Summary: Neurons generated from stem cells taken from combat veterans with post-traumatic stress disorder (PTSD) respond differently to stress hormones than neurons derived from veterans without PTSD. This discovery offers new insight into how genetic factors can increase vulnerability to PTSD after traumatic events.
Source: Mount Sinai Hospital
Researchers found that induced pluripotent stem cell–derived neurons from combat veterans with PTSD showed a distinct and heightened response to a stress hormone compared with neurons from veterans who did not develop PTSD, suggesting a genetic contribution to stress sensitivity that may underlie the disorder.
Published October 20 in Nature Neuroscience, this is the first study to apply human induced pluripotent stem cell (hiPSC) models directly to PTSD research. The collaborative team included scientists from the Icahn School of Medicine at Mount Sinai, the James J. Peters Veterans Affairs Medical Center, Yale School of Medicine and The New York Stem Cell Foundation Research Institute (NYSCF).
PTSD can develop after severe trauma and remains a major public health challenge for both veterans and civilians. While environmental exposures clearly matter, the relative contribution of genetic factors to individual risk and clinical outcomes has been unclear.
To investigate genetic influences on stress responses, the team recruited 39 combat veterans with and without PTSD from the James J. Peters Veterans Affairs Medical Center. Researchers collected skin biopsies and reprogrammed the skin cells into induced pluripotent stem cells, which were then differentiated into neurons for study.
“Reprogramming adult cells into induced pluripotent stem cells is like returning them to an embryonic-like state when they can generate any cell type in the body,” said Rachel Yehuda, Ph.D., Professor of Psychiatry and Neuroscience at Icahn Mount Sinai and senior author of the study. “When we make neurons from these stem cells, their gene expression reflects early developmental and genetic influences that existed before combat or trauma.”
Kristen Brennand, Ph.D., co-leader of the study and professor at Yale School of Medicine, emphasized that individual responses to trauma differ: “Two people can experience the same traumatic event and one may develop PTSD while the other does not. By modeling brain cells from people with and without PTSD, we can begin to understand how genetic differences shape resilience or vulnerability.”
To simulate the physiological effects of stress, researchers exposed the hiPSC-derived neurons to hydrocortisone, a pharmaceutical form of cortisol that mimics the body’s stress hormone response. This allowed the team to observe how gene networks in neurons react to a stress trigger in a controlled, patient-specific setting.
Using gene expression profiling and cellular imaging, the investigators observed that neurons from veterans with PTSD were hypersensitive to hydrocortisone. Specific gene networks in these neurons were activated differently compared with neurons from control veterans, revealing a PTSD-specific transcriptional response to glucocorticoid exposure.
Inside the cells of individuals with PTSD
Most prior molecular studies of PTSD used blood samples, but because PTSD is rooted in the brain, researchers sought a model that reflects neuronal biology. Induced neurons offer a noninvasive, patient-specific window into brain cell behavior and allow direct study of neuronal responses to stress hormones.
NYSCF scientists used an automated, scalable platform—the NYSCF Global Stem Cell Array—to generate standardized hiPSCs and then produce glutamatergic neurons from each donor. Glutamatergic neurons, which transmit excitatory signals in the brain, have been implicated previously in stress-related disorders including PTSD.
“Studying a sizable group of individuals was essential for this first stem cell–based PTSD study,” said Daniel Paull, Ph.D., who co-led the work. “Automation allowed us to produce consistent cells across many donors, enabling meaningful comparisons and highlighting reproducible differences relevant to disease mechanisms and potential therapies.”
Toward biomarkers and new treatments
The gene signature identified in PTSD-prone neurons following hydrocortisone exposure matched transcriptomic patterns seen in brain tissue from deceased individuals with PTSD, supporting the validity of the hiPSC-derived neuron model as a reflection of disease-relevant brain biology.
Differences in how neurons from PTSD-affected and non-affected individuals respond to stress may help predict who is at greater risk for the disorder. More importantly, the stem cell model establishes a platform for drug screening and biomarker discovery.
“These findings open opportunities to accelerate PTSD diagnosis and therapy development,” Dr. Paull said. “A robust stem cell model lets us screen candidate compounds in the dish across diverse patient-derived cells.”
The team is actively testing existing, approved drugs to determine whether any can normalize the hypersensitive neuronal response seen in PTSD-derived cells. Because these are already-approved medications, successful hits could move rapidly toward clinical testing.
Researchers plan to expand their use of induced neurons to explore genetic risk factors identified in this study and to examine how other brain cell types respond to stress, broadening avenues for therapeutic discovery.
“NYSCF is proud to have generated the first hiPSC models from individuals with PTSD for this collaborative study,” said Derrick Rossi, Ph.D., interim CEO of NYSCF. “This work highlights the power of stem cell models to reveal disease mechanisms and to inform new treatment strategies for complex psychiatric disorders.”
About this genetics and PTSD research news
Author: Press Office
Source: Mount Sinai Hospital
Contact: Press Office – Mount Sinai Hospital
Image: The image is in the public domain
Original Research: Open access. “Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression” by Daniel Paull et al., Nature Neuroscience.
Abstract (summary)
This study compared transcriptional responses to hydrocortisone in human induced pluripotent stem cell–derived glutamatergic neurons and peripheral blood cells from combat veterans with and without PTSD. Diagnosis-specific glucocorticoid-induced gene expression changes were observed in neurons but not in blood cells. PTSD-derived neurons exhibited glucocorticoid hypersensitivity, and the team identified genes and a coregulated transcription factor network that contribute to this heightened response. These results indicate that induced neurons provide a platform to study molecular mechanisms of PTSD, identify stress-response biomarkers, and support drug screening to discover new therapeutics.