RESUMEN
BACKGROUND: Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression. METHODS: In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants. MAIN BODY: Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA, histones, or chromatin remodeling complexes. CONCLUSION: Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics.
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Antidepresivos , Metilación de ADN , Epigénesis Genética , Epigénesis Genética/efectos de los fármacos , Humanos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Metilación de ADN/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Animales , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/genética , Histonas/metabolismo , Estrés Psicológico/genéticaRESUMEN
Unhealthy diets high in fat and sugar content may have an impact on psychological health and increase the risk of Major Depressive Disorder (MDD) and stress levels. On the other hand, MDD and stress might be related to food choices and intake. However, it is not clear whether diet, and specifically fat and sugar intake, is causally related to stress and MDD, and whether this relationship may be bi-directional. This study utilised Mendelian Randomisation (MR) to investigate the causal nature of the relationship of fat and sugar intake with MDD and cortisol (as a proxy of stress), and to shed light on the direction of this relationship. Summary-level data for all exposure and outcome variables were obtained from large-scale, non-overlapping GWASs in individuals of European ancestry. Bidirectional analyses were performed: one with macronutrients as exposures and one with MDD/cortisol as exposures. Random-effects inverse-variance weighted regression was used as the primary analytic method for genetic instruments with at least two single nucleotide polymorphisms (SNPs) available (and individual Wald ratio was used when only one SNP was available). Higher levels of genetically predicted relative sugar intake were causally associated with lower MDD risk, for both genome-wide significant p-value threshold of p < 1 × 10-8, (OR = 0.553, 95% CI: 0.395-0.775) and relaxed p-value threshold of p < 1 × 10-6 (OR = 0.786, 95% CI: 0.630-0.981). No reverse causality was detected in the opposite direction as MDD was not associated with sugar consumption. The associations observed for all the other pairs of variables were weak and imprecise. A number of limitations was present in the study, such as low-SNP based heritability for some exposures, inability to prove whether variants were correlated with unmeasured confounders and self-reporting of MDD data. Lifestyle and/or pharmacological interventions targeting sugar-related physiological mechanisms may help to reduce depressive symptoms. However, more research is necessary on short- and long-term effects of sugar on the risk of MDD. Additionally, future studies should investigate whether the amount and type of sugar consumed may underlie the impact of sugar on mood and stress levels.
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Trastorno Depresivo Mayor , Grasas de la Dieta , Estudio de Asociación del Genoma Completo , Hidrocortisona , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Hidrocortisona/metabolismo , Trastorno Depresivo Mayor/genética , Azúcares de la Dieta , Femenino , Estrés Psicológico/genética , MasculinoRESUMEN
This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression (BDI-II), acculturation/marginalization (ARSMA-II), and liver health as assessed by elastography. Heritability and genotype-by-environment (G×E) interactions were analyzed, focusing on the marginalization/separation measure of the ARSMA-II. Significant heritabilities were found for traits such as HbA1c (h2 = 0.52), marginalization (h2 = 0.30), AST (h2 = 0.25), ALT (h2 = 0.41), and BMI (h2 = 0.55). Genotype-by-environment interactions were significant for HbA1c, AST/ALT ratio, BDI-II, and CAP, indicating that genetic factors interact with marginalization to influence these traits. This study found that acculturation stress exacerbates the genetic response to chronic illness. These findings underscore the importance of considering G×E interactions in understanding disease susceptibility and may inform targeted interventions for at-risk populations. Further research is warranted to elucidate the underlying molecular pathways and replicate these findings in diverse populations.
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Aculturación , Interacción Gen-Ambiente , Americanos Mexicanos , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etnología , Masculino , Femenino , Americanos Mexicanos/genética , Adulto , Persona de Mediana Edad , Enfermedad Crónica , Genotipo , Estrés Psicológico/genética , Predisposición Genética a la Enfermedad , Obesidad/genética , Texas/epidemiologíaRESUMEN
Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer's and Huntington's diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review.
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Exosomas , Trastornos Mentales , MicroARNs , Exosomas/metabolismo , Exosomas/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Trastornos Mentales/genética , Trastornos Mentales/metabolismo , Animales , Estrés Psicológico/genética , Estrés Psicológico/metabolismoRESUMEN
To address the challenge of predicting psychological response to a psychosocial intervention we tested the possibility that baseline gene expression profiles might provide information above and beyond baseline psychometric measures. The genomics strategy utilized individual level inferences of transcription factor activity to predict changes in loneliness and affect in response to two well-established meditation interventions. Initial algorithm development analyses focused on three a-priori defined stress-related gene regulation pathways (CREB, GR, and NF-ĸB) as inferred from TELiS promoter-based bioinformatic analysis of basal (pre-intervention) blood samples from a randomized-controlled trial comparing a compassion-based meditation (CM, n = 45) with mindfulness meditation (MM, n = 44). Greater baseline CREB activity (but not GR or NF-ĸB) predicted greater reductions from pre- to post-intervention in loneliness (b = -0.24, p = 0.016) and negative emotions (b = -0.23, p = 0.017) for CM, but not for MM. A second algorithm validation analysis applied the same approach to another randomized controlled trial comparing CM (n = 42) with MM (n = 38) and a health education control condition (n = 41). Similarly, greater baseline CREB activity predicted greater pre- to post-intervention decreases in loneliness (b = -0.24, p = 0.029) and greater increases in satisfaction with life (b = 0.21, p = 0.046) for the CM condition only. Baseline CREB activity was not associated with baseline psychometric measures in either study. Results raise the possibility that pre-intervention gene expression profiles may reflect non-conscious psychobiological states that affect psychological responses to distinct psychosocial interventions, and thereby help personalize intervention selection.
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Soledad , Meditación , Atención Plena , Intervención Psicosocial , Estrés Psicológico , Humanos , Masculino , Femenino , Soledad/psicología , Meditación/métodos , Adulto , Atención Plena/métodos , Intervención Psicosocial/métodos , Estrés Psicológico/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/terapia , Persona de Mediana Edad , Expresión Génica/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Algoritmos , FN-kappa B/metabolismo , Empatía/fisiologíaRESUMEN
BACKGROUND: Social isolation not only increases the risk of mortality in later life but also causes depressive symptoms, cognitive and physical disabilities. Although RNA m6A modifications are suggested to play key roles in brain development, neuronal signaling and neurological disorders, both the roles of m6A and the enzymes that regulate RNA m6A modification in social isolation induced abnormal behavior is unknown. The present study aims to explore the possible epitranscriptomic role of RNA m6A modifications and its enzymes in social isolation induced impaired behavior. METHODS: 3-4 weeks mice experiencing 8 weeks social isolation stress (SI) were used in the present study. We quantified m6A levels in brain regions related to mood and cognitive behavior. And the expression of hippocampal m6A enzymes was also determined. The role of hippocampal m6A and its enzymes in SI induced abnormal behavior was further verified by the virus tool. RESULTS: SI led to not only depressive and anxiety-like behaviors but also cognitive impairment, with corresponding decreases in hippocampal m6A and METTL14. Hippocampal over-expression METTL14 with lentivirus not only rescued these behaviors but also enhanced the hippocampal m6A level. Hippocampal over-expression METTL14 resulted in increased synaptic related genes. CONCLUSIONS: We provide the first evidence that post-weaning social isolation reduces hippocampal m6A level and causes altered expression of m6A enzyme in mice. Importantly, hippocampal METTL14 over-expression alleviated the SI-induced depression/anxiety-like and impaired cognitive behaviors and enhanced m6A level and synaptic related genes expression.
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Hipocampo , Metiltransferasas , Aislamiento Social , Animales , Hipocampo/metabolismo , Masculino , Ratones , Metiltransferasas/genética , Metiltransferasas/metabolismo , Depresión/genética , Depresión/metabolismo , Conducta Animal/fisiología , Ansiedad/genética , Ansiedad/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/genética , Ratones Endogámicos C57BL , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Epigénesis Genética , Metilación de ARNRESUMEN
Objectives: Maternal stress has long been associated with lower birthweight, which is associated with adverse health outcomes including many adult diseases. The underlying mechanisms remain elusive although changes in gene expression may play a role. Studies are only beginning to test how maternal stress impacts gene expression as reflected in the transcriptome. Materials and Methods: In a cohort of mothers and newborns in the eastern Democratic Republic of Congo (n=93), we studied the effects of four maternal stress measures (chronic stress, war trauma, sexual trauma, and general trauma) on the transcriptomes of maternal venous blood, newborn venous blood, and placental tissues, and on newborn birthweight. Maternal stress was investigated as independent measures, principal components, and clusters identified through machine learning. The transcriptome was assayed using the ClariomD chip. Multiple regression models were used to test for associations between maternal stress measures, the transcriptome, and newborn birthweight. Results: None of the maternal stress measures showed an association with expression of individual genes. In contrast, when testing global gene expression, war trauma was significantly associated with the placental transcriptome. War trauma was also significantly associated with birthweight in multiple models. Mediation analysis indicated that ~14% of the effect of war trauma on birthweight was mediated by a placental gene expression component. Discussion: Our results suggest that gene expression in the placenta, which represents the interface between mother and developing fetus, may partially mediate the negative impact of maternal stress on newborn birthweight.
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Peso al Nacer , Humanos , República Democrática del Congo/epidemiología , Femenino , Recién Nacido , Peso al Nacer/genética , Embarazo , Adulto , Estrés Psicológico/genética , Placenta/metabolismo , Transcriptoma , Adulto Joven , Expresión GénicaRESUMEN
Early-life positive and adverse parental factors, such as positive parent personality and parental stress, affect the environmental context in which children develop and may influence individual differences in children's sleep health. This study examined the moderating role of early-life parental factors in the heritability (i.e., the extent to which individual differences are due to genetic influences) of objectively assessed childhood sleep duration. A total of 351 families from the Arizona Twin Project were studied. Primary caregivers (95% mothers) reported on multiple dimensions of stress and facets of their own personality when the twins were 12 months old. Seven years later (Mage = 8.43 years, SD = 0.68), families completed a home visit, and twins (51% female; 57% White, 29% Hispanic; 30% monozygotic, 39% same-sex dizygotic, 31% other-sex dizygotic) wore actigraph watches to assess their sleep, with caregivers completing similar assessments on their personality attributes and stress. Early-life positive parent personality moderated the heritability of sleep duration (Δ-2LL [-2 log likelihood] = 2.54, Δdf = 2, p = .28), such that as positive parent personality increased, the heritability of duration decreased. Early-life parental stress also moderated the genetic contribution to sleep duration (Δ-2LL = 2.02, Δdf = 2, p = .36), such that as stress increased, the heritability of duration increased. Concurrent positive parent personality and parental stress composites showed similar patterns of findings. Results highlight the likely contribution of parent positive traits and adverse experiences to the etiology of children's sleep health, with genetic influences on children's sleep more prominent in "riskier" environments. Understanding how genetics and environments work together to influence the etiology of sleep may inform prevention programs.
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Sueño , Humanos , Masculino , Femenino , Niño , Sueño/genética , Sueño/fisiología , Padres/psicología , Personalidad/genética , Estrés Psicológico/psicología , Estrés Psicológico/genética , Interacción Gen-Ambiente , Arizona , Lactante , Actigrafía , Duración del SueñoRESUMEN
BACKGROUND: Both genetic predispositions and exposures to stressors have collectively contributed to the development of major depressive disorder (MDD). To deep dive into their roles in MDD, our study aimed to examine which susceptible gene expression interacts with various dimensions of stressors in the MDD risk among a large population cohort. METHODS: Data analyzed were from a longitudinal community-based cohort from Southwest Montreal, Canada (N = 1083). Latent profile models were used to identify distinct patterns of stressors for the study cohort. A transcriptome-wide association study (TWAS) method was performed to examine the interactive effects of three dimensions of stressors (threat, deprivation, and cumulative lifetime stress) and gene expression on the MDD risk in a total of 48 tissues from GTEx. Additional analyses were also conducted to further explore and specify these associations including colocalization, and fine-mapping analyses, in addition to enrichment analysis investigations based on TWAS. RESULTS: We identified 3321 genes linked to MDD at the nominal p-value <0.05 and found that different patterns of stressors can amplify the genetic susceptibility to MDD. We also observed specific genes and pathways that interacted with deprivation and cumulative lifetime stressors, particularly in specific brain tissues including basal ganglia, prefrontal cortex, brain amygdala, brain cerebellum, brain cortex, and the whole blood. Colocalization analysis also identified these genes as having a high probability of sharing MDD causal variants. LIMITATIONS: The study cohort was composed exclusively of individuals of Caucasians, which restricts the generalizability of the findings to other ethnic population groups. CONCLUSIONS: The findings of the study unveiled significant interactions between potential tissue-specific gene expression × stressors in the MDD risk and shed light on the intricate etiological attributes of gene expression and specific stressors across the lifespan in MDD. These genetic and environmental attributes in MDD corroborate the vulnerability-stress theory and direct future stress research to have a closer examination of genetic predisposition and potential involvements of omics studies to specify the intricate relationships between genes and stressful environments.
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Trastorno Depresivo Mayor , Predisposición Genética a la Enfermedad , Estrés Psicológico , Humanos , Trastorno Depresivo Mayor/genética , Femenino , Masculino , Estrés Psicológico/genética , Adulto , Predisposición Genética a la Enfermedad/genética , Persona de Mediana Edad , Estudios Longitudinales , Estudio de Asociación del Genoma Completo , Expresión Génica/genética , Encéfalo/metabolismo , Interacción Gen-Ambiente , Canadá , Transcriptoma , Anciano , Estudios de CohortesRESUMEN
Importance: African American men experience greater prostate cancer incidence and mortality than White men. Growing literature supports associations of neighborhood disadvantage, which disproportionately affects African American men, with aggressive prostate cancer; chronic stress and downstream biological impacts (eg, increased inflammation) may contribute to these associations. Objective: To examine whether several neighborhood disadvantage metrics are associated with prostate tumor RNA expression of stress-related genes. Design, Setting, and Participants: This cross-sectional study leveraged prostate tumor transcriptomic data for African American and White men with prostate cancer who received radical prostatectomy at the University of Maryland Medical Center between August 1992 and January 2021. Data were analyzed from May 2023 to April 2024. Exposures: Using addresses at diagnosis, 2 neighborhood deprivation metrics (Area Deprivation Index [ADI] and validated bayesian Neighborhood Deprivation Index) as well as the Racial Isolation Index (RI) and historical redlining were applied to participants' addresses. Self-reported race was determined using electronic medical records. Main Outcomes and Measures: A total of 105 stress-related genes were evaluated with each neighborhood metric using linear regression, adjusting for race, age, and year of surgery. Genes in the Conserved Transcriptional Response to Adversity (CTRA) and stress-related signaling genes were included. Results: A total of 218 men (168 [77%] African American, 50 [23%] White) with a median (IQR) age of 58 (53-63) years were included. African American participants experienced greater neighborhood disadvantage than White participants (median [IQR] ADI, 115 [100-130] vs 92 [83-104]; median [IQR] RI, 0.68 [0.34-0.87] vs 0.11 [0.06-0.14]). ADI was positively associated with expression for 11 genes; HTR6 (serotonin pathway) remained significant after multiple-comparison adjustment (ß = 0.003; SE, 0.001; P < .001; Benjamini-Hochberg q value = .01). Several genes, including HTR6, were associated with multiple metrics. We observed higher expression of 5 proinflammatory genes in the CTRA with greater neighborhood disadvantage (eg, CXCL8 and ADI, ß = 0.008; SE, 0.003; P = .01; q value = .21). Conclusions and Relevance: In this cross-sectional study, the expression of several stress-related genes in prostate tumors was higher among men residing in disadvantaged neighborhoods. This study is one of the first to suggest associations of neighborhood disadvantage with prostate tumor RNA expression. Additional research is needed in larger studies to replicate findings and further investigate interrelationships of neighborhood factors, tumor biology, and aggressive prostate cancer to inform interventions to reduce disparities.
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Negro o Afroamericano , Neoplasias de la Próstata , Blanco , Anciano , Humanos , Masculino , Persona de Mediana Edad , Negro o Afroamericano/estadística & datos numéricos , Negro o Afroamericano/genética , Estudios Transversales , Maryland/epidemiología , Características del Vecindario , Prostatectomía/estadística & datos numéricos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Características de la Residencia/estadística & datos numéricos , Estrés Psicológico/genética , Blanco/genética , Blanco/estadística & datos numéricosRESUMEN
Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.
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Histonas , Lisina , Núcleo Accumbens , Complejo Represivo Polycomb 2 , Estrés Psicológico , Animales , Histonas/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/genética , Ratones , Núcleo Accumbens/metabolismo , Metilación , Lisina/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/genética , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Procesamiento Proteico-Postraduccional , Derrota SocialRESUMEN
Adolescence is a critical developmental period when the brain is plastic, and stress exposure can have lasting physiological consequences. One mechanism through which adolescent stress may have lasting effects is by altering microRNAs (miRNAs), leading to wide-scale gene expression changes. Three prior independent studies used unbiased approaches (RNA sequencing or microarray) to identify miRNAs differentially expressed by chronic variable stress in male rodents. In all three studies, miRNA-200a was differentially expressed in areas of the brain associated with emotion regulation. The current study extends this research to determine if chronic non-variable adolescent stress downregulates miRNA-200a expression by looking at two strains (BALB/cJ and C57BL/6J) of male and female mice. We utilized a 14-day (2 h/day) restraint stress protocol and verified stress effects on adolescent body weight gain and circulating corticosterone concentrations relative to non-restraint controls. Mice were then left undisturbed until they were euthanized in adulthood, at which time brains were collected to measure miRNA-200a in the ventral hippocampus. Three weeks after adolescent stress ended, differences in body weight between groups were no longer significant; however, animals exposed to stress had less miRNA-200a expression in the ventral hippocampus than control animals. These data implicate miRNA-200a expression as a potential mechanism by which adolescent stress can have persistent impacts on multiple outcomes in both male and female mice.
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Ratones Endogámicos C57BL , MicroARNs , Restricción Física , Estrés Psicológico , Animales , MicroARNs/genética , Femenino , Masculino , Ratones , Estrés Psicológico/genética , Ratones Endogámicos BALB C , Regulación hacia Abajo , Hipocampo/metabolismo , Corticosterona/sangreRESUMEN
Stress is a major risk factor for the development of psychiatric disorders, including depression. However, its effects are not the same in all the subjects as only a portion of individuals exposed to stress will eventually develop negative mental outcomes, while others can be considered resilient. However, the biological processes underlying the development of a vulnerable or resilient phenotype are still poor understood. In order to cover this, we here used both transcriptomic and miRNomic based approaches in the ventral hippocampus of control (CON) and rats exposed to the chronic mild stress (CMS) paradigm, which were then divided into vulnerable (VULN) or resilient (RES) animals according to the sucrose consumption test. Transcriptomic analyses in VULN rats, compared to both the group of CON and RES animals, revealed the activation of inflammatory/immune-related pathways, specifically involved in antibodies and cytokine production, and the inhibition of pathways involved in protein synthesis. Conversely, transcriptomic data in RES animals suggested the activation of several pathways involved in neurotransmission. We then performed a mRNA-miRNA integration analysis by using miRComb R package, and we found that the most significant mRNA-miRNA pairs were involved in promoting the inflammatory status in VULN animals and, vice versa, by decreasing it in RES rats. Moreover, in VULN animals, the mRNA-miRNA combining analyses revealed the modulation of the olfactory sensory system, a key biological process that has been already found involved in the etiology of stress related disorders such as depression. Overall, our mRNA-miRNA integration-based approach identified distinct biological processes that are relevant for the development of a vulnerable or resilient phenotype in response to the negative effects of CMS exposure, which could allow the identification of novel targets for prevention or treatment.
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Modelos Animales de Enfermedad , Hipocampo , MicroARNs , ARN Mensajero , Resiliencia Psicológica , Estrés Psicológico , Transcriptoma , Animales , Estrés Psicológico/metabolismo , Estrés Psicológico/genética , MicroARNs/metabolismo , MicroARNs/genética , Ratas , Masculino , ARN Mensajero/metabolismo , Hipocampo/metabolismo , Depresión/metabolismo , Depresión/genética , Ratas Wistar , Perfilación de la Expresión Génica/métodosRESUMEN
The oxytocin system plays a role in social stress adaptation, and this role is likely to be particularly important in adolescence. One method of regulating the oxytocin system is through DNA methylation in the promoter of the oxytocin receptor gene (OXTRm), which reduces the gene's expression. This multi-method, longitudinal study, using a diverse community sample of 184 adolescents followed from age 13-28, examined the links between OXTRm and exposure to over-controlling parenting in adolescence and conflict with romantic partners and internalizing symptoms in adulthood. Female, but not male, adolescents who were exposed to psychologically controlling parenting at age 13 had lower levels of OXTRm at site -924 at age 28. Reduced OXTRm at site -924 was associated with greater romantic partner-reported relationship conflict at age 27, and reduced OXTRm at site -934 was marginally associated with greater participant-reported conflict for males. Reduced OXTRm at site -924 was also associated with fewer internalizing symptoms at ages 24-25. These results in adulthood are consistent with an upregulated oxytocin system reducing the salience of negative socioemotional stimuli. Overall, findings are consistent with oxytocin playing a role in the stress response system, and more specifically, by helping us to adapt to social environments like parenting and romantic relationships, reducing the salience of negativity, and reducing risk for common emotional problems.
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Adaptación Psicológica , Metilación de ADN , Epigénesis Genética , Oxitocina , Responsabilidad Parental , Receptores de Oxitocina , Humanos , Masculino , Femenino , Receptores de Oxitocina/genética , Receptores de Oxitocina/metabolismo , Responsabilidad Parental/psicología , Adulto , Oxitocina/metabolismo , Oxitocina/genética , Adolescente , Epigénesis Genética/genética , Epigénesis Genética/fisiología , Estudios Longitudinales , Adulto Joven , Metilación de ADN/fisiología , Adaptación Psicológica/fisiología , Funcionamiento Psicosocial , Estrés Psicológico/genética , Estrés Psicológico/metabolismo , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: Stress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic-pituitary-adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic-pituitary-adrenal axis-related genes FKBP5 and NR3C1. We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation. METHODS: This study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation. RESULTS: Mothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels. CONCLUSIONS: Food insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up. Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.
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Metilación de ADN , Epigénesis Genética , Receptores de Glucocorticoides , Humanos , Metilación de ADN/genética , Femenino , Kenia , Adulto , Embarazo , Lactante , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Proteínas de Unión a Tacrolimus/genética , Madres/psicología , Masculino , Estrés Psicológico/genética , Granjas , Sistema Hipotálamo-Hipofisario/metabolismo , Adulto Joven , Inseguridad Alimentaria , Sistema Hipófiso-Suprarrenal/metabolismo , Recién Nacido , Productos Agrícolas/genéticaRESUMEN
BACKGROUND: Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes. METHODS: For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG. RESULTS: The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, P=1×10-5). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (P<0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (P=3.2×10-5). CONCLUSIONS: This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.
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Recuperación de la Función , Accidente Cerebrovascular , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular/genética , Recuperación de la Función/genética , Estudios Prospectivos , Variación Genética/genética , Rehabilitación de Accidente Cerebrovascular , Estudios Longitudinales , Factor Neurotrófico Derivado del Encéfalo/genética , Estrés Psicológico/genética , Catecol O-Metiltransferasa/genéticaRESUMEN
Aberrant functioning of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of conditions such as depression, anxiety disorders, and post-traumatic stress disorder. Early-life adversity and genetic variation can interaction to disrupt HPA axis regulation, potentially contributing to certain forms of psychopathology. This study employs a rhesus macaque model to investigate how early parental neglect interacts with a single nucleotide polymorphism within the promoter region of the corticotropin-releasing hormone (CRH-248) gene, impacting the development of the HPA axis. For the initial six months of life, 307 rhesus monkey infants (n = 146 females, n = 161 males) were either reared with their mothers (MR) in conditions emulating the natural environment (control group) or raised without maternal care in groups with constant or 3-hours daily access to same-aged peers (NR). Blood samples collected on days 30, 60, 90, and 120 of life under stressful conditions were assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. Findings revealed that NR subjects exhibited a significant blunting of both ACTH and cortisol concentrations. Notably, there was a gene-by-environment interaction observed for ACTH and cortisol levels, with NR subjects with the polymorphism displaying higher ACTH concentrations and lower cortisol concentrations. To the extent that these results generalize to humans, they suggest that early parental neglect may render individuals vulnerable to HPA axis dysfunction, a susceptibility that is modulated by CRH-248 genotype-a gene-by-environment interaction that leaves a lasting developmental signature.
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Hormona Liberadora de Corticotropina , Hidrocortisona , Sistema Hipotálamo-Hipofisario , Macaca mulatta , Sistema Hipófiso-Suprarrenal , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Animales , Sistema Hipotálamo-Hipofisario/metabolismo , Femenino , Hormona Liberadora de Corticotropina/genética , Masculino , Hidrocortisona/sangre , Genotipo , Estrés Psicológico/genética , Interacción Gen-Ambiente , Privación Materna , Hormona Adrenocorticotrópica/sangreRESUMEN
In recent years, there has been a burgeoning interest in exploring the nuances of animal stress physiology, particularly in relation to parameters such as sex and behavioral phenotype-dependent variations, which is crucial for understanding phenotypic variation and its role in evolutionary selection. However, a significant dearth remains in how chronic stressors affect organismal stress physiology concerning the aforesaid parameters. This void is even wider pertaining to the response of peripheral tissues, such as the skin, the organ with the highest surface contact area with the environment. Hence, we behaviorally grouped the zebrafishes based on their boldness and the body condition, whole body cortisol response, along with examining the transcriptional response, global DNA methylome, and oxidative DNA damage in the skin upon chronic crowding. Upon baseline conditions, clear distinction between bold and shy phenotypes was found, particularly in males. The boldness index score distribution exhibited greater uniformity in males than in females. Regarding the body condition response to chronic crowding, shy males showed a significant relative decline compared with their bold counterparts, while this trend did not hold true for females. qPCR data revealed distinctive expression patterns in key genes that play critical roles in cellular processes such as stress-mediated gene regulation, immune response, oxidative stress protection, and maintenance of genomic integrity through epigenetic modifications across behavioral phenotypes and sexes under both with and without chronic crowding stress. Global DNA methylation levels significantly declined only in chronically crowded shy males, and sex/behavioral phenotype-dependent trends in oxidative DNA damage were identified.NEW & NOTEWORTHY This paper analyzes the response of zebrafish to crowding stress through a new approach focused on the peripheral response dynamics of the skin, the main mucosal tissue, and involving sex and behavioral phenotype influences. Shy males showed significant distress as observed by body condition, physiological and transcriptional response, and global DNA methylation. Nuances in stress response across behavioral phenotypes and sex indicate a genetic and behavioral specificity and further inherent epigenetic regulatory dimension.
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Conducta Animal , Aglomeración , Metilación de ADN , Estrés Psicológico , Pez Cebra , Animales , Femenino , Masculino , Estrés Psicológico/fisiopatología , Estrés Psicológico/genética , Daño del ADN , Fenotipo , Hidrocortisona/sangre , Hidrocortisona/metabolismo , Estrés Oxidativo , Factores Sexuales , Epigénesis GenéticaRESUMEN
Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to white men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in 15 lung tumor samples in relation to GR target gene expression levels and zip code level residential violent crime rates. Spatial transcriptomics and a version of ChIP sequencing known as CUT&RUN were used. Heatmap of genes, pathway analysis, and motif analysis were conducted at the statistical significance of P < 0.05. GR recruitment to chromatin was correlated with zip code level residential violent crime rate and overall GR binding increased with higher violent crime rates. Our findings suggest that exposure to residential violent crime may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high levels of violent crime, may reduce racial disparities in lung cancer. SIGNIFICANCE: Exposure to neighborhood violent crime is correlated with glucocorticoid signaling and lung tumor gene expression changes associated with increased tumor aggressiveness, suggesting social conditions have downstream biophysical consequences that contribute to lung cancer disparities.
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Neoplasias Pulmonares , Receptores de Glucocorticoides , Características de la Residencia , Transducción de Señal , Estrés Psicológico , Violencia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/metabolismo , Masculino , Características de la Residencia/estadística & datos numéricos , Estrés Psicológico/genética , Estrés Psicológico/epidemiología , Estrés Psicológico/metabolismo , Violencia/estadística & datos numéricos , Violencia/etnología , Chicago/epidemiología , Negro o Afroamericano/genética , Negro o Afroamericano/estadística & datos numéricos , Regulación Neoplásica de la Expresión Génica , Persona de Mediana EdadRESUMEN
Background and aims: The association between perceived stress (PS) and gaming addiction (GA) is well documented. However, the mechanism for explaining this association remains unclear. Using a genetically informative design, this study aims to distinguish between the diathesis-stress and bio-ecological models of gene by environment interaction (G x E) to explain the underlying mechanism of the relationship. Methods: In total, 1,468 twins (mean age = 22.6 ± 2.8 years) completed an online survey including the GA and PS scales. Twin correlations for GA and PS were computed and univariate model-fitting analysis was conducted to determine genetic and environmental influences on GA and PS. The bivariate G x E model-fitting analysis was performed to determine the best G x E interaction model. Results: Additive genetic, shared environmental, and non-shared environmental effects were 0.70 (95%CI = 0.61, 0.77), 0.00, and 0.30 (95%CI = 0.26, 0.33), and 0.38 (95%CI = 0.24, 0.55), 0.35 (95% CI = 0.18, 0.51), and 0.22 (95%CI = 0.20, 0.26) for GA and PS, respectively. Bivariate G x E model-fitting analysis supported the diathesis-stress model, where genetic influences on GA were greater in higher levels of PS, whereas environmental influences on GA were small and constant across levels of PS. Discussion and conclusions: The evidence for the diathesis-stress model for GA is consistent with the etiological process of many forms of psychopathology. The findings should be incorporated in clinical settings to improve the treatment of GA, and used in developments of intervention and prevention methods for GA.