In mice, ‘flipping’ cells reverses cognitive and behavioral problems

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New research in mice paves the way for the development of post-concussion therapies that could prevent cognitive decline and depression, two common conditions in people who have suffered 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, the researchers knocked out these cells in injured mouse brains for a week, then left them to repopulate for two weeks.

“It’s almost like hitting the reset button,” said the study’s lead author, Jonathan Godbout, professor of neuroscience at Ohio State University College of Medicine.

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

Although it is not possible to temporarily eliminate these cells, called microglia, in humans, the results shed light on targeting pathways that could reduce the overall inflammatory profile of the brain after concussion, potentially reducing the risk of behavioral and cognitive problems long after the injury. .

“In the case of moderate brain injury, if the CT scan shows no damage, patients go home with a concussion protocol. Sometimes people come back weeks, months later with neuropsychiatric issues. C ‘is a huge problem that affects millions of people,’ said Godbout, faculty director of the Chronic Brain Injury Program at Ohio State and associate director of basic sciences at the Institute for Medical Research. behavioral.

“How do you treat this? At least in mice, by returning microglia to the brain, we had a very positive effect on their behavior, cognitive state and level of inflammation in the brain. We can now focus on the cellular pathways that generate chronic diseases, 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 a scattered impact to the head that causes brain tissue to impact against the skull. Previous research suggests that at least 75% of people who experience moderate brain injury have long-term cognitive and mental health complications.

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

“It was proof of principle to show that a lot of inflammation, especially long-term, is mediated by microglia,” he said. “But there’s 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 goes on for a long time and doesn’t fully resolve, that’s when it’s dangerous.”

In this new study, researchers waited seven days after brain injury to force microglia to turn over, giving the cells time to do their initial healing-promoting job. An experimental drug that inhibits a protein that microglia in mice need to survive was added to their food for a week, causing more than 95% depletion of microglia in their brains.

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

Other analyzes of injured brain tissue suggested that cell turnover reversed some damage to neurons caused by injury, reduced overall inflammation, and improved the brain’s ability to adapt to change. The 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 results suggest that the repopulated microglia have returned to a less “primed” state of readiness, reducing the chances of exaggerated inflammatory responses in the brain to any immune system challenge – this brain inflammation being the likely culprit behind the neuropsychiatric complications following head trauma.

“If the 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’s causing problems. Even getting a viral infection after a concussion can evolve into a cognitive or behavioral issue or amplify another part of the behavior, such as depression,” Godbout said. “There is a real link between a head injury and mental health, and the risk doesn’t go away. .

“Now we’re taking a closer look at the pathways that cause changes in microglia and targeting something specific in that pathway. This 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, a Presidential Fellowship from The Ohio State University, and the Thailand Research Fund-Royal Golden Jubilee Program.

Co-writers 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 from Ohio State, and Titikorn Chunchai and Siriporn Chattipakorn from Chiang Mai University in Thailand.

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