológico/genética
19.
Int Rev Neurobiol ; 150: 107-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32204828

RESUMO

Aging is the single most important risk factor for diseases that are currently the leading causes of morbidity and mortality. However, there is considerable inter-individual variability in risk for aging-related disease, and studies suggest that biological age can be influenced by multiple factors, including exposure to psychosocial stress. Among markers of biological age that can be affected by stress, the present article focuses on the so-called measures of epigenetic aging: DNA methylation-based age predictors that are measured in a range of tissues, including the brain, and can predict lifespan and healthspan. We review evidence linking exposure to diverse types of psychosocial stress, including early-life stress, cumulative stressful experiences, and low socioeconomic status, with accelerated epigenetic aging as a putative mediator of the effects of psychosocial environment on health and disease. The chapter also discusses methodological differences that may contribute to discordant findings across studies to date and plausible mechanisms that may underlie the effects of stress on the aging epigenome. Future studies examining the effects of adversity on epigenetic and other indicators of biological weathering may provide important insights into the pathogenesis of aging-related disease states.


Assuntos
Senescência Celular/genética , Epigênese Genética/genética , Classe Social , Estresse Psicológico/genética , Adolescente , Adulto , Criança , Humanos , Adulto Jovem
20.
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
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