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Stem Cell Study Investigates How Genetics Increases Risk of PTSD

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Stem cell-derived neurons from combat veterans with and without post-traumatic stress disorder (PTSD) provide insights into how genetics can make someone more susceptible to developing PTSD following trauma exposure, according to a study conducted by scientists from several research institutions, including Yale School of Medicine.

Post-traumatic stress disorder can develop following severe trauma and is an enormous public health problem for both veterans and civilians. However, the extent to which genetic and environmental factors contribute to individual clinical outcomes remains unknown.

To bridge this information gap, the research team studied a cohort of 39 combat veterans with and without PTSD who were recruited from the James J. Peters Bronx Veterans Affairs Hospital. Veterans underwent skin biopsies and their skin cells were reprogrammed into induced pluripotent stem cells.

“Reprogramming cells into induced pluripotent stem cells is like virtually taking cells back in time to when they were embryonic and had the ability to generate all the cells of the body,” said Rachel Yehuda, PhD, professor of psychiatry and neuroscience at Icahn Mount Sinai, director of mental health for the Department of Veterans Affairs and senior author of the paper. “These cells can then be differentiated into neurons with the same properties as that person’s brain cells had before trauma occurred to change the way they function. The gene expression networks from these neurons reflect early gene activity resulting from genetic and very early developmental contributions, so they are a reflection of the ‘pre-combat’ or ‘pre-trauma’ gene expression state.”

“Two people can experience the same trauma, but they won't necessarily both develop PTSD,” said Kristen Brennand, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry at Yale School of Medicine who co-led the study. “This type of modeling in brain cells from people with and without PTSD helps explain how genetics can make someone more susceptible to PTSD.”

Published October 20 in Nature Neuroscience, this is the first study to use induced pluripotent stem cell models to study PTSD.

The study involved researchers from Yale School of Medicine, Icahn School of Medicine at Mount Sinai, the Office of Veterans Affairs, and The New York Stem Cell Foundation Research Institute (NYSCF).

To mimic the stress response that triggers PTSD, 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.

“The addition of stress hormones to these cells simulates biological effects of combat, which allows us to determine how different gene networks mobilize in response to stress exposure in brain cells,” Yehuda said.

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

You can’t easily reach into a living person’s brain and pull out cells, so stem cells are our best way to examine how neurons are behaving in a patient.

Kristen Brennand, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry at Yale School of Medicine

Most similar studies of PTSD to date have used blood samples from patients, but since PTSD is rooted in the brain, scientists need a way to capture how the neurons of prone individuals are affected by stress. Therefore, the team opted to use stem cells, as they are uniquely equipped to provide a patient-specific, non-invasive window into the brain.

“You can’t easily reach into a living person’s brain and pull out cells, so stem cells are our best way to examine how neurons are behaving in a patient,” Brennand said.

NYSCF scientists used their scalable, automated, robotic system – 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.

“As this was the first study using stem cell models of PTSD, it was important to study a large number of individuals,” said Daniel Paull, PhD, NYSCF Senior Vice President, Discovery & Platform Development, and co-leader of the study. “At the scale of this study, automation is essential. With the Array, we can make standardized cells that allow for meaningful comparisons between numerous individuals, pointing to key differences that could be critical for discovering new treatments.”

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.

Moreover, 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 researchers plan to continue leveraging their induced pluripotent stem cell models to further investigate the genetic risk factors pinpointed by this study and to study how PTSD affects other types of brain cells, helping to broaden opportunities for therapeutic discovery.

“What’s special about this study is that it could have only been done by this group,” Brennand said. “It involved some of the best clinicians in this space, incredible stem cell biologists, and amazing psychiatric geneticists. Each group has unique expertise, and none of this could have been accomplished by any one team alone.”

“This study is a true testament to the power of team science,” Paull said. “When researchers combine forces, we are able to ask bigger questions, make bigger discoveries, and hopefully, make a bigger difference for patients.

Reference: Seah C, Breen MS, Rusielewicz T, et al. Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression. Nat Neurosci. Published online October 20, 2022:1-12. doi:10.1038/s41593-022-01161-y

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