Bench to Bedside | April 2016

Restoring Balance in the Brain After Concussion

As he falls to the ground from a football tackle, a boy’s brain shakes in its skull from the impact. He begins to experience dizziness and balance problems in the hours and days that follow, and a visit to his doctor confirms that he has a concussion, a mild traumatic brain injury.

The physician explains to the boy’s parents to be on the lookout during his recovery process for mood disruptions and cognitive problems such as difficulty concentrating, learning, and remembering. While these are common concussion symptoms that can be seen outwardly, much less is known about what is happening inside the brain during and after concussions.

Scientists at The Children’s Hospital of Philadelphia want to zoom in to better understand the basic science of how and why these effects occur. Their goal is to develop targeted treatments that could someday accelerate recovery and even prevent some clinical symptoms and damage.

Akiva Cohen, PhD, an investigator at CHOP and research associate professor of Anesthesiology and Critical Care at the Perelman School of Medicine at the University of Pennsylvania, is at the forefront of discovery of the neurobiology of brain injury. His lab has focused on a variety of brain regions to describe the cellular and molecular nature of impairment in emotional stability, working memory, and spatial memory, among other functions.

In a new study funded by the National Institutes of Health, Dr. Cohen and colleagues are testing whether a specific set of neurons implicated in cognitive impairment could be a useful target for future therapies to restore cognitive function after concussion.

“We are looking at specific neurons in the hippocampus that are frequently damaged by traumatic brain injury and are also important in learning and memory,” said Brian Johnson, PhD, a research associate in Dr. Cohen’s lab who leads this project.

In general, brain injuries cause shifts in the complex and delicate balance between “stop” and “go” signaling systems for activation and inhibition in different directions in different regions of the brain. The study team is focusing on CCK positive interneurons from the CA1 region of the hippocampus, which are part of the brain’s “stop” system. Like other “stop” neurons, when activated, they release the chemical GABA to signal other neurons to shut down their activity. These particular neurons shut down processes involved in learning and memory.

In the new study, Dr. Cohen and Dr. Johnson are working with an unusual model of brain injury in mice. The CCK interneurons in the hippocampus region CA1, and no other cells in the body, have been genetically altered to be responsive to a drug they can use to experimentally silence these cells’ “stop” signal without affecting the animal in any other way. (They are building this specialized model with a technique called designed receptors exclusively activated by designed drugs, or DREADDS, in which a viral vector implants only these specific cells with a receptor channel for the desired drug.)

With this experimental setup, the team can proceed with classic behavioral experiments — seeing how well or poorly the animals learn or remember to avoid a negative stimulus when their CCK interneurons are active, compared to when researchers have injected the drug intended to restore normal brain function by deactivating these cells.

“We are using behavior as a bioassay,” Dr. Cohen said. “If we take these neurons that are altered after brain injury and we make them quiescent so they can’t release GABA, will we mitigate the problem or even restore the hippocampal effects to normal?”

The team will cross-check these experiments with in vitro investigations to see if adding the designed drug to the modified CCK interneurons does indeed restore normal outputs of other cells in the hippocampus. If successful, these findings would point toward a need for further studies to find ways to target these neurons in future clinical therapies for cognitive impairment resulting from concussion.


www.research.chop.edu

Produced by The Children’s Hospital of Philadelphia Research Institute.

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