TY - JOUR
AU - Carina Seah
AU - Michael S. Breen
AU - Tom Rusielewicz
AU - Heather N. Bader
AU - Changxin Xu
AU - Christopher J. Hunter
AU - Barry McCarthy
AU - P. J. Michael Deans
AU - Mitali Chattopadhyay
AU - Jordan Goldberg
AU - Frank Desarnaud
AU - Iouri Makotkine
AU - Janine D. Flory
AU - Linda M. Bierer
AU - Migle Staniskyte
AU - NYSCF Global Stem Cell Array® Team
AU - Lauren Bauer
AU - Katie Brenner
AU - Geoff Buckley-Herd
AU - Sean DesMarteau
AU - Patrick Fenton
AU - Peter Ferrarotto
AU - Jenna Hall
AU - Selwyn Jacob
AU - Travis Kroeker
AU - Gregory Lallos
AU - Hector Martinez
AU - Paul McCoy
AU - Frederick J. Monsma
AU - Dorota Moroziewicz
AU - Reid Otto
AU - Kathryn Reggio
AU - Bruce Sun
AU - Rebecca Tibbets
AU - Dong Woo Shin
AU - Hongyan Zhou
AU - Matthew Zimmer
AU - Scott A. Noggle
AU - Laura M. Huckins
AU - Daniel Paull
AU - Kristen J. Brennand
AU - Rachel Yehuda
AB - Abstract
            
              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.
BT - Nature Neuroscience
DA - 11/2022
DO - 10.1038/s41593-022-01161-y
IS - 11
LA - en
N2 - Abstract
            
              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.
PY - 11
SP - 1434
EP - 1445
T2 - Nature Neuroscience
TI - Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression
UR - https://www.nature.com/articles/s41593-022-01161-y
VL - 25
Y2 - 2022-11-04
SN - 1097-6256, 1546-1726
ER -