A late-life neurogenetic signature of exposure to combat stress - A monozygotic discordant twin study

Abstract

Animal models suggest that experiencing high-stress levels induces changes in amygdalar circuitry and gene expression. In humans, combat exposure has been shown to alter amygdalar responsivity and connectivity, but abnormalities have been indicated to normalize at least partially upon the termination of stress exposure. In contrast, other evidence suggests that combat exposure continues to exert influence on exposed individuals well beyond deployment and homecoming, as indicated by longitudinal psychosocial evidence from veterans, and observation of greater health decline in veterans late in life. Accordingly, the experience of combat stress early in life may affect amygdalar responsivity late in life, a possibility requiring careful consideration of the confounding effects of aging, genetic factors, and symptoms of post-traumatic stress disorder. Here, we investigated amygdalar responsivity in a unique sample of 16 male monozygotic (MZ) twin pairs in their sixties, where one but not the other sibling had been exposed to combat stress in early adulthood. Forty years after combat experience, a generally blunted amygdalar response was observed in combat-exposed veterans compared to their non-exposed twin siblings. Spatial associations between these phenotypical changes and patterns of gene expression in the brain were found for genes involved in the synaptic organization and chromatin structure. Protein-protein interactions among the set of identified genes pointed to histone modification mechanisms. We conclude that exposure to combat stress early in life continues to impact brain function beyond the termination of acute stress and appears to exert prolonged effects on amygdalar function later in life via neurogenetic mechanisms.

Keywords: Amygdala; Combat exposure; Stress; Trauma; Twins; fMRI.

FIG. 1.. Within-pair differences in amygdalar responsivity.

Amygdalar responsivity to fearful faces is presented for Ux and Ex siblings separately (left), revealing significant responsivity in Ux but not in Ex siblings. This difference is significant in the direct within-pair comparison (right, p_FWE = 0.001, small-volume corrected). The minimum t value threshold of 1.8 used for display is equivalent to a threshold of p < 0.05, uncorrected.

FIG. 2.. Brain phenotype – gene expression association analysis.

(a.) histogram displaying the extent of spatial similarity of stress-induced changes in brain responsivity (phenotype) and gene expression patterns. Both for positive and negative associations, the ten genes for which expression showed the highest similarity with the brain phenotype changes are provided (positive list/association: magenta; negative list/association: light blue). (b.) Gene ontology functions associated with the positive list of genes. (c.) two networks identified by protein-protein interaction analyses indicating histone modification/deubiquitination.