Prenatal maternal stress and offspring aggressive behavior: Intergenerational and transgenerational inheritance.

Even though studies have shown that prenatal maternal stress is associated with increased reactivity of the HPA axis, the association between prenatal maternal stress and fetal glucocorticoid exposure is complex and most likely dependent on unidentified and poorly understood variables including nature and timing of prenatal insults. The precise mechanisms in which prenatal maternal stress influence neuroendocrine signaling between the maternal-placental-fetal interface are still unclear. The aim of this review article is to bring comprehensive basic concepts about prenatal maternal stress and mechanisms of transmission of maternal stress to the fetus. This review covers recent studies showing associations between maternal stress and alterations in offspring aggressive behavior, as well as the possible pathways for the "transmission" of maternal stress to the fetus: (1) maternal-fetal HPA axis dysregulation; (2) intrauterine environment disruption due to variations in uterine artery flow; (3) epigenetic modifications of genes implicated in aggressive behavior. Here, we present evidence for the phenomenon of intergenerational and transgenerational transmission, to better understands the mechanism(s) of transmission from parent to offspring. We discuss studies showing associations between maternal stress and alterations in offspring taking note of neuroendocrine, brain architecture and epigenetic changes that may suggest risk for aggressive behavior. We highlight animal and human studies that focus on intergenerational transmission following exposure to stress from a biological mechanistic point of view, and maternal stress-induced epigenetic modifications that have potential to impact on aggressive behavior in later generations.

Childhood trauma and genetic variation in the DAT 40-bp VNTR contribute to HIV-associated neurocognitive disorders.

HIV/AIDS is a major public health burden in South Africa, currently affecting an estimated 13.5% of the population. Despite improved access to antiretroviral therapies, HIV-associated neurocognitive disorders (HAND), characterised by a spectrum of neurocognitive impairment, emotional disturbances and motor abnormalities, continue to persist. Gene-environment interactions contribute to HAND pathophysiology and previous research has identified childhood trauma as an environmental risk factor. Dopaminergic signalling in the prefrontal cortex plays a key role in cognitive function. Thus, variants in genes encoding the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT), which are responsible for dopamine transport and metabolism, could represent genetic risk factors for HAND. This study investigated whether the DAT variable number of tandem repeats (VNTR) and COMT Val158Met (rs4680) polymorphisms are associated with longitudinal change in cognitive function in the context of childhood trauma and HIV. Participants (n = 49 HIV-negative and n = 64 HIV-positive women) completed the Childhood Trauma Questionnaire - Short Form (CTQ-SF) and provided blood for genetic analyses. Global cognitive scores were generated from baseline and one-year follow-up assessments. Following polymerase chain reaction, genotypes were determined using gel electrophoresis and confirmed by Sanger sequencing. Baseline global cognitive scores, genotype, HIV status and CTQ-SF scores were regressed on one-year global cognitive scores in regression models. Analysis of variance was used to examine the effect of including predictor variable interactions on model fit. HIV seropositivity was associated with poorer cognitive performance at one-year follow-up (p = 2.46 ×10-4). The combination of HIV and DAT 10-repeat homozygosity (DAT 10/10) was associated with reduced global cognitive scores in longitudinal models (p = 0.010). Including the interaction between DAT 10/10, childhood trauma, and HIV explained significantly more of the variance in longitudinal cognitive scores (p = 0.008). There were no significant associations with the COMT genotype. Our research indicates that childhood trauma and genetic variation in DAT contribute toward the aetiology of HAND. Future studies in larger cohorts are warranted to verify these results.

Risk and protective factors affecting the symptom trajectory of posttraumatic stress disorder post-rape.

INTRODUCTION: The prevalence of posttraumatic stress disorder (PTSD) in rape survivors is considerably higher than the prevalence in non-sexual trauma survivors. Few studies have investigated risk and protective factors in survivors early-after-rape in a prospective longitudinal design. METHODS: In a sample of 639 rape-exposed women who were assessed within 20 days of rape and over 6 months, baseline data were used to predict PTSD symptom severity scores up to 6 months post-rape. RESULTS: The incidence of PTSD at 3 months was 48.5% and the cumulative incidence at 6 months post-rape was 54.8%. Baseline experience of rape stigma (guilt, shame, self-blame, social devaluation and discredit) and depression were significant predictors of PTSD symptom scores over time, in mixed linear regression models. Higher levels of depression and rape stigma were associated with higher PTSD scores. Assault-related factors were not associated with PTSD scores. LIMITATIONS: We could not measure PTSD symptom trajectories in all rape survivors, some of who may be at greater risk for PTSD e.g. non-disclosing rape survivors, those who declined participation and those who were extremely distressed at the time of recruitment. CONCLUSION: Addressing internalised and externalised stigma and resultant mental health effects on women who present to rape clinics may reduce the long-term adverse effects of rape on mental health outcomes, such as PTSD. Rape survivors who present with high levels of depression soon after a rape should be carefully monitored and appropriately treated in order to reduce PTSD severity.

Genome-wide differentially methylated genes associated with posttraumatic stress disorder and longitudinal change in methylation in rape survivors.

Rape is associated with a high risk for posttraumatic stress disorder (PTSD). DNA methylation changes may confer risk or protection for PTSD following rape by regulating the expression of genes implicated in pathways affected by PTSD. We aimed to: (1) identify epigenome-wide differences in methylation profiles between rape-exposed women with and without PTSD at 3-months post-rape, in a demographically and ethnically similar group, drawn from a low-income setting; (2) validate and replicate the findings of the epigenome-wide analysis in selected genes (BRSK2 and ADCYAP1); and (3) investigate baseline and longitudinal changes in BRSK2 and ADCYAP1 methylation over six months in relation to change in PTSD symptom scores over 6 months, in the combined discovery/validation and replication samples (n = 96). Rape-exposed women (n = 852) were recruited from rape clinics in the Rape Impact Cohort Evaluation (RICE) umbrella study. Epigenome-wide differentially methylated CpG sites between rape-exposed women with (n = 24) and without (n = 24) PTSD at 3-months post-rape were investigated using the Illumina EPIC BeadChip in a discovery cohort (n = 48). Validation (n = 47) and replication (n = 49) of BRSK2 and ADCYAP1 methylation findings were investigated using EpiTYPER technology. Longitudinal change in BRSK2 and ADCYAP1 was also investigated using EpiTYPER technology in the combined sample (n = 96). In the discovery sample, after adjustment for multiple comparisons, one differentially methylated CpG site (chr10: 61385771/ cg01700569, p = 0.049) and thirty-four differentially methylated regions were associated with PTSD status at 3-months post-rape. Decreased BRSK2 and ADCYAP1 methylation at 3-months and 6-months post-rape were associated with increased PTSD scores at the same time points, but these findings did not remain significant in adjusted models. In conclusion, decreased methylation of BRSK2 may result in abnormal neuronal polarization, synaptic development, vesicle formation, and disrupted neurotransmission in individuals with PTSD. PTSD symptoms may also be mediated by differential methylation of the ADCYAP1 gene which is involved in stress regulation. Replication of these findings is required to determine whether ADCYAP1 and BRSK2 are biomarkers of PTSD and potential therapeutic targets.

Longitudinal telomere length profile does not reflect HIV and childhood trauma impacts on cognitive function in South African women.

HIV-associated neurocognitive disorders (HAND) present a challenge in South Africa where the burden of HIV infection is the highest. Identification of biological correlates of HAND is required to improve diagnosis and inform interventions. Telomeres maintain genomic integrity and their shortening is a marker of biological aging sensitive to environmental influences. This study examined relative telomere length (rTL) as a predictor of cognitive function in the context of HIV and childhood trauma (CT), a risk factor for HAND. Two hundred and eighty-six women completed a neurocognitive assessment battery and the Childhood Trauma Questionnaire-Short Form (CTQ). Quantitative polymerase chain reaction for amplification of telomeric repeats and the reference gene human beta-globin was used to calculate rTL. Neurocognitive and rTL assessments were repeated at 1 year in 110 participants. Cross-sectional and longitudinal data were assessed using linear and mixed models, respectively. Participants with HIV (n = 135 in cross-sectional and n = 62 in longitudinal study groups) reported more severe CT and had shorter baseline rTL compared to seronegative controls. Participants without HIV had a greater 1-year decline in rTL. Global cognitive and attention/working memory scores declined in participants with HIV. Our data indicate that baseline rTL in the context of CT and HIV did not predict decline in cognitive scores. HIV-associated pathophysiological processes driving cognitive decline may also engage mechanisms that protect against telomere shortening. The results highlight the importance of examining biological correlates in longitudinal studies.

Genetic variation in neuropeptide Y interacts with childhood trauma to influence anxiety sensitivity.

BACKGROUND AND OBJECTIVES: Anxiety sensitivity (AS) refers to a fear of the negative implications of anxiety, and arises due to gene-environment interactions. We investigated whether genetic variation in two neuropeptides implicated in the stress response, neuropeptide Y (NPY) and pituitary adenylate cyclase-activating polypeptide receptor 1, interacted with childhood trauma (CT) to influence AS. DESIGN AND METHODS: This cross-sectional study examined the CT x genetic variant effects on AS in 951 adolescents who self-identified as Xhosa or South African Colored (SAC) ethnicity. RESULTS: In Xhosa females, the NPY rs5573 A allele and rs3037354 deletion variant were associated with increased (p = 0.035) and decreased (p = 0.034) AS, respectively. The interaction of CT and the NPY rs5574 A allele increased AS in SAC female participants (p = 0.043). The rs3037354 deletion variant protected against AS with increased CT in SAC male participants (p = 0.011). CONCLUSIONS: The NPY rs5574 A allele and rs3037354 deletion variant interact with CT to act as risk and protective factors, respectively, for AS in an ethnicity- and sex- differentiated manner. Our results reaffirm the role of NPY and gene-environment interactions in anxiety-related behaviors and reinforce the need for psychiatric genetics studies in diverse populations.

Childhood emotional neglect and oxytocin receptor variants: Association with limbic brain volumes.

Objectives: Childhood emotional neglect (EN) is a predictor for the development of affective disorders. Oxytocin (OXT) may mediate the interplay between EN and changes in stress biological systems, brain development, and mental health outcomes. We investigated, in a cross-sectional study, the associations between EN, (epi)genetic variation in the OXT receptor (OXTR) gene, and amygdalar and hippocampal volumes, two brain regions implicated in emotional processing.Methods: We recruited 63 Caucasian South African adults (35 women) with and without social anxiety disorder. Childhood EN was assessed using the Childhood Trauma Questionnaire. rs53576 and rs2254298 genotypes, as well as methylation status, was determined using DNA purified from whole blood. Bilateral amygdalar and hippocampal volumes were determined by structural magnetic resonance imaging. The relationships between these variables were investigated using linear regression.Results: The interaction of the rs2254298 A risk allele and EN was nominally associated with reduced left hippocampal volume. The rs2254298 A risk allele was independently associated with reduced bilateral amygdalar volumes. We found no association between EN, OXTR methylation and amygdalar or hippocampal volumes. The rs53576 GG risk genotype was, however, associated with decreased OXTR methylation.Conclusions: The rs2254298 A allele may increase susceptibility to the structural brain effects of EN.

Epigenetic alterations associated with childhood trauma and adult mental health outcomes: A systematic review.

Objectives: Multiple, chronic and repeated trauma exposure in childhood is associated with adverse mental health outcomes in adulthood. In this paper we synthesise the literature on epigenetic modifications in childhood trauma (CT) and the mediating effects of differential epigenetic mechanisms on the association between CT and the later onset of psychiatric disorders.Methods: We reviewed the literature up to March 2018 in four databases: PubMed, Web of Science, EBSCOhost and SCOPUS. Non-human studies were excluded. All studies investigating CT exposure both in healthy adults (18 years and older) and adults with psychiatric disorders were included.Results: Thirty-six publications were included. For mood disorders, methylation of the glucocorticoid receptor NR3C1 gene, specifically at the NGFI-A binding site in exon 1F, and correlation with CT was a robust finding. Several studies documented differential methylation of SLC6A4, BDNF, OXTR and FKBP5 in association with CT. Common pathways identified include neuronal functioning and maintenance, immune and inflammatory processes, chromatin and histone modification, and transcription factor binding.Conclusions: A variety of epigenetic mediators that lie on a common pathway between CT and psychiatric disorders have been identified, although longitudinal studies and consistency in methodological approach are needed to disentangle cause and effect associations.

Appetitive and reactive aggression are differentially associated with the STin2 genetic variant in the serotonin transporter gene.

Appetitive aggression is a sub-category of instrumental aggression, characterised by the primary intrinsic enjoyment of aggressive activity. Aggression is heritable, and serotonergic and monoaminergic neurotransmitter systems have been found to contribute to the underlying molecular mechanisms. The aim of this study was to investigate the role that genetic variants in the serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) genes play in the aetiology of appetitive aggression in South African Xhosa males (n = 290). SLC6A4 5-HTTLPR, rs25531, and STin2 variants, as well as MAOA-uVNTR were investigated for their association with levels of appetitive aggression using Poisson regression analysis. The STin2 VNTR12 allele was found to be associated with increased levels of appetitive aggression (p = 0.003), but with decreased levels of reactive aggression (p = 7 × 10-5). This study is the first to investigate genetic underpinnings of appetitive aggression in a South African population, with preliminary evidence suggesting that SCL6A4 STin2 variants play a role in its aetiology, and may also be important in differentiating between appetitive and reactive aggression. Although the results require replication, they shed some preliminary light on the molecular dichotomy that may underlie the two forms of aggression.

No gene-by-environment interaction of BDNF Val66Met polymorphism and childhood maltreatment on anxiety sensitivity in a mixed race adolescent sample.

Background: Anxiety disorders in youth are attributable to multiple causal mechanisms, comprising biological vulnerabilities, such as genetics and temperament, and unfavourable environmental influences, such as childhood maltreatment (CM). Objective: A gene-environment (G x E) interaction study was conducted to determine the interactive effect of the BDNF Val66Met polymorphism and CM to increase susceptibility to anxiety sensitivity (AS) in a sample of mixed race adolescents. Method: Participants (n = 308, mean age = 15.8 years) who were all secondary school students and who completed measures for AS and CM were genotyped for the BDNF Val66Met polymorphism. Hierarchical multiple regression analysis was conducted to assess G x E influences on AS. Age and gender were included in the models as covariates as age was significantly associated with AS total score (p < .05), and females had significantly higher AS scores than males (p < .05). Results: A main effect of CM on AS was evident (p < .05), however, no main effect of BDNF genotype on AS was observed (p > .05). A non-significant G x E effect on AS was revealed (p < .05). Conclusions: Our results suggest that CM does not have a moderating role in the relationship between the BDNF Val66Met genotype and the increased risk of anxiety-related phenotypes, such as AS. Given the exploratory nature of this study, findings require replication in larger samples and adjustment for population stratification to further explore the role of BDNF Val66Met and CM on AS in mixed race adolescents.

Antecedentes: los trastornos de ansiedad en los jóvenes son atribuibles a múltiples mecanismos causales, que comprenden vulnerabilidades biológicas, como la genética y el temperamento; y las influencias ambientales desfavorables, como el maltrato infantil (MI). Objetivo: Se realizó un estudio interacción gen-ambiente (GxA) para determinar el efecto interactivo del polimorfismo Val66Met del BDNF y MI para aumentar la susceptibilidad para la sensibilidad a la ansiedad (SA) en una muestra de adolescentes de raza mixta.Método: los participantes (n=308, Edad Media:15.8 años) que fueron todos estudiantes de secundaria que completaron las medidas para SA y MI, fueron genotipificados para el polimorfismo Val66Met del BDNF. Se realizó un análisis de regresión múltiple jerárquica para evaluar las influencias GxA en SA. La edad y género se incluyeron como covariables en los modelos, ya que la edad se asoció significativamente con el puntuación total SA (p<0.05), y las mujeres tuvieron puntuaciones de SA significativamente mayores que los hombres (p<0.05).Resultados: Un efecto principal de MI en SA fue evidente (p<0.05), sin embargo, no se observó ningún efecto principal del genotipo BDNF en SA (p>0.05). Se reveló un efecto GxA No significativo sobre SA (p<0.05).Conclusiones: Nuestros resultados sugieren que MI no tiene un rol moderador en la relación entre el genotipo Val66Met del BDNF y el mayor riesgo de fenotipos relacionados con la ansiedad, como SA. Dada la naturaleza exploratoria de este estudio, los hallazgos requieren la replicación en muestras más grandes y el ajuste de la estratificación de la población para explorar más a fondo el rol de Val66Met del BDNF y MI en SA en adolescentes de raza mixta.

Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.

BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder.

Childhood trauma has been linked to the development of later psychopathology, including obsessive-compulsive disorder (OCD). Although evidence exists to suggest that genetic and environmental factors are involved in the aetiology of OCD, little attention has been paid to the interactions that exist between genes and environment. The aim of this study was to investigate gene-by-environment interactions between childhood trauma and the BDNF Val66Met variant in patients with OCD. Childhood trauma was assessed in 134 OCD patients and 188 controls using the Childhood Trauma Questionnaire (CTQ). Linear regression models were used for statistical analyses. Gene-environment interactions were estimated by including a combined genotype and CTQ score in the models as interaction terms. All analyses were adjusted for age, gender, CTQ minimisation-denial score and home language by including them in the logistic regression models as covariates. Childhood trauma, specifically emotional abuse and neglect, increased the odds of having OCD significantly (p < 0.001). Although no significant association was observed between BDNF Val66Met and the development of OCD, interaction analysis indicated that the BDNF Met-allele interacted with childhood emotional abuse to increase the risk of OCD significantly in a dose-dependent manner (p = 0.024). To our knowledge, this is one of the first studies to investigate gene-environment interactions in OCD, and the findings indicate the importance of collating genetic and environmental variables in future studies.

Shorter telomere length - A potential susceptibility factor for HIV-associated neurocognitive impairments in South African women [corrected].

The neuropathogenesis of the human immunodeficiency virus (HIV) may manifest as various neurocognitive impairments (NCI). HIV-positive individuals also have significantly shorter telomere length (TL) in peripheral blood mononuclear cells (PBMCs) and CD8+ T cells compared to HIV-negative individuals. Additionally, reduced TL has been found to be associated with chronic psychological stress. This study focused on the effects of HIV-infection and chronic stress associated with childhood trauma on telomere length, and investigated whether leukocyte TL (LTL), in particular, represents a risk factor for NCI. Eighty-three HIV-positive and 45 HIV-negative women were assessed for childhood trauma and were subjected to detailed neurocognitive testing. Blood from each participant was used to extract Deoxyribonucleic acid (DNA). Relative LTL were determined by performing real time quantitative PCR reactions as described by Cawthon et al. (2002). As expected, relative LTL in the HIV-positive individuals was significantly shorter than that of HIV-negative individuals (F = 51.56, p = <0.01). Notably, a significant positive correlation was evident between relative LTL and learning performance in the HIV-positive group. In addition, a significant negative correlation was observed between relative LTL and verbal fluency, but this association was only evident in HIV-positive individuals who had experienced trauma. Our results suggest that reduced LTL is associated with worse learning performance in HIV-positive individuals, indicating that TL could act as a susceptibility factor in increasing neurocognitive decline in HIV-infected individuals.

Big effects of small RNAs: a review of microRNAs in anxiety.

Epigenetic and regulatory elements provide an additional layer of complexity to the heterogeneity of anxiety disorders. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that have recently drawn interest as epigenetic modulators of gene expression in psychiatric disorders. miRNAs elicit their effects by binding to target messenger RNAs (mRNAs) and hindering translation or accelerating degradation. Considering their role in neuronal differentiation and synaptic plasticity, miRNAs have opened up new investigative avenues in the aetiology and treatment of anxiety disorders. In this review, we provide a thorough analysis of miRNAs, their targets and their functions in the central nervous system (CNS), focusing on their role in anxiety disorders. The involvement of miRNAs in CNS functions (such as neurogenesis, neurite outgrowth, synaptogenesis and synaptic and neural plasticity) and their intricate regulatory role under stressful conditions strongly support their importance in the aetiology of anxiety disorders. Furthermore, miRNAs could provide new avenues for the development of therapeutic targets in anxiety disorders.