The impact of sex and the serotonin transporter polymorphism on (neural) stress reactions

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Stress has originally been defined as a non-specific bodily response to any demand placed upon it, representing the response to demands that exceed the individuals resources. Several influencing factors on the stress response have been identified, thus one major challenge for contemporary stress research is to explain and model individual differences in stress vulnerability. A common observation is that reactions to stress are different in females and males. Whereas men indeed report enhanced physiological reactivity towards stress, women report more subjective distress and negative affect. Despite the fact that animal studies indicate a significant impact of sex and stressor type on cognition, it is currently unclear how this effect is modulated in humans. One promising approach to address these differences is the investigation of the impact of genetic and epigenetic parameters. A polymorphism of the serotonin transporter gene (5-HTT) has repeatedly been demonstrated to confer a vulnerability to stress. However, several attempts failed to replicate these results, presumably because the effect of 5-HTTLPR may also be moderated by complex interactions of sex, sex hormones, and other genetic variants. Additionally, there is evidence suggesting that early-life environmental influences can induce permanent structural and regulatory alterations e.g. disturbed programming of the hypothalamic-pituitary-adrenal (HPA) axis which is of particular importance for the stress response. The underlying biological mechanisms are still poorly understood, but evidence is emerging that they involve stable changes in epigenetic mechanisms that regulate gene expression and ultimately complex neural functions. One such mechanism is DNA methylation. Therefore, in the proposed project we want to investigate the subjective, psychophysiological and neural stress reaction of 165 female and 165 male participants genotyped for 5-HTTLPR (leaving 3 groups with different expressions à 55 females and 55 males) during a psychosocial stress task at two sites, Aachen and Tübingen. Methylation level of the serotonin transporter gene (SCL6A4) will be analyzed in all participants. Additionally, the impact of endogenous testosterone levels on the multi-level stress response as well as the interaction with genotype and epigenotype will be further explored in females and males. Moreover, neuropsychological, psychophysiological and self-report data will be collected and associated with stress reactions. Investigating the specificity of the stress response by taking into account sex, genetic as well as epigenetic parameters and testosterone levels will essentially contribute to our understanding of individual differences in stress vulnerability and stress regulation processes. As many psychiatric disorders are associated with stress, our findings will also have relevant implications for clinical research.