How PTSD Disrupts Brain Cell Communication

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