“Reset button” for cells in the brain hints at new treatments for concussion

The way the brain responds to traumatic injuries is a matter of intense interest to medical scientists investigating concussion and its significant health impacts. Through experiments on mice in which a key set of immune cells were essentially reset after the injury, researchers have shown how a heightened sense of alert may drive some of the long-term consequences to cognitive function, and opened up new possibilities around post-concussion therapies for human sufferers.

Carried out by scientists at Ohio State University, the study centers on microglia, a type of immune cell found throughout the brain and spinal cord. The researchers have been investigating the role these cells play in concussion and inflammation, and the ways they may contribute to long-term impacts such as depression and cognitive decline.

Through previous experiments in mice, the researchers had shown that head injuries can trigger microglia to enter a sustained state of “high alert,” causing excessive inflammation in response to other threats and leading to depressive behaviors as a result. They’ve also shown that these types of complications could be reduced by using a technique called forced cell turnover on the microglia. This involves eliminating the cells then allowing them to repopulate.

“That was a proof of principle to show that a lot of the inflammation, especially in the long term, is mediated by microglia,” said senior study author Jonathan Godbout. “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.”

To explore this idea, in the new study the scientists allowed seven days for the microglia to do their healing work in mice after a brain injury. They then used an experimental drug to starve the cells of a protein they need to survive, causing more than 95 percent of them to be eliminated. They then allowed 16 days for the microglia to repopulate, and studied the mouse brains and cognitive function alongside a group of control mice.

In tasks designed to test their memory and depressive symptoms, the treated mice outperformed the control mice. Analysis of the injured brain tissue indicated reversal of some damage to neurons, lower inflammation and an improved ability of the brain to adapt to change. In a follow-up experiment designed to mimic an infection, the treated mice also exhibited less sickness compared to the controls.

The scientists believe that the cell turnover technique causes the microglia to return in a less heightened state, so they don’t respond so dramatically to challenges to the immune system. This reduces the chances of sustained, exaggerated inflammation, therefore lowering the chances of long-term impacts to cognitive health.

“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,” Godbout said. “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. There is a real connection between a head injury and mental health, and the risk doesn’t go away.”

Godbout likens the technique to “hitting the reset button” and while the breakthrough is significant, it’s not a technique that can be readily applied to humans, where temporarily clearing out of microglia isn’t feasible, according to the team. But better understanding of the role microglia play in brain injury and inflammation provides new targets for treatment, which could lessen the probability of concussion sufferers experiencing long-term impacts to mental health.

“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,” said Godbout. “Now we can focus on cellular pathways that generate chronic inflammation as a target.”

The research was published in the Journal of Neuroscience.

Source: Ohio State University

The way the brain responds to traumatic injuries is a matter of intense interest to medical scientists investigating concussion and its significant health impacts. Through experiments on mice in which a key set of immune cells were essentially reset after the injury, researchers have shown how a heightened sense of alert may drive some of the long-term consequences to cognitive function, and opened up new possibilities around post-concussion therapies for human sufferers.

Carried out by scientists at Ohio State University, the study centers on microglia, a type of immune cell found throughout the brain and spinal cord. The researchers have been investigating the role these cells play in concussion and inflammation, and the ways they may contribute to long-term impacts such as depression and cognitive decline.

Through previous experiments in mice, the researchers had shown that head injuries can trigger microglia to enter a sustained state of “high alert,” causing excessive inflammation in response to other threats and leading to depressive behaviors as a result. They’ve also shown that these types of complications could be reduced by using a technique called forced cell turnover on the microglia. This involves eliminating the cells then allowing them to repopulate.

“That was a proof of principle to show that a lot of the inflammation, especially in the long term, is mediated by microglia,” said senior study author Jonathan Godbout. “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.”

To explore this idea, in the new study the scientists allowed seven days for the microglia to do their healing work in mice after a brain injury. They then used an experimental drug to starve the cells of a protein they need to survive, causing more than 95 percent of them to be eliminated. They then allowed 16 days for the microglia to repopulate, and studied the mouse brains and cognitive function alongside a group of control mice.

In tasks designed to test their memory and depressive symptoms, the treated mice outperformed the control mice. Analysis of the injured brain tissue indicated reversal of some damage to neurons, lower inflammation and an improved ability of the brain to adapt to change. In a follow-up experiment designed to mimic an infection, the treated mice also exhibited less sickness compared to the controls.

The scientists believe that the cell turnover technique causes the microglia to return in a less heightened state, so they don’t respond so dramatically to challenges to the immune system. This reduces the chances of sustained, exaggerated inflammation, therefore lowering the chances of long-term impacts to cognitive health.

“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,” Godbout said. “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. There is a real connection between a head injury and mental health, and the risk doesn’t go away.”

Godbout likens the technique to “hitting the reset button” and while the breakthrough is significant, it’s not a technique that can be readily applied to humans, where temporarily clearing out of microglia isn’t feasible, according to the team. But better understanding of the role microglia play in brain injury and inflammation provides new targets for treatment, which could lessen the probability of concussion sufferers experiencing long-term impacts to mental health.

“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,” said Godbout. “Now we can focus on cellular pathways that generate chronic inflammation as a target.”

The research was published in the Journal of Neuroscience.

Source: Ohio State University