Journal Article

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression

Dobariya, Saunil, Seah, Carina, Xu, Changxin, Flory, Janine D., Paull, Daniel, Brennand, Kristen J., Bader, Heather N., McCarthy, Barry, Yehuda, Rachel, Breen, Michael S., Chattopadhyay, Mitali, Bierer, Linda M., Staniskyte, Migle, Noggle, Scott A., Goldberg, Jordan, Deans, P. J. Michael, Huckins, Laura M., Rusielewicz, Tom, Hunter, Christopher J., Desarnaud, Frank, Makotkine, Iouri

2022

Overview

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. The authors generated stem cell-derived neurons from combat veterans with and without PTSD and found PTSD-dependent gene expression changes in response to glucocorticoids. This highlights how stress response may be altered in individuals with PTSD.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/100 / 38/91 / 631/208/191/2018 / 692/699/476/1830 / Animal Genetics and Genomics / Behavioral Sciences / Biological Techniques / Biomarkers / Biomedical and Life Sciences / Biomedicine / Diagnosis / Drug screening / Environment models / Environmental risk / Gene Expression / Gene-Environment Interaction / Glucocorticoids / Glucocorticoids - pharmacology / Glutamatergic transmission / Humans / Hydrocortisone / Hypersensitivity / Induced Pluripotent Stem Cells - metabolism / Leukocytes, Mononuclear / Mental disorders / Military psychology / Molecular modelling / Neurobiology / Neurogenesis / Neurons / Neurons - metabolism / Neurosciences / Peripheral blood mononuclear cells / Pluripotency / Post traumatic stress disorder / Psychological stress / Risk factors / Stem cells / Stress Disorders, Post-Traumatic - genetics / Transcription factors / Transcriptomics / Trauma / Veterans