Abstract
Post-traumatic stress disorder (PTSD) is a condition of stress reactivity, whose clinical manifestations are evident when patients are triggered following exposure to a traumatic event. While baseline differences in gene expression of glucocorticoid signaling and inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) have been associated with PTSD, these alterations do not fully recapitulate the molecular response to physiological triggers, such as stress hormones. Therefore, it is critical to develop new techniques that will capture the dynamic transcriptional response associated with stress-activated conditions relative to baseline conditions. To achieve this goal, cultured PBMCs from combat-exposed veterans with PTSD(+) (n = 10) and without PTSD(−) (n = 10) were incubated with increasing concentrations (vehicle, 2.5 nM, 5 nM, 50 nM) of dexamethasone (DEX). Across diagnosis and dosage, several genes and gene networks were reliable markers of glucocorticoid stimulation (FDR < 5%), including enhanced expression of FKPB5, VIPR1, NR1I3, and apoptosis-related pathways, and reduced expression of NR3C1, STAT1, IRF1, and related inflammatory and cellular stress-responsive pathways. Dose-dependent differential transcriptional changes in several genes were also identified between PTSD+ and PTSD−. Robust changes in expression were observed at 2.5 nM DEX in PTSD− but not PTSD+ participants; whereas, with increasing concentrations (5 nM and 50 nM), several genes were identified to be uniquely up-regulated in PTSD+ but not PTSD− participants. Collectively, these preliminary findings suggest that genome-wide gene expression profiling of DEX-stimulated PBMCs is a promising method for the exploration of the dynamic differential molecular responses to stress hormones in PTSD, and may identify novel markers of altered glucocorticoid signaling and responsivity in PTSD.
Highlights
Biological studies of post-traumatic stress disorder (PTSD) have consistently pointed to hypothalamic-pituitary-adrenal (HPA) axis dysregulation and functional alterations of the glucocorticoid receptor (GR) as major contributors to the development and progression of the disorder[1,2,3,4]
Studies used dexamethasone (DEX) challenge tests in cultured peripheral blood mononuclear cells (PBMCs) from combat-exposed veterans with and without PTSD and observed that DEX-induced inhibition of lysozyme activity was greater in veterans with PTSD11
Clinical features and demographics: characterizing known sources of expression variation Genome-wide RNA-sequencing profiles were generated from live cultured PBMCs incubated with increasing concentrations of DEX from a primary cohort of combatexposed veterans with PTSD (PTSD+; n = 10) and without PTSD (PTSD−; n = 10) (Table S1)
Summary
Biological studies of post-traumatic stress disorder (PTSD) have consistently pointed to hypothalamic-pituitary-adrenal (HPA) axis dysregulation and functional alterations of the glucocorticoid receptor (GR) as major contributors to the development and progression of the disorder[1,2,3,4]. Changes in GR sensitivity and alterations in peripheral blood gene expression profiles, including genes implicated in glucocorticoid signaling and inflammatory cytokine production – whether derived from a candidate[5] or genome-wide exploratory approaches6–8— reflect some of the most robust laboratory findings for. Studies used dexamethasone (DEX) challenge tests in cultured peripheral blood mononuclear cells (PBMCs) from combat-exposed veterans with and without PTSD and observed that DEX-induced inhibition of lysozyme activity was greater in veterans with PTSD11. In studies of major depression, in vivo assessments of GR function have been conducted by analyzing gene expression profiles following DEX administration and report robust and reproducible changes in peripheral blood gene expression as well as decreased glucocorticoid sensitivity in depression[12,13,14]. DEX-induced gene expression revealed significantly increased FKBP5 mRNA expression, which was dependent on FKBP5 risk variants in depressed patients[15,16]
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