Brain and blood gene expression pathways associated with susceptibility to PTSD

Abstract

Background : The identification of molecular post-traumatic stress disorder (PTSD) susceptibility pathways associated with different patterns of behavioral response to trauma is essential to an understanding of the neurobiology of PTSD and can pave the design for new treatments. Although several genes have been reported to be differentially expressed in PTSD, methodological constraints have limited the interpretation, for example, variation in the type or magnitude of trauma exposure, inter-individual genetic variation, and tissue specificity of response. Animal models are useful in delineating some of these issues. In this study, we used a unique animal model of PTSD with ecological and population validity. Adult rats were exposed briefly to predator scent stress, which mimics a threatening situation. Rats respond heterogeneously to this type of traumatic stress behaviorally and physiologically, similar to human response variability. In this model, two behavioral extremes can be studied – vulnerable and resistant ‘subtypes’. Methods : Sprague-Dawley rats were exposed to the scent of cat urine. The outcome measures included behavior in an elevated plus-maze and the acoustic startle response 7 days after exposure. Cut-off behavioral criteria classified exposed rats according to their behavioral response as those with ‘extreme behavioral response’ and ‘minimal behavioral response’ (MBR), with unexposed rats as controls. From the tissue obtained 24 h after the behavioral tests, basal gene expression using Illumina BeadArrays was evaluated for whole blood and three brain areas: amygdala, anterior cortex and hippocampus. For data quality control and differential expression analysis, we used R and LIMMA (as included in MeV software), respectively. Pathway analysis was performed with ingenuity. Results : There was only minimal overlap in gene expression across brain regions and gender demonstrating the existence of distinct tissue-specific susceptibility pathways in male and female rats. Among the differentially expressed genes, the ones regulated by the glucocorticoid receptor (e.g., FKBP5, Per-1, and NPY) were particularly over-represented (especially in blood and hippocampus), indicating that glucocorticoid regulation is involved in vulnerability and resistance to trauma. The observed gene expression profiles may also indicate the over-representation of discrete functional biological clusters and pathways (e.g., MAPK signaling and circadian rhythm). Conclusions : Glucocorticoid-related gene expression is underlying the different response pattern following trauma, with distinct regional/structural differences between male and female rats.

Keywords

• PTSD
• gene expression
• susceptibility
• glucocorticoid regulation
• neurobiology
• glucocorticoid receptor