Summary: A new study has examined brains affected by PTSD at the level of individual cells, discovering different genetic alterations that can boost the disorder. The researchers focused on the dorsolateral prefrontal cortex, a brain region linked to emotional regulation, analyzing the individual cell nuclei to map the communication differences between the PTSD, the major depression and the control brains.
They found a deteriorated signage in inhibitory neurons in the PTSD, which can explain hyperatous symptoms and opposite patterns of microglial activity in PTSD versus depression. Vascular endothelial cells in PTSD brains also showed signs of dysfunction, possibly increasing exposure to stress hormone.
Key facts:
Inbitilla nurons inser: PTSD brains showed a decrease in communication of inhibitory neurons, possibly causing hyperexcitable, exaggerated brain states. Endothelial cells in the PTSD brains also altered genetically, which affected access to stress hormone. New therapeutic tips: The study identified genes of genes that could be directed with precision drugs specifically developed for PTSD.
Source: Yale
The human brain is composed of billions of interconnected cells that constantly speak with each other.
A new study of nature is close to the level of a single cell to see how this cellular communication can be wrong in the brains affected by posttraumatic stress disorder (PTSP).
Until recently, researchers did not have technology to study genetic variation within individual cells.
But now that it is available, a team led by Matthew Girgenti, PHD, Assistant Professor of Psychiatry at Yale Medicine Faculty, has been analyzing brain cells to discover genetic variants that could be associated with psychiatric diseases such as the major depressive disorder (MDD) and the TTSD.
His latest study is one of the first to examine an important psychiatric disorder, the PTSD, at the level of a single cell.
For years, doctors have been recopping antidepressants to treat the condition because there are currently no medications specifically designed for PTSD.
Girgenti hopes that identifying new molecular firms associated with psychiatric disease can help researchers learn how to develop new medications or reuse existing ones to treat it more effectively.
“We are trying to discover what went wrong in psychiatric disorders so that we can understand the neurobiological mechanisms that are at stake in these diseases,” he says.
“The hope is that we can identify areas where we can treat them potentially, that is the final objective.”
For the new study, the researchers used postmortem human brain tissue of donors with and without PTSD.
They also analyzed the fabric of people who had been diagnosed with MDD, which is often diagnosed in people with PTSD, to better understand both the points in common and where molecular mechanisms diverge between conditions.
Specifically, they observed the dorsolateral prefrontal cortex, the region of the brain associated with executive functioning and emotional regulation.
“It is the most unique region of the brain,” explains Girgenti.
In the three groups, the researchers isolated individual cells in this brain region, paying special attention to the nuclei, which package the DNA of the cells and produce RNA. This allowed the team to observe the genetic variation between the groups.
Key alterations of the genome revealed in brains with PTSD and MDD
Among the brains with PTSD, the analysis revealed genetic alterations in a type of neuron known as inhibitory neurons.
“These are tight neurons,” says Girgenti.
They regulate other neurons and prevent them from exaggerating.
In brains with PTSD and MDD, the team observed a decrease in the amount of communication of these neurons. Researchers believe that this decrease in communication can contribute to a hyperexcitable state in the prefrontal cortex.
After a traumatic event, this hyperexcitability could cause symptoms typically associated with PTSD, such as hyperatousal (exaggerated fighting or flight response) and nightmares.
The researchers also discovered differences in microglia, which are the immune cells of the brain. Interestingly, they discovered that these cells communicated excessively in the brain with MDD, but under communication in those with PTSD.
“The PTSD and MDD are generally very similar to each other and have a lot of shared genetic variability,” says Girgenti.
“This is a finding that seems to differentiate the two.” His team hopes to investigate these differences more thoroughly and how the two disorders could boost.
In addition, they found that PTSD brains also had alterations of the genome associated with deregulated endothelial cells. These cells are part of the brain vasculature and interact with the rest of the body. Previous investigations have shown that people with PTSD have high levels of stress hormones, which travel to the brain through blood vessels.
“We believe there could be an increase in the amount of stress hormone that is reaching the brain because these endothelial cells are compromised,” says Girgenti.
Unlocking of brain secrets to inform new therapies
Unlike Alzheimer’s disease and Parkinson’s disease, which are associated with notable changes in the brain when images are taken, scientists know very little about the neurobiological mechanisms underlying PTSD. As you approach the molecular level, Girgenti hopes that these ideas will help lead to better therapies for the disorder.
“We have already identified the tracks, the roads referring to how genes talk to each other, which we believe are airsible for private drugs,” he says.
“This was only made possible by observing those individual cells and those individual molecular changes. Now we have to try to find medications that will reverse it.”
In future studies, the Girgenti team plans to examine other regions in the brain that could be involved in the PREPT 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 much less, and they are so likely to have secrets for what is wrong. And there could be even better regions to see when it comes to therapy.”
FINANCING: 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 Department of Mental Health Services and Addiction of the State of Connecticut, the National Institutes of Health (R01A031017 Awards, DP1DA060811, R012852 and R01HG0125722222222222S.
The content is the exclusive responsibility of the authors and does not necessarily represent the official opinions of the National Health Institutes.
About this Tept and Neuroscience research news
Author: Isabella Backman
Source: Yale
Contact: Isabella Backman – Yale
Image: The image is accredited to Neuroscience News
Original research: open access.
“Transcriptomic dynamics and chromatin of individual cells of the human brain in the PTSD” by Matthew Girgenti et al. Nature
Abstract
Transcriptomic and chromatin dynamics of individual cells of the human brain in the PTSD
Post -traumatic stress disorder (PTSD) is a polygenic disorder that occurs after extreme trauma exposure. Recent studies have begun to detail the MOLECULAR BIOLOGY OF PREPT.
However, given the matrix of molecular roads with PTSD identified so far, it is unlikely that a unique cell is responsible.
Here we profile the molecular responses in more than two million nuclei of the dorsolateral prefrontal cortex of 111 human brains, collected post -mortem of individuals with and without PPEP and major depressive disorder.
We identify clusters of neuronal and non -neuronal cell type, changes of gene expression and transcriptive regulators, and assign the epigenomic reguloma of the PTSP in a specific cellular way.
Our analysis revealed genetic alterations associated with PTSD in inhibitory neurons, endothelial cells and microglia and discovered genes and pathways associated with the signage of glucocorticoids, gabaergic transmission and neuroinflammation.
We also validate these findings using a specific cellular -type space transcriptomic, confirming the interruption of key genes such as SST and FKBP5.
When integrating the genetic, transcriptomical and epigenetic data, we discover the regulatory mechanisms of credible variants that interrupt the PTSD genes, including ELFN1, MAD1L1 and KCNIP4, in a specific cellular context.
Together, these findings provide an integral characterization of the specific molecular regulatory mechanisms of cells that underlie the persistent effects of the traumatic stress response in the human prefrontal cortex.
