Nat Neurosci: Let the petri dish "develop" PTSD and then expand the treatment for humans

Introduction: Although netizens often talk about "I have PTSD", expressing that certain things have a profound and lasting impact on themselves, the original meaning of PTSD, that is, post-traumatic stress disorder, is a major public health problem
.
However, how genetic and environmental factors make some people more susceptible to PTSD is unclear
.
To this end, scientists use induced pluripotent stem cells to model and observe
PTSD.

Since 2006, when Japanese scientist Shinya Yamanaka first reprogrammed mouse somatic cells into pluripotent stem cells similar to embryonic stem cells, induced pluripotent stem cells (iPSCs) have received extensive attention in the field of regenerative medicine and tissue engineering and are considered to have great clinical potential due to their considerable differentiation and regenerative ability compared to embryonic stem cells and the need to face many ethical and legal obstacles
。

At the same time, iPS technology is also very promising
in disease modeling because it can provide complex genetic characteristics of human tissues, observation during pathological development, and a certain degree of unlimited disease sample size.

In 2008, scientists at the Harvard Stem Cell Institute first studied diseased iPS cells by inducing iPS cells into motor neurons from an 82-year-old woman diagnosed with familial amyotrophic lateral sclerosis (ALS), and then observing the destruction of
these cells in ALS.

In 2010, when the Icahn School of Medicine at Mount Sinai in New York first performed iPS modeling of adult heart disease, the research team found that derived cardiomyocytes derived from LEOPARD syndrome-iPS cells were more hypertrophied, and provided insights
into disease phenotypic-related signaling pathways.

Modeling neurodegenerative diseases is also a popular study in the field of iPS, such as Alzheimer's disease modeling, which found that iPS cell-derived neurons exhibit different pathophysiology in different patients, especially in the accumulation of β amyloid oligomers, which may explain why the same treatment regimen has different
efficacy for patients who do not use it.

In the modeling of Parkinson's disease, because iPSC-derived cells are immature and too young to simulate geriatric diseases, in order to overcome this problem, the researchers used progerin progerin treatment to successfully make the cells exhibit some characteristics of
Parkinson's disease.

PTSD is a relatively young concept that began to be used in the 1970s and was not officially recognized as a diagnosable condition
until the American Psychiatric Association's 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders, published in 1980.
This definition of mental disorder is largely derived from a diagnosis
of U.
S.
veterans of the Vietnam War.
Combat military personnel, survivors of natural disasters, and survivors of violent crime are all at high risk of
PTSD.

However, not all people who experience a major traumatic event develop PTSD, and patients are not the same
in severity.
To identify genetic and environmental factors specific to high-risk populations, a team of scientists at Mount Sinai's Icahn School of Medicine, James J.
Peters Veterans Affairs Medical Center, Yale University School of Medicine, and the New York Stem Cell Foundation Institute studied PTSD using an induced pluripotent stem cell model Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression" was published Oct.
20 in Nature Neuroscience
。

Figure 1 Research results (Source: [1])

People produce glucocorticoids
in stressful situations.
Past studies have found that PTSD patients have higher glucocorticoid sensitivity and their interference with glutamatergic neural activity, and identified gene loci significantly related to PTSD, but the interaction between genes and the environment (gene × environment) has not been deeply explored, and previous PTSD pathophysiology studies mainly revolve around blood samples of PTSD patients or brain tissue samples after death.
No one compared neurons between
people with PTSD and people who also experienced trauma but did not develop PTSD.
To mimic the stress response that triggers PTSD, glucocorticoids were used to process iPSC-derived glutamatergic neurons and blood samples from a total of 49 PTSD or non-PTSD veterans and analyze changes in gene expression
.

The study found that:

■ Treatment of blood samples with the synthetic glucocorticoid dexamethasone (DEX) was consistent with previous studies, with an increase
in the number of differentially expressed genes unrelated to PTSD and other potential interfering factors as DEX concentrations increased.

■ Derived neurons were treated with hydrocortisone (HCort), a glucocorticoid synthesized by the human body, and as the concentration of HCort increased, the number of differentially expressed genes unrelated to PTSD and other potential interfering factors also increased
.

■ Comparing the gene expression profiles of PTSD group and non-PTSD group derived neurons without HCort addition, no significant gene expression differences
were found.
Low-concentration HCort treatment identified more differentially expressed genes
than high-concentration HCort treatment.

■ For the above genes with significant diagnostic significance, they can be divided into three categories according to the dependence on HCort dose: (1) the difference in expression is significant with the dose of HCort, and the change is opposite in the PTSD group and non-PTSD group; (2) HCort dose increase only led to significant changes in the non-PTSD group; (3) HCort dose increase only led to significant changes
in the PTSD group.

■ Found 38 significantly enriched transcription factors that target the above (3) genes
.
These transcription factors may mediate hypersensitivity
to glucocorticoids in PTSD.

The findings are consistent with genetic signatures of brain tissue from deceased PTSD patients, suggesting that "stem cell models very accurately reflect what
is happening in the brains of living patients.
" Dr.
Daniel Paul, senior vice president of discovery and platform development at the New York Stem Cell Foundation Institute, one of the co-leaders of this study, said, "This provides an opportunity
to accelerate the development of diagnostic and therapeutic treatments for PTSD.
" ”

Stem cell models in petri dishes also provide an ideal pathway
for drug screening.
Researchers are trying to find those that can reverse the high sensitivity of glucocorticoids from approved drugs, "so that we can help patients
in the fastest way.
" Kristen Brennand, another leader and corresponding author of the study, said
.
In the future, the researchers plan to continue using iPSC models to further explore the genetic risk factors identified and how PTSD affects other types of brain cells
.

Original source:

Seah， C.
， Breen， M.
S.
， Rusielewicz， T.
et al.
Modeling gene × environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression.
Nat Neurosci (2022).
https：//doi.
org/10.
1038/s41593-022-01161-y.