Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume

Abstract

Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective selfreport (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. Abstract Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stresssensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxelbased morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective selfreport (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-env...

Single-Nucleotide Polymorphism of the FKBP5 Gene and Childhood Maltreatment as Predictors of Structural Changes in Brain Areas Involved in Emotional Processing in Depression

“…Another study has also found, in participants carrying the T allele, an association between increased activity in the dorsal amygdala during a face-recognition paradigm and self-reported childhood emotional neglect (White et al, 2012). Regarding depressed patients, on the other hand, the FKBP5 gene and childhood adversity have been shown to interact and to be associated with abnormal activity in the amygdala, hippocampus, and orbitofrontal cortex (Holz et al, 2014).…”

“…In healthy participants, the T allele of rs1360780 has been thus associated with an increase in BOLD responses in the hippocampus during a dot probe task, accompanied by alterations in hippocampal shape and with an attention bias toward threat (Fani et al, 2013;Holz et al, 2014). Another study has also found, in participants carrying the T allele, an association between increased activity in the dorsal amygdala during a face-recognition paradigm and self-reported childhood emotional neglect (White et al, 2012).…”

Amygdala–Hippocampal Connectivity Changes During Acute Psychosocial Stress: Joint Effect of Early Life Stress and Oxytocin

“…Gee et al (2013) reported changes in amygdalamPFC FC during emotion perception in adolescents who have experienced ELS. In line with the recent discovery of stress-dependent epigenetic changes in the hippocampus (Klengel et al, 2013), Holz et al (2015) investigated subjects with a genetic variant that makes them more sensitive to stress-dependent epigenetic modifications in the hippocampus and reported enhanced amygdala-hippocampus FC during emotion perception in these individuals. These findings further support that task-evoked FC changes in the limbic-prefrontal circuit are also influenced by ELS.…”

Development of Psychopathy from Childhood

“…Speciically, an interaction efect of FKBP5 diplotypes and childhood trauma was found on lifetime aggressive behavior in 411 male prisoners; carriers of the diplotype linked to increased FKBP5 expression were found to exhibit increased aggression and violent behavior in jail following childhood abuse [59]. This inding has been replicated on a brain imaging by two studies showing that FKBP5 variants interacted with childhood adversity to predict threat-induced activity in the amygdala [60,61].…”