Research explores how neurons from PTSD patients respond to stress

The first induced pluripotent stem cell model of PTSD has provided fresh insights into underlying genetics as well as prospects for new therapeutics.

The study, published in Nature Neuroscience, is the first to investigate PTSD using induced pluripotent stem cell models. It was carried out by a group of scientists from Mount Sinai’s Icahn School of Medicine, the James J. Peters Veterans Affairs Medical Center, Yale School of Medicine, and The New York Stem Cell Foundation Research Institute (NYSCF). Post-traumatic stress disorder (PTSD) can develop in the aftermath of extreme trauma and is a major public health issue for both veterans and civilians. However, it is unknown how much hereditary and environmental factors influence individual clinical outcomes.

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 Veterans Affairs Medical Center in the Bronx. 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 James J. Peters Veterans Affairs Medical Center, and senior author of the paper.

Rachel added, “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,” explained Kristen Brennand, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry at Yale School of Medicine and a NYSCF — Robertson Stem Cell Investigator Alumna, 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.”

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,” explained Dr. Yehuda.

Using gene expression profiling and imaging, the researchers discovered that neurons from PTSD patients were hypersensitive to this pharmacological trigger. The researchers were also able to identify distinct gene networks that responded differently after being exposed to stress chemicals.

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