'Resetting' the injured brain offers clues for concussion treatment
In mice, 'turning over' cells reverses cognitive, behavior problems

Date:
May 2, 2022
Source:
Ohio State University
Summary:
New research in mice raises the prospects for development of post-
concussion therapies that could ward off cognitive decline and
depression, two common conditions among people who have experienced
a moderate traumatic brain injury.



FULL STORY ==========================================================================
New research in mice raises the prospects for development of
post-concussion therapies that could ward off cognitive decline and
depression, two common conditions among people who have experienced a
moderate traumatic brain injury.


==========================================================================
The study in mice clarified the role of specific immune cells in the
brain that contribute to chronic inflammation. Using a technique called
forced cell turnover, researchers eliminated these cells in the injured
brains of mice for a week and then let them repopulate for two weeks.

"It's almost like hitting the reset button," said senior study author
Jonathan Godbout, professor of neuroscience in The Ohio State University College of Medicine.

Compared to brain-injured mice recovering naturally, mice that were
given the intervention showed less inflammation in the brain and fewer
signs of thinking problems 30 days after the injury.

Though temporarily clearing away these cells, called microglia, in
humans isn't feasible, the findings shed light on pathways to target that
could lower the brain's overall inflammatory profile after a concussion, potentially reducing the risk for behavioral and cognitive problems long
after the injury.

"In a moderate brain injury, if the CT scan doesn't show damage, patients
go home with a concussion protocol. Sometimes people come back weeks,
months later with neuropsychiatric issues. It's a huge problem affecting millions of people," said Godbout, faculty director of Ohio State's
Chronic Brain Injury Program and assistant director of basic science in
the Institute for Behavioral Medicine Research.



==========================================================================
"How do you treat that? At least in mice, by turning over the microglia
in the brain we had a very positive effect on their behavior, cognitive
status and level of inflammation in the brain. Now we can focus on
cellular pathways that generate chronic inflammation as a target."
The research is published online in the Journal of Neuroscience.

About 85% of traumatic brain injuries are similar to the type of
concussion examined in this study, involving dispersed impact to the head
that causes brain tissue to bump against the skull. Previous research
suggests that at least 75% of people who experience a moderate brain
injury have long-term mental health and cognitive complications.

Godbout's lab previously linked depressive symptoms in mice to
microglia's sustained "high alert" status after a head injury, which
causes the cells to overreact to later challenges to the immune system
and become excessively inflammatory. In a more recent study in mice,
his team showed that forced turnover of microglia before a head injury
could reduce later neuropsychiatric complications.

"That was a proof of principle to show that a lot of the inflammation, especially in the long term, is mediated by microglia," he said. "But
there is an acute phase of inflammation -- you want to initiate that
repair process.

There's a positive to that early inflammatory response in the brain or
spinal cord. If it lasts a long time and doesn't fully resolve, that's
when it's dangerous." In this new study, researchers waited for seven
days after the brain injury to force the turnover of microglia, giving
the cells time to carry out their work promoting initial healing. An experimental drug that inhibits a protein that microglia in mice need
for survival was added to their food for a week, resulting in depletion
of over 95% of microglia in their brains.



========================================================================== After allowing 16 days for the microglia to repopulate, researchers
compared the intervention mice to injured mice that recovered without
the cell turnover treatment. The intervention mice performed better than control mice on tasks testing their memory and depressive symptoms.

Further analyses of injured brain tissue suggested the cell
turnover reversed some injury-related damage to neurons, lowered
overall inflammation and improved the brain's ability to adapt to
change. Researchers also injected mice with a molecule that triggers an
immune response to mimic an infection, and found that sickness behavior
was lower in the intervention mice.

Godbout said these combined findings suggest that the repopulating
microglia returned in a less "primed" state of readiness, lowering
chances for a lifetime of exaggerated inflammatory responses in the
brain to any challenge to the immune system -- that brain inflammation
being the likely culprit behind the neuropsychiatric complications that
follow a head injury.

"If microglia in the human brain don't return to normal and chronic inflammation persists after a head injury, it's not just a secondary
brain injury that causes problems. Even getting a viral infection
after concussion recovery can progress into a cognitive or behavioral
issue or amplify some other part of behavior, like depression," Godbout
said. "There is a real connection between a head injury and mental health,
and the risk doesn't go away.

"Now we're looking more closely at the pathways that cause changes in microglia, and targeting something specific in that pathway. That is
a way forward." This work was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Institute of Dental and Craniofacial Research, an Ohio State University Presidential Fellowship and the Thailand Research Fund-Royal
Golden Jubilee Program.

Co-authors include Chelsea Bray, Kristina Witcher, Dunni
Adekunle-Adegbite, Michelle Ouvina, Mollie Witzel, Emma Hans, Zoe Tapp, Jonathan Packer, Ethan Goodman, Fangli Zhao, Shane O'Neil, John Sheridan,
Olga Kokiko-Cochran and Candice Askwith, all of Ohio State, and Titikorn Chunchai and Siriporn Chattipakorn of Chiang Mai University in Thailand.


========================================================================== Story Source: Materials provided by Ohio_State_University. Original
written by Emily Caldwell. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Chelsea E. Bray, Kristina G. Witcher, Dunni Adekunle-Adegbite,
Michelle
Ouvina, Mollie Witzel, Emma Hans, Zoe M. Tapp, Jonathan Packer,
Ethan Goodman, Fangli Zhao, Titikorn Chunchai, Shane O'Neil,
Siriporn C Chattipakorn, John Sheridan, Olga N. Kokiko-Cochran,
Candice Askwith, Jonathan P. Godbout. Chronic Cortical Inflammation,
Cognitive Impairment and Immune Reactivity Associated with
Diffuse Brain Injury are Ameliorated by Forced Turnover of
Microglia. The Journal of Neuroscience, 2022; JN-RM-1910-21 DOI:
10.1523/JNEUROSCI.1910-21.2022 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220502170928.htm

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