Genetic gating of human fear, fear learning and extinction : psychophysiological, brain imaging (fMRI) and clinical studies

Abstract: Individuals differ in their reaction to the same environmental stressor. After being opposed to the same trauma, some individuals will develop affective pathologies, while others will not. This is assumed to result, at least partly, from a differential genetic vulnerability. Fear conditioning and extinction have been suggested to be mechanisms involved in anxiety disorders and treatment respectively and represent laboratory models to study the reaction of individuals to a stressor in a controlled setting. In this thesis we investigated the effect of common polymorphisms on fear conditioning and extinction (Study I & II) and aimed to translate our results into the clinical setting using a sample of patients suffering from panic disorder (Study III & IV). As the amygdala is the core region involved in fear learning and extinction as well as highly implicated in anxiety disorders, we also studied the effect of common polymorphisms on amygdala reactivity and habituation to negative emotional stimuli using functional magnetic resonance imaging (Study V). In Study I we report facilitated fear conditioning in healthy individuals carrying at least one 5 ] HTTLPR s ]allele (as opposed to non ]carriers, l/l), and resistance to extinction in individuals with the COMTval158met met/met genotype (as opposed to val ]allele carriers), using fearpotentiated startle (FPS) as an index of conditioned fear. Similarly, in Study II we show that also carriers of the BDNFval66met met ]allele (as opposed to non ]carriers, val/val) display deficits in the acquisition of FPS reactions. In Study III and IV we aimed to translate the experimental findings from Study I into a clinical setting using a sample of patients suffering from panic disorder. In Study III, we report a more severe symptomatic profile (both panic and depressive symptoms) in carriers of the 5 ]HTTLPR s ]allele and in Study IV, we report reduced efficacy of exposure ]based cognitive behavioural treatment modules in panic patients with the COMTval158met met/met genotype. Study V investigated amygdala reactivity and habituation during the passive viewing of angry faces in healthy volunteers, selected based on gender, 5 ]HTTLPR/rs25531 and COMTval158met genotype. We report higher right amygdala reactivity and less habituation in 5 ]HTTLPR scarriers as opposed to non ]carriers (l/l) as well as enhanced left amygdala reactivity in individuals with the COMT met/met genotype as opposed to those carrying at least one valallele. In sum, the results of this thesis support a role for 5 ]HTTLPR/rs25531, BDNFval66met and COMTval158met in fear learning and extinction respectively which may have important implications for the risk to develop anxiety disorders (in particular after traumatic events) as well as the efficacy of their treatment. In addition, our results may have unraveled a mechanism underlying gene x environment interactions in anxiety disorders. Our finding of slower amygdala habituation may furthermore represent an underlying mechanism of the enhanced amygdala reactivity commonly found in 5 ]HTTLPR s ]carriers in imaging genetic studies.