Brain’s never-before-seen cellular response to concussions could lead to therapy

Dec. 11, 2013 The lifelong fallout of a concussive brain injury is well-documented. A blow to the head -- whether it comes from an NFL tackle, a battlefield explosion or a fall off a ladder -- can cause brain damage responsible for a debilitating degree of memory loss, mood swings, seizures and more.

And though the blunt instrument that inflicts such damage is typically known, the cellular mechanisms that inflict such trouble have so far remained a mystery.

Now, a biology student at Stanford and researchers at the National Institutes of Health have devised a method for observing the immediate effects of a mild traumatic brain injury (TBI) in real time in mice. The work has revealed how individual cells respond to the injury and has helped the researchers suggest a possible therapeutic approach for limiting brain damage in humans.

The results were published online in Nature on Dec. 8.

The bulk of direct research concerning the physiological effects of TBIs is conducted post mortem. Scientists dissect a deceased patient's tissue to learn the full extent of the injury and what types of brain cells were damaged or killed.

But very little is known about what happens at the cellular level in the first hours after an injury, which has hindered the development of therapies that could prevent such damage from occurring in the first place.

For the past several years, Theo Roth, a senior majoring in biology at Stanford, has spent his summers and other academic breaks working in Dorian McGavern's lab at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. In that time, Roth and other members of McGavern's research group designed a model in which they could inflict a specific injury to a mouse's brain and use an intracranial microscope to image individual cells, starting at five minutes after the injury.

"We can actually see how all the cell populations there react dynamically," said Roth, the first author on the research paper. "Then, knowing what the cells do -- how they change function and morphology -- we could piece together what their roles are and how they interact, and then what types of interventions might be relevant."

Evidence in humans

The brain's first line of defense is called the meninges, a thin layer of tissue that wraps the brain and creates a nearly impermeable barrier to harmful molecules. At the direct site of the injury, however, Roth found that the meninges can become damaged, tearing blood vessels and causing hemorrhaging. As cells in the meninges and other nearby tissues die, their toxic innards -- in particular, molecules called reactive oxygen species (ROS) -- can leak through the meninges onto healthy brain cells.

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Brain's never-before-seen cellular response to concussions could lead to therapy