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Effects of negative stressors on DNA methylation in the brain: implications for mood and anxiety disorders.

ABSTRACT: Stress is a major contributor to anxiety and mood disorders. The recent discovery of epigenetic changes in the brain resulting from stress has enhanced our understanding of the mechanism by which stress is able to promote these disorders. Although epigenetics encompasses chemical modifications that occur at both DNA and histones, much attention has been focused on stress-induced DNA methylation changes on behavior. Here, we review the effect of stress-induced DNA methylation changes on physiological mechanisms that govern behavior and cognition, dysregulation of which can be harmful to mental health. A literature review was performed in the areas of DNA methylation, stress, and their impact on the brain and psychiatric illness. Key findings center on genes involved in the hypothalamic-pituitary-adrenal axis, neurotransmission and neuroplasticity. Using animal models of different stress paradigms and clinical studies, we detail how DNA methylation changes to these genes can alter physiological mechanisms that influence behavior. Appropriate levels of gene expression in the brain play an important role in mental health. This dynamic control can be disrupted by stress-induced changes to DNA methylation patterns. Advancement in other areas of epigenetics, such as histone modifications and the discovery of the novel DNA epigenetic mark, 5-hydroxymethylcytosine, could provide additional avenues to consider when determining the epigenetic effects of stress on the brain.

SUBMITTER: Hing B

PROVIDER: S-EPMC5096645 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Effects of negative stressors on DNA methylation in the brain: implications for mood and anxiety disorders.

Hing Benjamin B Gardner Caleb C Potash James B JB

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20140819 7

Stress is a major contributor to anxiety and mood disorders. The recent discovery of epigenetic changes in the brain resulting from stress has enhanced our understanding of the mechanism by which stress is able to promote these disorders. Although epigenetics encompasses chemical modifications that occur at both DNA and histones, much attention has been focused on stress-induced DNA methylation changes on behavior. Here, we review the effect of stress-induced DNA methylation changes on physiolog ...[more]

PMID: 25139739

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Project description:BackgroundMood and anxiety disorders are ubiquitous but current treatment options are ineffective for many sufferers. Moreover, a number of promising pre-clinical interventions have failed to translate into clinical efficacy in humans. Improved treatments are unlikely without better animal-human translational pipelines. Here, we translate a rodent measure of negative affective bias into humans, exploring its relationship with (1) pathological mood and anxiety symptoms and (2) transient induced anxiety.MethodsAdult participants (age = 29 ± 11) who met criteria for mood or anxiety disorder symptomatology according to a face-to-face neuropsychiatric interview were included in the symptomatic group. Study 1 included N = 77 (47 = asymptomatic [female = 21]; 30 = symptomatic [female = 25]), study 2 included N = 47 asymptomatic participants (25 = female). Outcome measures were choice ratios, reaction times and parameters recovered from a computational model of reaction time - the drift diffusion model (DDM) - from a two-alternative-forced-choice task in which ambiguous and unambiguous auditory stimuli were paired with high and low rewards.ResultsBoth groups showed over 93% accuracy on unambiguous tones indicating intact discrimination, but symptomatic individuals demonstrated increased negative affective bias on ambiguous tones [proportion high reward = 0.42 (s.d. = 0.14)] relative to asymptomatic individuals [0.53 (s.d. = 0.17)] as well as a significantly reduced DDM drift rate. No significant effects were observed for the within-subjects anxiety-induction.ConclusionsHumans with pathological anxiety symptoms directly mimic rodents undergoing anxiogenic manipulation. The lack of sensitivity to transient anxiety suggests the paradigm might be more sensitive to clinically relevant symptoms. Our results establish a direct translational pipeline (and candidate therapeutics screen) from negative affective bias in rodents to pathological mood and anxiety symptoms in humans.

Project description:ImportanceChildren with strabismus have poorer functional vision and decreased quality of life than those without strabismus.ObjectiveTo evaluate the association between strabismus and mental illness among children.Design, setting, and participantsThis cross-sectional study analyzed claims data from the OptumLabs Data Warehouse, a longitudinal deidentified commercial insurance claims database, from 12 005 189 patients enrolled in the health plan between January 1, 2007, and December 31, 2017. Eligibility criteria included age younger than 19 years at the time of strabismus diagnosis, enrollment in the health plan between 2007 and 2018, and having at least 1 strabismus claim based on International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification codes. Controls were children in the same database with no eye disease codes other than refractive error reported. Demographic characteristics and mental illness claims were compared. Statistical analysis was conducted from December 1, 2018, to July 31, 2021.Main outcomes and measuresPresence of mental illness claims.ResultsAmong the 12 005 189 patients (6 095 523 boys [50.8%]; mean [SD] age, 8.0 [5.9] years) in the study, adjusted odds ratios for the association of mental illnesses with strabismus were 2.01 (95% CI, 1.99-2.04) for anxiety disorder, 1.83 (95% CI, 1.76-1.90) for schizophrenia, 1.64 (95% CI, 1.59-1.70) for bipolar disorder, 1.61 (95% CI, 1.59-1.63) for depressive disorder, and 0.99 (95% CI, 0.97-1.02) for substance use disorder. There was a moderate association between each strabismus type (esotropia, exotropia, and hypertropia) and anxiety disorder, schizophrenia, bipolar disorder, and depressive disorder; odds ratios ranged from 1.23 (95% CI, 1.17-1.29) for the association between esotropia and bipolar disorder to 2.70 (95% CI, 2.66-2.74) for the association between exotropia and anxiety disorder.Conclusions and relevanceThis cross-sectional study suggests that there was a moderate association between strabismus and anxiety disorder, schizophrenia, bipolar disorder, and depressive disorder but not substance use disorder. Recognizing that these associations exist should encourage mental illness screening and treatment for patients with strabismus.

Project description:Importance:The symptoms that define mood, anxiety, and trauma disorders are highly overlapping across disorders and heterogeneous within disorders. It is unknown whether coherent subtypes exist that span multiple diagnoses and are expressed functionally (in underlying cognition and brain function) and clinically (in daily function). The identification of cohesive subtypes would help disentangle the symptom overlap in our current diagnoses and serve as a tool for tailoring treatment choices. Objective:To propose and demonstrate 1 approach for identifying subtypes within a transdiagnostic sample. Design, Setting, and Participants:This cross-sectional study analyzed data from the Brain Research and Integrative Neuroscience Network Foundation Database that had been collected at the University of Sydney and University of Adelaide between 2006 and 2010 and replicated at Stanford University between 2013 and 2017. The study included 420 individuals with a primary diagnosis of major depressive disorder (n?=?100), panic disorder (n?=?53), posttraumatic stress disorder (n?=?47), or no disorder (healthy control participants) (n?=?220). Data were analyzed between October 2016 and October 2017. Main Outcomes and Measures:We followed a data-driven approach to achieve the primary study outcome of identifying transdiagnostic subtypes. First, machine learning with a hierarchical clustering algorithm was implemented to classify participants based on self-reported negative mood, anxiety, and stress symptoms. Second, the robustness and generalizability of the subtypes were tested in an independent sample. Third, we assessed whether symptom subtypes were expressed at behavioral and physiological levels of functioning. Fourth, we evaluated the clinically meaningful differences in functional capacity of the subtypes. Findings were interpreted relative to a complementary diagnostic frame of reference. Results:Four hundred twenty participants with a mean (SD) age of 39.8 (14.1) years were included in the final analysis; 256 (61.0%) were female. We identified 6 distinct subtypes characterized by tension (n=81; 19%), anxious arousal (n=55; 13%), general anxiety (n=38; 9%), anhedonia (n=29; 7%), melancholia (n=37; 9%), and normative mood (n=180; 43%), and these subtypes were replicated in an independent sample. Subtypes were expressed through differences in cognitive control (F5,383?=?5.13, P?<?.001, ?p2?=?0.063), working memory (F5,401?=?3.29, P?=?.006, ?p2?=?0.039), electroencephalography-recorded ? power in a resting paradigm (F5,357?=?3.84, P?=?.002, ?p2?=?0.051), electroencephalography-recorded ? power in an emotional paradigm (F5,365?=?3.56, P?=?.004, ?p2?=?0.047), social functional capacity (F5,414?=?21.33, P?<?.001, ?p2?=?0.205), and emotional resilience (F5,376?=?15.10, P?<?.001, ?p2?=?0.171). Conclusions and Relevance:These findings offer a data-driven framework for identifying robust subtypes that signify specific, coherent, meaningful associations between symptoms, behavior, brain function, and observable real-world function, and that cut across DSM-IV-defined diagnoses of major depressive disorder, panic disorder, and posttraumatic stress disorder.

Project description:IntroductionWhile a growing body of research is adopting Research Domain Criteria (RDoC)-related methods and constructs, there is still a lack of comprehensive reviews on the state of published research on Positive Valence Systems (PVS) and Negative Valence Systems (NVS) in mood and anxiety disorders consistent with the RDoC framework.MethodsFive electronic databases were searched to identify peer-reviewed publications covering research on "positive valence" and "negative valence" as well as "valence," "affect," and "emotion" for individuals with symptoms of mood and anxiety disorders. Data was extracted with a focus on disorder, domain, (sub-) constructs, units of analysis, key results, and study design. Findings are presented along four sections, distinguishing between primary articles and reviews each for PVS, NVS, and cross-domain PVS and NVS.ResultsA total of 231 abstracts were identified, and 43 met the inclusion criteria for this scoping review. Seventeen publications addressed research on PVS, seventeen on NVS, and nine covered cross-domain research on PVS and NVS. Psychological constructs were typically examined across different units of analysis, with the majority of publications incorporating two or more measures. Molecular, genetic, and physiological aspects were mainly investigated via review articles, primary articles focused on self-report, behavioral, and, to a lesser extent, physiological measures.ConclusionsThis present scoping review shows that mood and anxiety disorders were actively studied using a range of genetic, molecular, neuronal, physiological, behavioral, and self-report measures within the RDoC PVS and NVS. Results highlight the essential role of specific cortical frontal brain structures and of subcortical limbic structures in impaired emotional processing in mood and anxiety disorders. Findings also indicate overall limited research on NVS in bipolar disorders and PVS in anxiety disorders, a majority of self-report studies, and predominantly observational studies. Future research is needed to develop more RDoC-consistent advancements and intervention studies targeting neuroscience-driven PVS and NVS constructs.

Dataset Information

Effects of negative stressors on DNA methylation in the brain: implications for mood and anxiety disorders.

Publications

Effects of negative stressors on DNA methylation in the brain: implications for mood and anxiety disorders.

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