Project description:Objective: Posttraumatic stress disorder (PTSD) affects a high proportion of returning combat veterans, but the biological mechanisms of PTSD remain unclear. Circulating micro RNAs (miRNAs) have been associated with depression, and anxiety disorders, but there is little understanding of how miRNAs may relate to PTSD. In this study we compare profiles of circulating miRNA in combat veterans with and without PTSD in order to better understand biological mechanisms of PTSD. Methods: Blood from 24 male military service members was collected following deployment to Operation Iraqi Freedom (OIF) or Operation Enduring Freedom (OEF), and subjects were assessed for PTSD symptoms using the PTSD checklist-military version. miRNA was isolated from whole blood and sequenced on the Ion Torrent PGM™ using the Ion 316 Chip v2. Differences in miRNA expression was compared between subjects with PTSD (N=15) and combat matched controls without PTSD (N=9). Significantly different miRNA, according to a FDR≤0.05, were assessed for predictive putative targets, and pathway analysis of related targets was completed. Results: PTSD was associated with 4 upregulated and 4 downregulated miRNA, including a 2.94 fold increase in miR-19a-3p and a 1.56 fold decrease in miR-15b. Pathway analysis show that PTSD is related to the axon guidance and Wnt signaling pathways, which work together along with the adherens junction and MAPK signaling pathways to support neuronal development through regulation of growth cones. The PTSD associated miRNAs related to transcription factors, including Transcription factor 7 (T-cell specific, HMG-box), Transcription factor 7 like 1, and Transcription factor 7 like 2. Conclusions: PTSD is associated with miRNAs that regulate biological functions that include neuronal activities, suggesting that they play a role in PTSD symptomatology.
Project description:In the present study, we used the single prolonged stress (SPS) model to mimic posttraumatic stress disorder. High-throughput sequencing were utilized to analyze differentially expressed genes (DEGs) in the hippocampus of control and SPS rats. RNA-seq analysis revealed 230 significantly DEGs between the control and SPS groups.
Project description:Gene expression has provided promising insights into the pathophysiology of posttraumatic stress disorder (PTSD), but specific regulatory transcriptomic mechanisms remain unknown. The current study addressed this limitation by analyzing transcriptome-wide RNA-Seq of whole blood samples from N=226 World Trade Center responders. The investigation focused on differential expression (DE) at gene, isoform, and alternative splicing (AS) levels associated with Posttraumatic Stress Disorder symptoms: total burden and its re-experiencing, avoidance, numbing, and hyperarousal subdimensions; and is the first study to characterize the AS landscape in PTSD. These dimensions were associated with 76, 1, 48, 15, and 49 genes, respectively (FDR<0.05). Similarly, they were associated with 103, 11, 0, 43, and 32 AS events. Avoidance differed the most from other dimensions with regard to DE genes, isoforms and AS correlates. Gene set enrichment analysis (GSEA) identified pathways involved in inflammatory and metabolic processes, which may have implications for the treatment of PTSD. Overall, findings shed a novel light on the wide range of transcriptomic alterations associated with PTSD at gene and AS levels. The DE analysis associated with PTSD subdimensions highlights the importance of studying PTSD symptom heterogeneity.
Project description:We have used a social defeat (SD) mouse model of post-traumatic stress disorder (PTSD) that is based on a brief exposure of a mouse to the aggressor mice for either 5 d or 10 d stress periods. Mice simulating aspects of posttraumatic stress disorder exhibit behavioral changes, body weight gain, increased body temperature, and inflammatory and fibrotic histopathologies and transcriptomic changes of heart tissue. Liver tissue of these mice was subjected to mRNA analysis. Transcriptomic analysis of liver indicated chronic toxicities and metabolic alterations in aggressor-exposed mice that possibly contributed to the persistent metabolic disturbance Two-condition experiment, C57BL6/J mice Biological replicates: 4-6 control replicates, 5-6 stressed replicates.
Project description:Many veterans live with military grade heavy metal fragments retained in soft tissue. Retained heavy metal fragments may negatively impact health in various organ systems and can manifest as gastrointestinal, neurocognitive, pulmonary and renal disturbances. As such, a better understanding of the long-term effects of retained metals and identification of biomarkers indicative of detrimental health outcomes would benefit clinical decision making. In this study, we analyzed serum microRNAs from rats with military-relevant pure metals implanted in the gastrocnemius muscle for 1, 3, 6, and 12 months in order to identify potential microRNA biomarkers that are indicative of exposure to one or more metals.
Project description:Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n = 19 hiPSC and n = 20 PBMC donors) and controls (n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.