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Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Psychosocial stress effects of urban living are associated with substantially increased risk for schizophrenia, mood and anxiety disorders, by altering stress-induced activity in the amygdala and pregenual anterior cingulate cortex (ACC). Genetic factors are likely to modulate the impact of city living on stress processing. Growing evidence suggests a key role of FKBP5 , a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of stress-related disorders. Here we investigated the interaction of city living and genetic variation in FKBP5 (rs3800373) on neural activity in stress-sensitive brain systems. Functional magnetic resonance imaging was performed in 31 healthy young adults using the Montreal Imaging Stress Task. Subjects were divided into groups depending on the number of inhabitants of their current residency. There was a significant main effect of city living on neural activity in the amygdala-hippocampus complex, replicating prior findings. Moreover, we found an interaction between rs3800373 and city living modulating responses in the bilateral subgenual ACC and right pregenual ACC. Specifically, only city dwellers carrying the FKBP5 minor risk allele showed increased stress responses in the subgenual and pregenual ACC when compared to those living in small towns. A significant gene-environment interaction on neural stress responses in the amygdala or hippocampus was only found in FKBP5 major allele carriers. These results point to a potential role of the FKBP5 rs3800373 minor risk allele in predisposing those who live in bigger cities to changes of functional responsivity in the pre- and subgenual ACC, thereby increasing the risk for developing stress-related mental disorders.

Acute and chronic stress are important factors in the development of mental disorders. Reliable measurement of stress reactivity is therefore pivotal. Critically, experimental induction of stress often involves multiple "hits" and it is an open question whether individual differences in responses to an earlier stressor lead to habituation, sensitization, or simple additive effects on following events. Here, we investigated the effect of the individual cortisol response to intravenous catheter placement (IVP) on subsequent neural, psychological, endocrine, and autonomous stress reactivity. We used an established psychosocial stress paradigm to measure the acute stress response (Stress) and recovery (PostStress) in 65 participants. Higher IVP-induced cortisol responses were associated with lower pulse rate increases during stress recovery (b = -4.8 bpm, p = .0008) and lower increases in negative affect after the task (b = -4.2, p = .040). While the cortisol response to IVP was not associated with subsequent specific stress-induced neural activation patterns, the similarity of brain responses Pre- and PostStress was higher IVP-cortisol responders (t[64] = 2.35, p = .022) indicating faster recovery. In conclusion, preparatory stress induced by IVP reduced reactivity in a subsequent stress task by modulating the latency of stress recovery. Thus, an individually stronger preceding release of cortisol may attenuate a second physiological response and perceived stress suggesting that relative changes, not absolute levels are crucial for stress attribution. Our study highlights that considering the entire trajectory of stress induction during an experiment is important to develop reliable individual biomarkers., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The identification and understanding of resilience mechanisms holds potential for the development of mechanistically informed prevention and interventions in psychiatry. However, investigating resilience mechanisms is conceptually and methodologically challenging because resilience does not merely constitute the absence of disease-specific risk but rather reflects active processes that aid in the maintenance of physiological and psychological homeostasis across a broad range of environmental circumstances. In this conceptual review, we argue that the principle used in gene-by-environment interaction studies may help to unravel resilience mechanisms on different investigation levels. We present how this could be achieved by top-down designs that start with gene-by-environment interaction effects on disease phenotypes as well as by bottom-up approaches that start at the molecular level. We also discuss how recent technological advances may improve both top-down and bottom-up strategies., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities., Competing Interests: Conflict of interest statement: E.B.B. receives a research grant from Böhringer-Ingelheim to develop cellular and animal models of enhanced FKBP5 function. She is also coinventor on the following patent application: “FKBP5: a novel target for antidepressant therapy” (European Patent no. EP 1687443 B1)., (Copyright © 2019 the Author(s). Published by PNAS.)

Chronic adolescent stress alters behavior in a sex-specific manner at the end of adolescence and in adulthood. Although prolonged behavioral repercussions of chronic adolescent stress have been documented, the potential underlying mechanisms are incompletely understood. In this study we demonstrate that a history of chronic adolescent stress modified the adult stress response, as measured by corticosterone concentration, such that a history of chronic adolescent stress resulted in a blunted response to a novel acute stressor. In order to begin to address potential mechanistic underpinnings, we assessed the extent to which chronic adolescent stress impacted global DNA methylation. Reduced global hippocampal methylation was evident in females with a history of chronic adolescent stress; thus, it was possible that chronic adolescent stress altered global transcription in the whole hippocampi of adult male and female rats. In addition, because acute stress can stimulate a genomic response, we assessed the transcriptome following exposure to an acute novel stressor to determine the extent to which a history of chronic adolescent stress modifies the adult transcriptional response to an acute stressor in males and females. In addition to the reduction in global methylation, chronic adolescent stress resulted in distinct patterns of gene expression in the adult hippocampus that differentiated by sex. Furthermore, both sex and a history of chronic adolescent stress influenced the transcriptional response to an acute novel stressor in adulthood, suggesting both latent and functional effects of chronic adolescent stress at the level of gene transcription. Pathway analysis indicated that ESR1 and IFN-α may be particularly influential transcription factors mediating these transcriptional differences and suggest candidate mechanisms for future studies. Collectively, these studies demonstrate sex-specific and enduring effects of adolescent stress exposure that are more pronounced in females than in males.

Background: Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported., Results: We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS., Conclusion: Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.

While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N = 113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methylation of selected stress-response-associated genes (FK506 binding protein 51 [FKBP5], glucocorticoid receptor [NR3C1], corticotropin-releasing hormone receptor 1 [CRHR1]) in isolated immune cells from maternal blood and neonatal umbilical cord blood. In mothers, CM was associated with decreased levels of DNA methylation of FKBP5 and CRHR1 and increased NR3C1 methylation, but not with changes in gene expression profiles. Rs1360780 moderated the FKBP5 epigenetic CM-associated regulation profiles in a gene × environment interaction. In newborns, we found no evidence for any intergenerational transmission of CM-related methylation profiles for any of the investigated epigenetic sites. These findings support the hypothesis of a long-lasting impact of CM on the biological epigenetic regulation of stress-response mediators and suggest for the first time that these specific epigenetic patterns might not be directly transmitted to the next generation.

Early-life adversity is an important risk factor for major depressive disorder (MDD) and schizophrenia (SCZ) that interacts with genetic factors to confer disease risk through mechanisms that are still insufficiently understood. One downstream effect of early-life adversity is the activation of glucocorticoid receptor (GR)-dependent gene networks that drive acute and long-term adaptive behavioral and cellular responses to stress. We have previously shown that genetic variants that moderate GR-induced gene transcription (GR-response eSNPs) are significantly enriched among risk variants from genome-wide association studies (GWASs) for MDD and SCZ. Here, we show that the 63 transcripts regulated by these disease-associated functional genetic variants form a tight glucocorticoid-responsive co-expression network (termed GCN). We hypothesized that changes in the correlation structure of this GCN may contribute to early-life adversity-associated disease risk. Therefore, we analyzed the effects of different qualities of social support and stress throughout life on GCN formation across distinct brain regions using a translational mouse model. We observed that different qualities of social experience substantially affect GCN structure in a highly brain region-specific manner. GCN changes were predominantly found in two functionally interconnected regions, the ventral hippocampus and the hypothalamus, two brain regions previously shown to be of relevance for the stress response, as well as psychiatric disorders. Overall, our results support the hypothesis that a subset of genetic variants may contribute to risk for MDD and SCZ by altering circuit-level effects of early and adult social experiences on GCN formation and structure.

Ample evidence links dysregulation of the stress response to the risk for psychiatric disorders. However, we lack an integrated understanding of mechanisms that are adaptive during the acute stress response but potentially pathogenic when dysregulated. One mechanistic link emerging from rodent studies is the interaction between stress effectors and neurovascular coupling, a process that adjusts cerebral blood flow according to local metabolic demands. Here, using task-related fMRI, we show that acute psychosocial stress rapidly impacts the peak latency of the hemodynamic response function (HRF-PL) in temporal, insular, and prefrontal regions in two independent cohorts of healthy humans. These latency effects occurred in the absence of amplitude effects and were moderated by regulatory genetic variants of KCNJ2 , a known mediator of the effect of stress on vascular responsivity. Further, hippocampal HRF-PL correlated with both cortisol response and genetic variants that influence the transcriptional response to stress hormones and are associated with risk for major depression. We conclude that acute stress modulates hemodynamic response properties as part of the physiological stress response and suggest that HRF indices could serve as endophenotype of stress-related disorders., Competing Interests: The authors declare no conflict of interest.

N 6 -methyladenosine (m 6 A) and N 6 ,2'-O-dimethyladenosine (m 6 Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m 6 A/m, in the stress response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using m 6 A/m-seq, global and gene-specific m 6 A/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter m 6 A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the m 6 A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m 6 A/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain m 6 A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m 6 A/m response may contribute to the pathophysiology of stress-related psychiatric disorders., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The inconsistency in results of cortisol alterations after childhood maltreatment (CM) might arise due to the fact that no study so far considered the effects of environmental factors such as maltreatment load and genetic factors such as the influence of FKBP5 genotype on stress hormone regulation. This study analyzed the interaction between the single nucleotide polymorphism rs1360780 within the FKBP5 gene and the severity of maternal CM experiences (maltreatment load) on hair steroid levels of mother-infant-dyads., Methods: Hair samples of N = 474 mothers and N = 331 newborns were collected < 1 week after parturition enabling a retrospective assessment of cortisol, cortisone, and dehydroepiandrosterone (DHEA) using mass spectrometry. The sum score of the Childhood Trauma Questionnaire operationalized the maternal maltreatment load. DNA from whole blood or buccal cells was used for FKBP5 genotyping., Results: The higher the maltreatment load, the higher maternal hair cortisol and cortisone levels in T allele carriers of FKBP5 rs1360780 were observed. Hair cortisol and DHEA levels of newborns with the T allele were reduced with an increasing maternal maltreatment load, while there was an increase of hair cortisol and DHEA in newborns homozygous for the C allele., Conclusions: This study is the very first uncovering a gene (FKBP5) × environment (maltreatment load) interaction on hair steroids in mothers and their offspring, indicating an intergenerational transmission of hypothalamic-pituitary-adrenal axis alterations. These results may help to explain the inconsistency in previous findings on steroid hormone alterations after chronic and traumatic stress and should be considered in future studies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Mood disorders affect nearly a quarter of the world's population. Therefore, understanding the molecular mechanisms underlying these conditions is of great importance. FK-506 binding protein 5 ( FKBP5 ) encodes the FKBP51 protein, a heat shock protein 90 kDa (Hsp90) co-chaperone, and is a risk factor for several affective disorders. FKBP51, in coordination with Hsp90, regulates glucocorticoid receptor (GR) activity via a short negative feedback loop. This signalling pathway rapidly restores homeostasis in the hypothalamic-pituitary-adrenal (HPA) axis following stress. Expression of FKBP5 increases with age through reduced DNA methylation. High levels of FKBP51 are linked to GR resistance and reduced stress coping behaviour. Moreover, common allelic variants in the FKBP5 gene are associated with increased risk of developing affective disorders like anxiety, depression and post-traumatic stress disorder (PTSD). This review highlights the current understanding of the Hsp90 co-chaperone, FKBP5, in disease from both human and animal studies. In addition, FKBP5 genetic implications in the clinic involving life stress exposure, gender differences and treatment outcomes are discussed.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'., (© 2017 The Author(s).)

Individuals who have experienced high levels of childhood stress are at increased risk for a wide range of behavioral problems that persist into adulthood, yet the neurobiological and molecular mechanisms underlying these associations remain poorly understood. Many of the difficulties observed in stress-exposed children involve problems with learning and inhibitory control. This experiment was designed to test individuals' ability to learn to inhibit responding during a laboratory task. To do so, we measured stress exposure among a community sample of school-aged children, and then followed these children for a decade. Those from the highest and lowest quintiles of childhood stress exposure were invited to return to our laboratory as young adults. At that time, we reassessed their life stress exposure, acquired functional magnetic resonance imaging data during an inhibitory control task, and assayed these individuals' levels of methylation in the FK506 binding protein 5 (FKBP5) gene. We found that individuals who experienced high levels of stress in childhood showed less differentiation in the dorsolateral prefrontal cortex between error and correct trials during inhibition. This effect was associated only with childhood stress exposure and not by current levels of stress in adulthood. In addition, FKBP5 methylation mediated the association between early life stress and inhibition-related prefrontal activity. These findings are discussed in terms of using multiple levels of analyses to understand the ways in which adversity in early development may affect adult behavioral adaptation.

Chronic stress is a major risk factor for depression. Interestingly, not all individuals develop psychopathology after chronic stress exposure. In contrast to the prevailing view that stress effects are cumulative and increase stress vulnerability throughout life, the match/mismatch hypothesis of psychiatric disorders. The match/mismatch hypothesis proposes that individuals who experience moderate levels of early life psychosocial stress can acquire resilience to renewed stress exposure later in life. Here, we have tested this hypothesis by comparing the developmental effects of 2 opposite early life conditions, when followed by 2 opposite adult environments. Male Balb/c mice were exposed to either adverse early life conditions (limited nesting and bedding material) or a supportive rearing environment (early handling). At adulthood, the animals of each group were either housed with an ovariectomized female (supportive environment) or underwent chronic social defeat stress (socially adverse environment) for 3 weeks. At the end of the adult manipulations, all of the animals were returned to standard housing conditions. Then, we compared the neuroendocrine, behavioral and molecular effects of the interaction between early and adult environment. Our study shows that early life adversity does not necessarily result in increased vulnerability to stress. Specific endophenotypes, like hypothalamic-pituitary-adrenal axis activity, anxiety-related behavior and glucocorticoid receptor expression levels in the hippocampus were not significantly altered when adversity is experienced during early life and in adulthood, and are mainly affected by either early life or adult life adversity alone. Overall our data support the notion that being raised in a stressful environment prepares the offspring to better cope with a challenging adult environment and emphasize the role of early life experiences in shaping adult responsiveness to stress., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Life stress has been associated with accelerated cellular aging and increased risk for developing aging-related diseases; however, the underlying molecular mechanisms remain elusive. A highly relevant process that may underlie this association is epigenetic regulation. In this review, we build upon existing evidence to propose a model whereby exposure to life stress, in part via its effects on the hypothalamic-pituitary axis and the glucocorticoid signaling system, may alter the epigenetic landscape across the lifespan and, consequently, influence genomic regulation and function in ways that are conducive to the development of aging-related diseases. This model is supported by recent studies showing that life stressors and stress-related phenotypes can accelerate epigenetic aging, a measure that is based on DNA methylation prediction of chronological age and has been associated with several aging-related disease phenotypes. We discuss the implications of this model for the prevention and treatment of aging-related diseases, as well as the challenges and limitations of this line of research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

MicroRNAs are important regulators of gene expression and associated with stress-related psychiatric disorders. Here, we report that exposing mice to chronic stress led to a specific increase in microRNA-15a levels in the amygdala-Ago2 complex and a concomitant reduction in the levels of its predicted target, FKBP51, which is implicated in stress-related psychiatric disorders. Reciprocally, mice expressing reduced levels of amygdalar microRNA-15a following exposure to chronic stress exhibited increased anxiety-like behaviors. In humans, pharmacological activation of the glucocorticoid receptor, as well as exposure to childhood trauma, was associated with increased microRNA-15a levels in peripheral blood. Taken together, our results support an important role for microRNA-15a in stress adaptation and the pathogenesis of stress-related psychopathologies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10(-6)). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability.

Stress responses and related outcomes vary markedly across individuals. Elucidating the molecular underpinnings of this variability is of great relevance for developing individualized prevention strategies and treatments for stress-related disorders. An important modulator of stress responses is the FK506-binding protein 51 (FKBP5/FKBP51). FKBP5 acts as a co-chaperone that modulates not only glucocorticoid receptor activity in response to stressors but also a multitude of other cellular processes in both the brain and periphery. Notably, the FKBP5 gene is regulated via complex interactions among environmental stressors, FKBP5 genetic variants, and epigenetic modifications of glucocorticoid-responsive genomic sites. These interactions can result in FKBP5 disinhibition that has been shown to contribute to a number of aberrant phenotypes in both rodents and humans. Consequently, FKBP5 blockade may hold promise as treatment intervention for stress-related disorders, and recently developed selective FKBP5 blockers show encouraging results in vitro and in rodent models. Although risk for stress-related disorders is conferred by multiple environmental and genetic factors, the findings related to FKBP5 illustrate how a deeper understanding of the molecular and systemic mechanisms underlying specific gene-environment interactions may provide insights into the pathogenesis of stress-related disorders.

Background: Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear., Results: We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias., Conclusions: Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.

A deeper understanding of the pathomechanisms leading to stress-related psychiatric disorders is important for the development of more efficient preventive and therapeutic strategies. Epidemiological studies indicate a combined contribution of genetic and environmental factors in the risk for disease. The environment, particularly early life severe stress or trauma, can lead to lifelong molecular changes in the form of epigenetic modifications that can set the organism off on trajectories to health or disease. Epigenetic modifications are capable of shaping and storing the molecular response of a cell to its environment as a function of genetic predisposition. This provides a potential mechanism for gene-environment interactions. Here, we review epigenetic mechanisms associated with the response to stress and trauma exposure and the development of stress-related psychiatric disorders. We also look at how they may contribute to our understanding of the combined effects of genetic and environmental factors in shaping disease risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure to early life stress (ELS), such as childhood abuse and neglect is a well established major risk factor for developing psychiatric and behavioral disorders later in life. Both prenatal and postnatal stressors have been shown to have a long-lasting impact on adult pathological states where the type and timing of the stressor are important factors to consider. There is a growing body of evidence suggesting that epigenetic mechanisms play a major role in the biological embedding of ELS. A number of studies now indicate that the epigenome is responsive to external environmental exposures, including the social environment, both during intra-uterine development and after birth. In this review, we summarize the evidence of long-lasting effects of ELS on mental health and behavior and highlight common and distinct epigenetic effects of stress exposure at different stages during development. These stages include postnatal stress, prenatal stress, i.e. in utero and stress occurring pre-conception, i.e. effects of stress exposure transmitted to the next generation. We also delineate the evidence for the possible molecular mechanisms involved in epigenetic programming by ELS and how these maybe distinct, according to the timing of the stress exposure., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Many studies have demonstrated that genotype (G) interacts with adverse life experiences (E) to produce individual differences in vulnerability and resilience to mental disorders, including schizophrenia. Genetic susceptibility to stress and the timing of the environmental exposure(s) are relevant for these interactions and represent common risk factors. We take the example of the FKBP5 gene to illustrate G × E interactions that predict pleiotropic psychiatric outcomes, including schizophrenia., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A large body of evidence describes the long term impact of stress on a number of biological systems and with it associated adverse health outcomes. This article will discuss the epigenetic mechanisms of the embedding of these long term changes, the differences in these mechanisms depending on the type and timing of stress exposure, including transgenerational effects as well as differences in the mechanisms for tissue specific versus more global epigenetic changes. A mechanistic understanding of the long term epigenetic consequences of stress may allow novel, targeted intervention and prevention strategies for psychiatric and other stress-associated disorders., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Single nucleotide polymorphisms (SNPs) in the FK506 binding protein 5 (FKBP5) gene combine with traumatic events to increase risk for post-traumatic stress and major depressive disorders (PTSD and MDD). These SNPs increase FKBP51 protein expression through a mechanism involving demethylation of the gene and altered glucocorticoid signaling. Aged animals also display elevated FKBP51 levels, which contribute to impaired resiliency to depressive-like behaviors through impaired glucocorticoid signaling, a phenotype that is abrogated in FKBP5-/- mice. But the age of onset and progressive stability of these phenotypes remain unknown. Moreover, it is unclear how FKBP5 deletion affects other glucocorticoid-dependent processes or if age-associated increases in FKBP51 expression are mediated through a similar epigenetic process caused by SNPs in the FKBP5 gene. Here, we show that FKBP51-mediated impairment in stress resiliency and glucocorticoid signaling occurs by 10 months of age and this increased over their lifespan. Surprisingly, despite these progressive changes in glucocorticoid responsiveness, FKBP5-/- mice displayed normal longevity, glucose tolerance, blood composition and cytokine profiles across lifespan, phenotypes normally associated with glucocorticoid signaling. We also found that methylation of Fkbp5 decreased with age in mice, a process that likely explains the age-associated increases in FKBP51 levels. Thus, epigenetic upregulation of FKBP51 with age can selectively impair psychological stress-resiliency, but does not affect other glucocorticoid-mediated physiological processes. This makes FKBP51 a unique and attractive therapeutic target to treat PTSD and MDD. In addition, aged wild-type mice may be a useful model for investigating the mechanisms of FKBP5 SNPs associated with these disorders.

The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes × environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, because Crhr1 mRNA expression and CRHR1 binding were enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single-nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating gene × stress exposure interactions. Our data support that the described gene × stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1-mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.

Psychiatric phenotypes are multifactorial and polygenic, resulting from the complex interplay of genes and environmental factors that act cumulatively throughout an organism's lifetime. Adverse life events are strong predictors of risk for a number of psychiatric disorders and a number of studies have focused on gene-environment interactions (GxEs) occurring at genetic loci involved in the stress response. Such a locus that has received increasing attention is the gene encoding FK506 binding protein 51 (FKBP5), a heat shock protein 90 cochaperone of the steroid receptor complex that among other functions regulates sensitivity of the glucocorticoid receptor. Interactions between FKBP5 gene variants and life stressors alter the risk not only for mood and anxiety disorders, but also for a number of other disease phenotypes. In this review, we will focus on molecular and system-wide mechanisms of this GxE with the aim of establishing a framework that explains GxE interactions. We will also discuss how an understanding of the biological effects of this GxE may lead to novel therapeutic approaches., (© 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Early life stress precipitates dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and this effect is most pronounced in females. The mechanisms that mediate female sensitivity to stress-induced HPA axis dysregulation are unknown. The purpose of this study was to determine whether sex moderates the effects of chronic adolescent stress on glucocorticoid receptor (GR) translocation and moderators of the GR system. Female adolescent rats with a history of chronic stress exposure demonstrated a delayed resolution of the plasma corticosterone response to an acute stressor and this delay was accompanied by attenuated GR translocation compared to control adolescent females. The chronic stress-induced phenotype in females was similar to the baseline phenotype in male adolescent rats. Conversely, the expression patterns of GR moderators/co-chaperones became more sexually dimorphic following chronic stress, suggesting divergent function of the GR system between male and female adolescent rats. Gene expression of Ppid, a positive regulator of the GR, was predicted by plasma estradiol and 34% lower in control adolescent females than males, indicating that sex steroids may play a role in the sexually dimorphic response. After chronic adolescent stress, females displayed elevated hippocampal expression of Bag1 and Ppid genes that was not observed in males. Overall, the GR output to an acute stressor, illustrated by transcription of Nr3c1 (encoding the GR), Bag1, Fkbp5, Ppid, and Src1, was significantly upregulated and differed in a sex-specific and chronic stress-dependent manner. This study provides new evidence for sex differences during development and adaptation of the glucocorticoid receptor chaperone system., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Early life stress, such as childhood abuse, neglect and loss, is a well established major risk factor for developing depressive disorders later in life. We here summarize and discuss current developments in human research regarding the link between early life stress and depression. Specifically, we review the evidence for the existence of sensitive periods for the adverse effects of early life stress in humans. We further review the current state of knowledge regarding gene×environment (G×E) interactions in the effects of early life stress. While multiple genes operate in multiple environments to induce risk for depression after early life stress, these same genes also seem to enhance the beneficial effects of a positive early environment. Also, we discuss the epigenetic mechanisms that might underlie these G×E interactions. Finally, we discuss the potential importance of identifying sensitive time periods of opportunity, as well as G×E interactions and epigenetic mechanisms, for early interventions that might prevent or reverse the detrimental outcomes of early life stress and its transmission across generations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-term memory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of short-term memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function.

A concatenation of findings from preclinical and clinical studies support a preeminent function for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically, variants in the gene encoding the CRF(1) receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In-depth characterization of these variants will likely be important in furthering our understanding of the long-term consequences of adverse experience.