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

压力最初被定义为对任何要求的非特异性身体反应，代表对超出个人资源的要求的反应。压力反应的几个影响因素已被确定，因此当代压力研究的一个主要挑战是解释和模拟压力脆弱性的个体差异。一个常见的观察结果是，女性和男性对压力的反应是不同的。虽然男性确实报告了对压力的生理反应增强，但女性报告了更多的主观痛苦和负面影响。尽管动物研究表明性别和应激源类型对认知有显著影响，但目前尚不清楚这种影响在人类中是如何调节的。解决这些差异的一个有希望的方法是调查遗传和表观遗传参数的影响。5-羟色胺转运体基因（5-HTT）的多态性已多次被证明赋予对压力的脆弱性。然而，几次尝试未能复制这些结果，可能是因为5-HTTLPR的作用也可能受到性别，性激素和其他遗传变异的复杂相互作用的调节。此外，有证据表明，生命早期的环境影响可以诱导永久性的结构和调节改变，例如下丘脑-垂体-肾上腺（HPA）轴的编程紊乱，这对应激反应特别重要。潜在的生物学机制仍然知之甚少，但有证据表明，它们涉及调节基因表达和最终复杂神经功能的表观遗传机制的稳定变化。其中一个机制是DNA甲基化。因此，在拟议的项目中，我们希望调查165名女性和165名男性参与者在亚琛和图宾根两个地点进行心理社会应激任务期间的主观、心理生理和神经应激反应，这些参与者的5-HTTLPR基因分型（留下3组，每组55名女性和55名男性）。将分析所有受试者的5-羟色胺转运蛋白基因（SCL 6A 4）的甲基化水平。此外，内源性睾酮水平对多水平应激反应的影响以及与基因型和表观基因型的相互作用将在女性和男性中进一步探讨。此外，还将收集神经心理学、心理生理学和自我报告数据，并将其与压力反应相关联。通过考虑性别、遗传和表观遗传参数以及睾酮水平来调查应激反应的特异性，将基本上有助于我们理解应激脆弱性和应激调节过程的个体差异。由于许多精神疾病与压力有关，我们的研究结果也将对临床研究产生相关影响。

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.