Department of Psychotherapy and Systems Neuroscience, Justus Liebig University Giessen, Giessen, Germany.
PLoS One. 2012;7(9):e44352. doi: 10.1371/journal.pone.0044352. Epub 2012 Sep 5.
Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.
恐惧的获得和消退是焦虑障碍发病和维持的关键机制。此外，它们可能在传递遗传和环境因素对（或多或少）更强的易感性或对精神病理学的弹性的影响方面发挥关键作用。在恐惧学习和消退的遗传和环境基础个体差异的神经生物学方面，只有很少的见解。在这项功能磁共振成像研究中，调查了 74 名健康受试者。这些受试者是根据 5-HTTLPR/rs25531（S+ 与 L(A)L(A)；三等位基因分类）和 TPH2（G(-703)T）（T+ 与 T-）基因型邀请的。目的是研究遗传因素和创伤性生活事件对皮肤电反应（SCR）和神经反应（杏仁核、岛叶、背侧前扣带皮层（dACC）和腹内侧前额叶皮层（vmPFC））的影响在差异恐惧条件反射范式中的获得和消退学习过程中。恐惧获得的特点是右岛叶的晚期条件和非条件反应更强，5-HTTLPR S 等位基因携带者。在消退过程中，创伤性生活事件与 S 等位基因携带者而非非携带者的杏仁核激活减少有关。除此之外，TPH2（G(-703)T）多态性的 T 等位基因携带者，创伤性生活事件较多，在获得期的杏仁核和消退期的 vmPFC 中表现出更强的反应性与非携带者相比。最后，在 dACC 中发现了两种多态性的联合效应，在消退过程中 S 和 T 等位基因携带者的反应更高。结果表明，5-HTTLPR S 等位基因携带者的岛叶中条件和非条件恐惧反应的表达增加。两种多态性在 dACC 中对消退期激活的联合效应可能与恐惧表达的延长有关。杏仁核和 vmPFC 激活的基因-环境相互作用可能反映了一种神经内表型，将遗传和不利环境影响转化为易感性或对发展情感精神病理学的弹性。
