Serotonin tranporter methylation and response to cognitive behaviour therapy in children with anxiety disorders

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT

Systematic meta-analyses and field synopsis of genetic association studies of violence and aggression

A large number of candidate gene studies for aggression and violence have been conducted. Successful identification of associations between genetic markers and aggression would contribute to understanding the neurobiology of antisocial behavior and potentially provide useful tools for risk prediction and therapeutic targets for high-risk groups of patients and offenders. We systematically reviewed the literature and assessed the evidence on genetic association studies of aggression and related outcomes in order to provide a field synopsis. We searched PubMed and Huge Navigator databases and sought additional data through reviewing reference lists and correspondence with investigators. Genetic association studies were included if outcome data on aggression or violent behavior either as a binary outcome or as a quantitative trait were provided. From 1331 potentially relevant investigations, 185 studies constituting 277 independent associations on 31 genes fulfilled the predetermined selection criteria. Data from variants investigated in three or more samples were combined in meta-analyses and potential sources of heterogeneity were investigated using subgroup analyses. In the primary analyses, which used relaxed inclusion criteria, we found no association between any polymorphism analyzed and aggression at the 5% level of significance. Subgroup analyses, including by severity of outcome, age group, characteristics of the sample and ethnicity, did not demonstrate any consistent findings. Current evidence does not support the use of such genes to predict dangerousness or as markers for therapeutic interventions

Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders

Stressor exposure during early life has the potential to increase an individual’s susceptibility to a number of neuropsychiatric conditions such as mood and anxiety disorders and schizophrenia in adulthood. This occurs in part due to the dysfunctional stress axis that persists following early adversity impairing stress responsivity across life. The mechanisms underlying the prolonged nature of this vulnerability remain to be established. Alterations in the epigenetic signature of genes involved in stress responsivity may represent one of the neurobiological mechanisms. The overall aim of this review is to provide current evidence demonstrating changes in the epigenetic signature of candidate gene(s) in response to early environmental adversity. More specifically, this review analyses the epigenetic signatures of postnatal adversity such as childhood abuse or maltreatment and later-life psychopathology in human and animal models of early life stress. The results of this review shows that focus to date has been on genes involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and its correlation to subsequent neurobiology, for example, the role of glucocorticoid receptor gene. However, epigenetic changes in other candidate genes such as brain-derived neurotrophic factor (BDNF) and serotonin transporter are also implicated in early life stress (ELS) and susceptibility to adult psychiatric disorders. DNA methylation is the predominantly studied epigenetic mark followed by histone modifications specifically acetylation and methylation. Further, these epigenetic changes are cell/tissue-specific in regulating expression of genes, providing potential biomarkers for understanding the trajectory of early stress-induced susceptibility to adult psychiatric disorders

Sex differences modulating serotonergic polymorphisms implicated in the mechanistic pathways of risk for depression and related disorders:

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137310/1/jnr23877.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137310/2/jnr23877_am.pd

Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression.

Although adverse early life experiences have been found to increase lifetime risk to develop violent behaviors, the neurobiological mechanisms underlying these long-term effects remain unclear. We present a novel animal model for pathological aggression induced by peripubertal exposure to stress with face, construct and predictive validity. We show that male rats submitted to fear-induction experiences during the peripubertal period exhibit high and sustained rates of increased aggression at adulthood, even against unthreatening individuals, and increased testosterone/corticosterone ratio. They also exhibit hyperactivity in the amygdala under both basal conditions (evaluated by 2-deoxy-glucose autoradiography) and after a resident-intruder (RI) test (evaluated by c-Fos immunohistochemistry), and hypoactivation of the medial orbitofrontal (MO) cortex after the social challenge. Alterations in the connectivity between the orbitofrontal cortex and the amygdala were linked to the aggressive phenotype. Increased and sustained expression levels of the monoamine oxidase A (MAOA) gene were found in the prefrontal cortex but not in the amygdala of peripubertally stressed animals. They were accompanied by increased activatory acetylation of histone H3, but not H4, at the promoter of the MAOA gene. Treatment with an MAOA inhibitor during adulthood reversed the peripuberty stress-induced antisocial behaviors. Beyond the characterization and validation of the model, we present novel data highlighting changes in the serotonergic system in the prefrontal cortex-and pointing at epigenetic control of the MAOA gene-in the establishment of the link between peripubertal stress and later pathological aggression. Our data emphasize the impact of biological factors triggered by peripubertal adverse experiences on the emergence of violent behaviors

Biobehavioral organization shapes the immune epigenome in infant rhesus Macaques (Macaca mulatta)

How individuals respond to and cope with stress is linked with their health and well-being. It is presumed that early stress responsiveness helps shape the health of the developing organism, but the relationship between stress responsiveness and early immune function during development is not well-known. We hypothesized that stress responsiveness may shape epigenetic regulation of immune genes in infancy. We investigated whether aspects of behavioral responsiveness and hypothalamic-pituitary adrenal stress-response were associated with epigenome-wide immune cell DNA methylation patterns in 154 infant rhesus monkeys (3-4 months old). Infants' behavioral and physiological responses were collected during a standardized biobehavioral assessment, which included temporary relocation and separation from their mother and social group. Genome-wide DNA methylation was quantified using restricted representation bisulfite sequencing (RRBS) from blood DNA collected 2-hours post-separation. Epigenome-wide analyses were conducted using simple regression, multiple regression controlling for immune cell counts, and permutation regression, all corrected for false discovery rate. Across the variables analyzed, there were 20,368 unique sites (in 9,040 genes) at which methylation was significantly associated with at least one behavioral responsiveness or cortisol measure across the three analyses. There were significant associations in 442 genes in the Immune System Process ontology category, and 94 genes in the Inflammation mediated by chemokine and cytokine signaling gene pathway. Out of 35 candidate genes that were selected for further investigation, there were 13 genes with at least one site at which methylation was significantly associated with behavioral responsiveness or cortisol, including two intron sites in the glucocorticoid receptor gene, at which methylation was negatively correlated with emotional behavior the day following the social separation (Day 2 Emotionality; β = -0.39, q < 0.001) and cortisol response following a relocation stressor (Sample 1; β = -0.33, q < 0.001). We conclude that biobehavioral stress responsiveness may correlate with the developing epigenome, and that DNA methylation of immune cells may be a mechanism by which patterns of stress response affect health and immune functioning

Oxytocin receptor binding in the titi monkey hippocampal formation is associated with parental status and partner affiliation.

Social cognition is facilitated by oxytocin receptors (OXTR) in the hippocampus, a brain region that changes dynamically with pregnancy, parturition, and parenting experience. We investigated the impact of parenthood on hippocampal OXTR in male and female titi monkeys, a pair-bonding primate species that exhibits biparental care of offspring. We hypothesized that in postmortem brain tissue, OXTR binding in the hippocampal formation would differ between parents and non-parents, and that OXTR density would correlate with frequencies of observed parenting and affiliative behaviors between partners. Subjects were 10 adult titi monkeys. OXTR binding in the hippocampus (CA1, CA2/3, CA4, dentate gyrus, subiculum) and presubiculum layers (PSB1, PSB3) was determined using receptor autoradiography. The average frequency of partner affiliation (Proximity, Contact, and Tail Twining) and infant carrying were determined from longitudinal observations (5-6 per day). Analyses showed that parents exhibited higher OXTR binding than non-parents in PSB1 (t(8) = - 2.33, p = 0.048), and that OXTR binding in the total presubiculm correlated negatively with Proximity (r = - 0.88) and Contact (r = - 0.91), but not Tail Twining or infant carrying. These results suggest that OXTR binding in the presubiculum supports pair bonding and parenting behavior, potentially by mediating changes in hippocampal plasticity