Post-Traumatic Stress Disorder: The Brain Short-Circuit Caused By Trauma
- Lidi Garcia
- Jul 1
- 5 min read
Researchers have studied the brains of people with PTSD and found that many different cells, including neurons and immune cells in the brain, have changes in their genes and how they are activated. These changes affect how the brain responds to stress and processes emotions. The study also showed that these changes vary between people with PTSD and people with depression, and that certain genes linked to stress and inflammation are particularly involved. These findings help us better understand how trauma affects the brain and may eventually help us develop more effective treatments.
Post-traumatic stress disorder, also known as PTSD, is a mental health condition that can develop after experiencing extremely traumatic events, such as war, abuse, serious accidents, or intense loss. Although many people recover emotionally over time, some develop persistent symptoms such as flashbacks, nightmares, intense anxiety, or difficulty concentrating.
An estimated 6% to 8% of the general population will develop post-traumatic stress disorder at some point in their lives. Furthermore, it is known that this condition may have a genetic origin, that is, part of the risk of developing PTSD lies in inherited genes, although it also depends on environmental factors.
However, despite being relatively common, the exact biological mechanisms that cause post-traumatic stress disorder are still not fully understood.
In recent years, science has made great progress in investigating the biology of the brains of people who have suffered from PTSD. Studies of brains from deceased donors have made it possible to analyze, in particular, key regions such as the prefrontal cortex (involved in controlling emotions) and the amygdala (linked to fear and emotional memory).
These studies have observed changes in genes and processes linked to emotional regulation, such as neurotransmitter signaling (substances that transmit information between neurons), immune response and brain inflammation.
It has also been noted that the stress hormone system, controlled by glucocorticoids, is altered in people with PTSD.
However, since these changes affect many areas and functions of the brain, scientists have concluded that a single type of cell cannot be blamed; the problem is more complex and involves multiple cells and interactions.
The new study discussed here goes a step further: the researchers analyzed more than two million brain cell nuclei, taken from a region called the dorsolateral prefrontal cortex (which helps control thoughts and behaviors), in the brains of three groups of people: those with PTSD, those with major depression and those without mental illness (the control group).
To do this, they used modern techniques that allow them to study, cell by cell, both which genes are active (using RNA sequencing) and which regions of DNA are accessible and can be activated (through a technique called ATAC-seq). These two approaches together help to understand not only what is happening in the genes, but also how and why this happens.
They identified all the main types of cells present in this area of the brain, including excitatory neurons (which activate signals), inhibitory neurons (which stop signals), and non-neuronal cells, such as microglia (linked to the brain's immune defense) and endothelial cells (which line blood vessels).
They were able to see which genes were abnormally activated or deactivated in PTSD, and compare these changes with what was seen in depression, noting commonalities and differences between the two disorders.
Using another technique called spatial transcriptomics, which shows exactly where these changes occur in brain tissue, the scientists confirmed that cells such as somatostatin-producing interneurons (SST) and microglia are profoundly affected in PTSD.
These cells appear to lose some of their ability to communicate with other brain cells. They also found that stress-related genes such as FKBP5 are strongly altered.
The image shows a part of the brain called the prefrontal cortex (PFC), comparing people without PTSD (control group) and people with PTSD. Scientists analyzed where exactly a gene called FKBP5 is active. This gene, linked to stress, appears marked in dark purple in the images. Each colored dot represents a cell nucleus, with the cells of the blood vessels (called endothelial cells) being in light purple. In the group without PTSD, there is little FKBP5 activity, but in a magnified area of the image it is possible to see a vessel with greater expression of this gene. In the group with PTSD, the image shows more dark dots, indicating that the FKBP5 gene is more active, especially in the cells of the vessels. This helps to understand how PTSD alters the activity of certain genes in specific cells of the brain.
One of the major advances of the study was the construction of a detailed map of how DNA regulatory elements, such as enhancers and gene promoters, control gene activation in specific cell types.
This allowed the scientists to pinpoint eight regions of DNA that are associated with genetic risk for PTSD, and that influence important genes such as ELFN1, MAD1L1 and KCNIP4, all of which are involved in brain function and stress regulation.
Interestingly, an unexpected finding was that some of the biggest changes in the stress hormone system were present in endothelial cells, which are not neurons, but rather cells that line the blood vessels of the brain. Finally, the study showed that somatostatin-releasing interneurons, which normally help balance brain activity and prevent exaggerated responses, are particularly vulnerable in PTSD.
Somatostatin-releasing neurons (green). Image by Therese Riedemann
Reduced activity of these neurons and the chemical messages they carry may contribute to the symptoms of the disease. Overall, the research provides a very detailed picture of how different types of cells in the brain respond to trauma, showing that PTSD does not affect just one system, but involves a broad network of genetic and epigenetic changes (i.e., changes that regulate genes without changing the DNA itself).
These results not only expand our understanding of how trauma alters the brain at a molecular level, but also open the door to new, more personalized treatments that take into account the different cell types and pathways involved in the disease.
The hope is that with this knowledge, we can develop more effective therapies to help those suffering from PTSD have a better quality of life.
READ MORE:
Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD
Ahyeon Hwang, Mario Skarica, Siwei Xu, Jensine Coudriet, Che Yu Lee, Lin Lin, Rosemarie Terwilliger, Alexa-Nicole Sliby, Jiawei Wang, Tuan Nguyen, Hongyu Li, Min Wu, Yi Dai, Ziheng Duan, Shushrruth Sai Srinivasan, Xiangyu Zhang, Yingxin Lin, Dianne Cruz, P. J. Michael Deans, Traumatic Stress Brain Research Group, Bertrand R. Huber, Daniel Levey, Jill R. Glausier, David A. Lewis, Joel Gelernter, Paul E. Holtzheimer,
Matthew J. Friedman, Mark Gerstein, Nenad Sestan, Kristen J. Brennand, Ke Xu, Hongyu Zhao, John H. Krystal, Keith A. Young, Douglas E. Williamson,
Alicia Che, Jing Zhang, and Matthew J. Girgenti
Nature (2025). 18 June 2025
Abstract:
Post-traumatic stress disorder (PTSD) is a polygenic disorder occurring after extreme trauma exposure. Recent studies have begun to detail the molecular biology of PTSD. However, given the array of PTSD-perturbed molecular pathways identified so far1, it is implausible that a single cell type is responsible. Here we profile the molecular responses in over two million nuclei from the dorsolateral prefrontal cortex of 111 human brains, collected post-mortem from individuals with and without PTSD and major depressive disorder. We identify neuronal and non-neuronal cell-type clusters, gene expression changes and transcriptional regulators, and map the epigenomic regulome of PTSD in a cell-type-specific manner. Our analysis revealed PTSD-associated gene alterations in inhibitory neurons, endothelial cells and microglia and uncovered genes and pathways associated with glucocorticoid signalling, GABAergic transmission and neuroinflammation. We further validated these findings using cell-type-specific spatial transcriptomics, confirming disruption of key genes such as SST and FKBP5. By integrating genetic, transcriptomic and epigenetic data, we uncovered the regulatory mechanisms of credible variants that disrupt PTSD genes, including ELFN1, MAD1L1 and KCNIP4, in a cell-type-specific context. Together, these findings provide a comprehensive characterization of the cell-specific molecular regulatory mechanisms that underlie the persisting effects of traumatic stress response on the human prefrontal cortex.
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