Neural correlates of stress-related gene-environment interactions
Final Report Abstract
The aim of the current project was to find out whether environmental stress leads to persistent alterations in the function or structure of neural networks underlying stress-related psychiatric disorders and whether these alterations are conditional on genetic factors. To this aim, we examined a sample of young adults (aged 24-25 years) from an epidemiological cohort study, the Mannheim Study of Children at Risk, by the use of multimodal neuroimaging. Of the initial sample of 384 participants, N=309 completed questionnaires on current psychiatric symptoms, temperament, life stress and living conditions. N=307 took part in an additional telephone interview yielding psychiatric diagnoses. N=200 individuals who were free of current psychopathology participated in a combined MRI, fMRI and EEG measurement. Of particular interest to the current study were the neural networks of emotion regulation and reward processing. With regard to emotion regulation, support was found for altered activation and structure in carriers of risk alleles of genes involved in the serotonin pathway when exposed to life stress. Contrary to expectations, gene-environment (GxE) interactions were observed mainly for stressors during childhood and not during the pre-, peri- and postnatal phase. For example, in male carriers of the MAOA L (=risk) allele, activity in the amygdala and the hippocampus during emotional face matching increased with the level of childhood life stress. This may suggest that heightened limbic responding following exposure to stress during childhood might represent a neurobiological pathway underlying the reported increased risk of aggression in these individuals. For carriers of the BDNF met (= risk) allele, the volume of the orbitofrontal cortex increased with the level of childhood life stress, possibly representing a compensatory recruitment of this area to control affective reactions. Most interestingly, we found evidence of an impact of early life adversity on emotion regulation which was independent of genotype. As an example, the offspring of mothers who smoked during pregnancy exhibited less activity in the inhibitory network including the anterior cingulate and the inferior frontal gyrus. Further evidence of an impact of early life stress was found with reference to reward processing. In both fMRI and EEG, higher levels of early adversity were associated with less activation in reward-related areas during reward anticipation. In contrast, when receiving a reward, the respective activation increased with early adversity, suggesting higher reward sensitivity in individuals exposed to early burdens. This pattern of activation was significantly related to symptoms of ADHD. Comparable results were obtained with respect to stress during childhood, indicating a moderating role for the COMT Val158Met polymorphism. An additional GxE interaction with regard to activation in the anterior cingulate cortex during reward processing emerged for genetic variation in the dopamine transporter (DAT 3’UTR VNTR and stressful life events during the sensitive period of adolescence. As a supplementary research question, the relationship between brain endophenotypes and specific behavioral phenotypes was examined. Amongst others, alterations of reward-related brain activity in the left medial frontal gyrus were shown to mediate the relationship between childhood stress and later alcohol abuse. Taken together, the current project demonstrated that GxE impacts emotional, reward-related and inhibitory neural function and structure although environmental effects tended to be more robust. It provided additional evidence that contributes to a more refined understanding of the neural mechanisms underlying differential susceptibility to environmental adversity.
