How neurons from PTSD patients respond to stress

Summary: Stem cell-derived neurons from combat veterans with PTSD responded differently to stress hormones compared to neurons derived from veterans without PTSD. The findings shed new light on how genetics can cause some to develop PTSD after a traumatic event.

Source: Mount Sinai Hospital

Stem cell-derived neurons from combat veterans with post-traumatic stress disorder (PTSD) respond differently to stress hormones than veterans without PTSD, a finding that may provide insight into how genetics can make someone more susceptible to developing PTSD after trauma exposure. can .

The study, published Oct. 20 Nature is neuroscience, was the first to use an induced pluripotent stem cell model to study PTSD. It was conducted by a team of scientists from the Icahn School of Medicine at Mount Sinai, 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 can develop after a serious injury and is a huge 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 address this data 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 virtually like taking cells back in time to when they were embryos and had the ability to make all the cells in the body,” said Rachel Yehuda, PhD, professor of psychiatry and neuroscience. , Icahn, director of mental health at the James J. Peters Veterans Affairs Medical Center at Mount Sinai and senior author of the paper.

“These cells can then differentiate into neurons with the same properties as the person’s brain cells that they had before the trauma to change the way they work. The gene expression networks of these neurons reflect early gene activity resulting from genetic and very early developmental contributions, so they reflect a ‘pre-combat’ or ‘pre-trauma’ gene expression state.”

“Two people can experience the same trauma, but they won’t both develop PTSD,” explains Kristen Brennand, PhD, the Elizabeth Meyers and House Jameson Professor of Psychiatry at Yale School of Medicine and a NYSCF-Robertson Stem Cell Investigator alumnus, who co-authored the study. – led

“Such modeling in brain cells of people with and without PTSD helps explain how genetics can make someone more susceptible to PTSD.”

To mimic the stress response that triggers PTSD, scientists exposed neurons derived from induced pluripotent stem cells 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 mimics the biological effects of combat, allowing us to determine how different gene networks are activated in brain cells in response to stress exposure,” explained Dr. Yehuda.

Using gene expression profiling and imaging, the scientists found that neurons in people with PTSD were hypersensitive to this pharmacological trigger. Scientists were able to identify specific gene networks that responded differently after exposure to stress hormones.

Inside the cells of PTSD-afflicted individuals

Most similar studies of PTSD to date have used blood samples from patients, but because PTSD is rooted in the brain, scientists need a way to capture how the neurons of people prone to the disorder are affected by stress. Therefore, the team decided 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 extract cells, so stem cells are our best way to test how neurons are behaving in a patient,” said Dr. Brenand.

NYSCF scientists used their scalable, automated, robotic system—the NYSCF Global Stem Cell Array—to generate stem cells and then glutamatergic neurons from patients with PTSD. Glutamatergic neurons help send excitatory signals to the brain and have previously been implicated in PTSD.

“Because this was the first study using a stem cell model of PTSD, it was important to study a large number of individuals,” said Daniel Paul, PhD, NYSCF Senior Vice President, Discovery and Platform Development, who co-led the study.

“At this scale of research, automation is essential. With arrays, we can create standard cells that allow meaningful comparisons between numerous individuals, indicating key differences that may be important for discovering new treatments.”

Harnessing hallmarks of stressed PTSD cells for new treatments

The team’s gene expression analysis revealed a set of genes that were specifically activated in PTSD-prone neurons after exposure to stress hormones.

“Importantly, the gene signature we found in neurons was also evident in brain samples from deceased individuals with PTSD, which tells us that the stem cell models are providing a pretty accurate reflection of what happens in the brains of living patients,” noted Dr. Paul.

Furthermore, differences between how PTSD and non-PTSD cells respond to stress may be informative in predicting which individuals are at greater risk for PTSD.

“What’s really exciting about our results is the opportunities they offer to accelerate PTSD diagnosis and treatment,” continued Dr. Paul.

“Importantly, having a robust stem cell model provides an ideal means for ‘on-the-dish’ drug screening, even across different patient populations.”

“We are working to find already-approved drugs that can reverse the hypersensitivity we see in neurons,” added Dr. Brenand.

“That way, any drug we discover will have the fastest possible path to helping patients.”

The researchers plan to continue to take advantage of their induced pluripotent stem cell models to further investigate the genetic risk factors identified by this study and how PTSD affects other types of brain cells, helping to expand opportunities for therapeutic discovery.

“NYSCF is incredibly proud to partner with world-class scientists to develop the first induced pluripotent stem cell model from individuals with PTSD as part of this groundbreaking research,” said NYSCF Interim CEO Derrick Rossi, Ph.D.

“This collaborative work underscores the unique value of stem cell modeling for studying and demystifying challenging diseases and discovering innovative strategies that can lead to urgently needed treatments.”

This is about genetics and PTSD research news

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Source: Mount Sinai Hospital
Contact: Press Office – Mount Sinai Hospital
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Original Research: Access to all.
“Modeling Gene × Environment Interactions in PTSD Using Human Neurons Revealing Diagnosis-Specific Glucocorticoid-Induced Gene ExpressionBy Daniel Paul et al. Nature is neuroscience

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abstract

Modeling Gene × Environment Interactions in PTSD Using Human Neurons Revealing Diagnosis-Specific Glucocorticoid-Induced Gene Expression

Post-traumatic stress disorder (PTSD) can develop after 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 cells (hiPSCs) derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (PTSD).n= 19 hiPSCs and n= 20 PBMC donor) and control (n= 20 hiPSCs and n= 20 PBMC donors).

In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression associated 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 for a regulated network of transcription factors that mediate glucocorticoid hyper-responsiveness in PTSD.

These results suggest that excitatory neurons represent a platform to examine the molecular mechanisms underlying PTSD, identify biomarkers of stress response, and conduct drug screening to identify new therapeutics.