Nature: The first induced pluripotent stem cell model for post-traumatic stress disorder

The stem cell-derived neurons of combat veterans with PTSD respond differently to stress hormones than veterans without PTSD, a finding that may provide insight
into how genes make a person more likely to develop PTSD after traumatic exposure.

The study, published Oct.
20 in Nature Neuroscience, is the first to use an induced pluripotent stem cell model to
study post-traumatic stress disorder.

PTSD can develop after severe trauma and is a huge public health problem
for both veterans and civilians.
However, the extent to which genetic and environmental factors influence individual clinical outcomes remains unclear
.
To fill this information gap, the research team studied 39 combat veterans with and without PTSD, who were recruited from James M.
Smith of the Bronx.
Recruited by
J.
Peters Veterans Affairs Medical Center.
Veterans undergo skin biopsies, where their skin cells are reprogrammed to induce pluripotent stem cells
.

"Reprogramming cells into induced pluripotent stem cells is like bringing cells back to the embryonic stage and having the ability to generate all the cells in the body," said
Rachel Yehuda, Ph.
D.
, professor of psychiatry and neuroscience at Mount Icahnay, director of mental health at James J.
Peters Veterans Affairs Medical Center and senior author of the paper.
These cells can then differentiate into neurons with the same properties as pre-injury brain cells, and trauma alters the function of
brain cells.
Gene expression networks from these neurons reflect early gene activity due to heredity and very early developmental contributions, so they are a reflection
of 'pre-combat' or 'pre-traumatic' gene expression states.
”

"Two people may experience the same trauma, but they don't necessarily both develop PTSD," explains
Dr.
Kristen Brennand, a professor of psychiatry at Yale School of Medicine.
"This modeling of brain cells in people with and without PTSD helps explain how genes make people more susceptible to PTSD.
"

To mimic the stress response that triggers PTSD, the scientists exposed induced pluripotent stem cell-derived neurons to the stress hormone hydrocortisone, a synthetic version of the body's own cortisol used as part of the "fight or flight" response

Dr Yehuda explains: "Adding stress hormones to these cells, mimicking the biological effects of combat, allowed us to determine how different gene networks respond
to stress exposure in brain cells.
"

Through gene expression analysis and imaging, the scientists found that neurons in PTSD patients are highly sensitive
to this pharmacological trigger.
The scientists were also able to identify specific gene networks
that respond differently after exposure to stress hormones.

Cells affected by PTSD

To date, most similar PTSD studies have used blood samples from patients, but because PTSD is rooted in the brain, scientists need a way to capture how neurons in individuals susceptible to PTSD are affected
by stress.
Therefore, the team chose to use stem cells because they have unique devices that can provide patient-specific, non-invasive windows
into the brain.

Dr Brennand said: "You can't easily enter a living person's brain and take out the cells, so stem cells are the best way for us to examine the behavior of
a patient's neurons.
"

NYSCF scientists used their scalable, automated robotic system to grow stem cells from PTSD patients and then glutamatergic neurons
.
Glutamatergic neurons help the brain send excitatory signals and have previously been linked to
post-traumatic stress disorder.

"Since this is the first study to use a PTSD stem cell model, it is important to conduct studies on a large number of individuals, and automation is essential
in terms of the scale of this study.
" With this array, we can make standardized cells that allow meaningful comparisons between numerous individuals, pointing out key differences that could be critical
to discovering new treatments.
" ”

New treatments utilizing the characteristics of poststress stress disorder cells

The team's gene expression analysis revealed that a group of genes in neurons susceptible to PTSD were particularly active
after exposure to stress hormones.

"Importantly, the genetic signatures we found in neurons were also evident in brain samples from deceased people with PTSD, which tells us that stem cell models provide a fairly accurate reflection of what is happening in the brains of living patients, and what is really exciting about our findings is that they provide an opportunity to accelerate the diagnosis and treatment of PTSD, and importantly, having a robust stem cell model is important for Screening drugs in Petri dishes provides an ideal pathway, even in different patient populations," notes
Dr.
Daniel Paull.

In addition, the distinction between how PTSD cells and non-PTSD cells respond to stress may help predict which individuals are at higher
risk of developing PTSD.
Dr Brennand added: "We are working hard to find drugs that have already been approved that can reverse the hypersensitivity reactions
we see in neurons.
In this way, any medication we find will be able to help the patient
as quickly as possible.
”

The researchers plan to continue using their induced pluripotent stem cell model to further study the genetic risk factors identified by this study and to study how PTSD affects other types of brain cells, helping to broaden the chances of
therapeutic discovery.

Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression