Summary: A new study has examined brains affected by PTSD at the single-cell level, uncovering distinct genetic alterations that may drive the disorder. Researchers focused on the dorsolateral prefrontal cortex, a brain region tied to emotional regulation, analyzing individual cell nuclei to map communication differences across PTSD, major depression, and control brains.
They found impaired signaling in inhibitory neurons in PTSD, potentially explaining hyperarousal symptoms, and opposing patterns of microglial activity in PTSD versus depression. Vascular endothelial cells in PTSD brains also showed signs of dysfunction, possibly increasing stress hormone exposure.
Key Facts:
- Inhibitory Neuron Disruption: PTSD brains showed decreased communication from inhibitory neurons, possibly causing hyperexcitable, overreactive brain states.
- Microglia and Endothelial Differences: Microglia were overactive in depression but underactive in PTSD; endothelial cells in PTSD brains were also genetically altered, affecting stress hormone access.
- New Therapeutic Pathways: The study identified gene pathways that could be targeted with precision drugs developed specifically for PTSD.
Source: Yale
The human brain is made up of billions of interconnected cells that are constantly talking to each other.
A new Nature study zooms in to the single-cell level to see how this cellular communication may be going wrong in brains affected by post-traumatic stress disorder (PTSD).
Until recently, researchers did not have the technology to study genetic variation within individual cells.
But now that it’s available, a team led by Matthew Girgenti, PhD, assistant professor of psychiatry at Yale School of Medicine, has been analyzing brain cells to uncover genetic variants that might be associated with psychiatric diseases such as major depressive disorder (MDD) and PTSD.
Their latest study is one of the first to examine a major psychiatric disorder, PTSD, at the single-cell level.
For years, doctors have been prescribing antidepressants to treat the condition because there are currently no drugs specifically designed for PTSD.
Girgenti hopes that identifying novel molecular signatures associated with the psychiatric disease can help researchers learn how to develop new drugs or repurpose existing ones to treat it more effectively.
“We’re trying to figure out what’s gone wrong in psychiatric disorders so that we can understand the neurobiological mechanisms that are in play in these diseases,” he says.
“The hope is that we can identify areas where we can potentially treat them—that’s the ultimate goal.”
For the new study, the researchers used postmortem human brain tissue from donors with and without PTSD.
They also analyzed tissue from individuals who had been diagnosed with MDD—which is often diagnosed in people with PTSD—to better understand both the commonalities and where molecular mechanisms diverge between the conditions.
Specifically, they looked at the dorsolateral prefrontal cortex, the region of the brain associated with executive functioning and emotional regulation.
“It’s the most uniquely human region of the brain,” Girgenti explains.
Across all three groups, the researchers isolated individual cells from this brain region, paying particular attention to the nuclei, which package the cells’ DNA and make RNA. This allowed the team to observe genetic variation across the groups.
Key genome alterations revealed in brains with PTSD and MDD
Among brains with PTSD, the analyses revealed gene alterations in a type of neuron known as inhibitory neurons.
“These are the fine-tuning neurons,” says Girgenti.
They regulate other neurons and prevent them from overfiring.
In brains with PTSD and MDD, the team observed a decrease in the amount of communication from these neurons. The researchers believe that this decrease in communication may contribute to a hyperexcitable state in the prefrontal cortex.
Following a traumatic event, this hyperexcitability could cause symptoms typically associated with PTSD such as hyperarousal (overreactive fight-or-flight response) and nightmares.
The researchers also discovered differences in the microglia, which are the brain’s immune cells. Interestingly, they found that these cells were overcommunicating in brains with MDD, but under communicating in those with PTSD.
“PTSD and MDD are generally very similar to each other and have a lot of shared genetic variability,” Girgenti says.
“This is a finding that seems to differentiate the two.” His team hopes to further investigate these differences and how they might drive the two disorders.
Furthermore, they found that brains with PTSD also had genome alterations associated with dysregulated endothelial cells. These cells are part of the brain’s vasculature and interact with the rest of the body. Prior research has shown that individuals with PTSD have elevated levels of stress hormones, which travel to the brain through blood vessels.
“We think there could be an increase in the amount of stress hormone that’s getting into the brain because these endothelial cells are compromised,” says Girgenti.
Unlocking secrets of the brain to inform new therapies
Unlike Alzheimer’s disease and Parkinson’s disease, which are associated with noticeable changes to the brain when imaged, scientists know very little about the neurobiological mechanisms underlying PTSD. By zooming in to the molecular level, Girgenti hopes these insights will help lead to better therapies for the disorder.
“We’ve already identified pathways—pathways refer to how genes talk to each other—that we think are targetable by particular drugs,” he says.
“This was only made possible by looking at those individual cells and those individual molecular changes. Now we have to try and find drugs that will reverse that.”
In future studies, Girgenti’s team plans to examine other regions in the brain that might be involved in PTSD pathology such as the hypothalamus, which regulates the production of stress hormones.
“The dorsolateral prefrontal cortex has been very well studied,” says Girgenti.
“But there are other regions of the brain that we know a lot less about, and they’re just as likely to hold secrets for what is wrong. And there could be even better regions to look at when it comes to therapy.”
Funding: The research reported in this news article was supported by the Department of Veterans Affairs, the Brain and Behavior Research Foundation, the American Foundation for Suicide Prevention, the State of Connecticut’s Department of Mental Health and Addiction Services, the National Institutes of Health (awards R01AA031017, DP1DA060811, R01NS128523, and R01HG012572) and Yale University.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
About this PTSD and neuroscience research news
Author: Isabella Backman
Source: Yale
Contact: Isabella Backman – Yale
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD” by Matthew Girgenti et al. Nature
Abstract
Single-cell transcriptomic and chromatin dynamics of the human brain in PTSD
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 far, 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.
