Lessons about traumatic brain injury

Faced with news of suicides and brain damage in former professional football players, geneticist Barry Ganetzky bemoaned the lack of model systems for studying the insidious and often delayed consequences linked to head injuries.

Then he remembered an unexplored observation from nearly 40 years ago: a sharp strike to a vial of fruit flies left them temporarily stunned, only to recover a short time later. At the time he had marked it only as a curiosity.

Now a professor of genetics at the University of Wisconsin - Madison, Ganetzky is turning his accidental discovery into a way to study traumatic brain injury (TBI). He and David Wassarman, a UW professor of cell and regenerative biology, report this week (Oct. 14) in the Proceedings of the National Academy of Sciences on the first glimpses of the genetic underpinnings of susceptibility to brain injuries and links to human TBI.

TBIs occur when a force on the body jostles the brain inside the head, causing it to strike the inside of the skull. More than 1.7 million TBIs occur each year in the United States, about one-third due to falls and the rest mainly caused by car crashes, workplace accidents, and sports injuries. TBIs are also a growing issue in combat veterans exposed to explosions.

In many cases, the immediate effects of TBI are temporary and may seem mild - confusion, dizziness or loss of coordination, headaches, vision problems. But over time, impacts may lead to neurodegeneration and related symptoms, including memory loss, cognitive problems, severe depression, or Alzheimer's-like dementia. Together TBIs cost tens of billions of dollars annually in medical expenses and indirect costs such as lost productivity.

Though TBIs can be classified from "mild" to "severe" based on symptoms, there is a poor understanding of the underlying medical causes.

"Unlike many important medical problems - high blood pressure, cancer, diabetes, heart disease - where we know something about the biology, we know almost nothing about TBI," Ganetzky says. "Why does a blow to the head cause epilepsy? Or how does it lead down the road to neurodegeneration? Nobody has answers to those questions - in part, because it's really hard to study in humans."

Enter the fruit fly. The fly brain is encased in a hard cuticle analogous to the skull, and the basic mechanisms affecting nervous system function are the same in flies and mammals. In the new study, Ganetzky and Wassarman describe a way to reproducibly inflict traumas that seem to mimic the injuries and symptoms of human TBI.

"Now we have a system where we can look at the variables that are the inputs into TBI and determine the relative contributions of each to the pathological outcomes. That's the real power of the flies," says Wassarman.

As with humans, few flies die from the immediate impact. Afterward, though, the treated flies show many of the same physical consequences as humans who sustain concussions or other TBIs, including temporary incapacitation, loss of coordination and activation of the innate immune response in the short term, followed by neurodegeneration and sometimes an early death.