Pluripotent stem cell model of PTSD sheds light on how neurons react to stress

By The Science Advisory Board staff writers

October 24, 2022 -- A team of scientists from the Icahn School of Medicine at Mount Sinai, the James J. Peters Veterans Affairs Medical Center, the Yale School of Medicine, and the New York Stem Cell Foundation Research Institute (NYSCF) have discovered that stem cell-derived neurons from combat veterans with post-traumatic stress disorder (PTSD) react differently to a stress hormone than those from veterans without PTSD.

The study, published October 20 in Nature Neuroscience, is the first to use induced pluripotent stem cell models to study PTSD, and the findings could provide insights into how genetics can make someone more susceptible to developing PTSD following trauma exposure, according to the authors.

The research team studied a cohort of 39 combat veterans with and without PTSD who were recruited from the James J. Peters Veterans Affairs Medical Center in the Bronx. The veterans underwent skin biopsies, and their skin cells were reprogrammed into induced pluripotent stem cells.

To mimic the stress response that triggers PTSD (in this case to simulate the biological effects of combat), the scientists exposed the induced pluripotent stem cell-derived neurons to the stress hormone hydrocortisone, a synthetic version of the body's own cortisol that is used as part of the "fight-or-flight" response.

Using gene expression profiling and imaging, the scientists found that neurons from individuals with PTSD were hypersensitive to this pharmacological trigger. They were also able to identify the specific gene networks that responded differently following exposure to the stress hormones.

Because PTSD is rooted in the brain, the team decided to use stem cells to provide a "patient-specific, non-invasive window into the brain." NYSCF scientists used their scalable, automated, robotic system called the NYSCF Global Stem Cell Array to create stem cells and then glutamatergic neurons from patients with PTSD. Glutamatergic neurons help the brain send excitatory signals and have previously been implicated in PTSD.

The team's gene expression analysis revealed a set of genes that were particularly active in PTSD-prone neurons following their exposure to stress hormones. The gene signature found in the neurons were also present in brain samples from deceased individuals with PTSD, highlighting the accuracy of the stem cell models.

The distinctions between how PTSD and non-PTSD cells responded to stress could be informative in predicting which individuals are at higher risk for PTSD. The study's findings could also help in accelerating the diagnosis and treatment of PTSD, said the authors.

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