Timid Mice Made Daring by Removing One Gene

By BENEDICT CAREY

Scientists working with mice have found that by removing a single gene they can turn normally cautious animals into daring ones, mice that are more willing to explore unknown territory and less intimidated by sights and sounds that they have learned can be dangerous.

The surprising discovery, being reported today in the journal Cell, opens a new window on how fear works in the brain, experts said.

Gene therapy to create daredevil warriors is likely to remain the province of screenwriters, but the new findings may help researchers design novel drugs to treat a wide array of conditions, from disabling anxiety in social settings to the sudden flights of poisoned memory that can persist in the wake of a disaster, an attack or the horror of combat.

The discovery may well prove applicable to humans, the experts said, because the brain system that registers fear is similar in all mammals. Moreover, the genetic change did not appear to affect the animals' development in other ways.

"Potential clinical applications could be quite important" for people with "fear-related mental disorders," said Dr. Gleb Shumyatsky, an assistant professor of genetics at Rutgers, who led a team that included investigators from Columbia, Harvard, the Howard Hughes Medical Institute and the Albert Einstein College of Medicine.

Brain scientists who were not involved in the study said the study's finding was unexpected.

"The way I see it, there are three types of studies in science: one that moves a theory along, one that closes it and another that opens a new door altogether," said Dr. Thomas Insel, director of the National Institute of Mental Health, which helped finance the research. "This one opens a new chapter, introducing an entirely new molecular candidate for the study of anxiety, and we're going to be hearing a lot about it in the next 10 years."

The researchers found the fear-related gene by analyzing brain tissue, in particular the tiny prune-shaped region called the amygdala, which previous studies had shown to be especially active when animals and humans were afraid or anxious. They found that a protein called stathmin, produced by the stathmin gene, was highly concentrated in the amygdala but hard to detect elsewhere in the brain.

Using genetic engineering, the scientists removed the gene from mice and bred a line of the animals, all missing the same gene. Those animals developed into normal adults, as far as the researchers could tell, and learned as ably on standard tests as a group of normal mice.

In one test, they learned to expect a small shock to their feet after hearing a loud tone.

"They looked normal," Dr. Shumyatsky said. "They weren't stupid. They would run away if you tried to pick them up."

But when presented with the same loud tone 24 hours later, the genetically engineered mice froze in place - a standard measure of learned fear - only about 60 percent as long as the control group.

When left alone on an unfamiliar white surface, the engineered mice also spent about twice as long exploring as did the normal mice. This "open field" test is standard measure of innate caution.

To be sure that it was the gene change and not some other quality that explained the differences, the researchers tested hearing and pain sensitivity in the altered mice. Both were normal.

In the paper, the authors suggest that stathmin, the protein that the engineered mice were missing, may help brain cells form new memories in the amygdala, where unconscious fears appear to be stored. (Conscious memories are filed elsewhere.)

In theory, a drug that inhibits the activity of stathmin could prevent or slow that process. That, in turn, might blunt the impact of traumatic experiences in people who are vulnerable to disabling memories of those experiences.

Reducing stathmin activity in the amygdala might also allow people to overcome innate or learned anxieties. Dr. Shumyatsky said doctors already had a drug that acts on the same brain molecules as stathmin does; it is Taxol, a cancer drug.

Taxol works throughout the brain, however, and not exclusively in the amygdala, which the new study suggests is the best target.

"It would be very interesting to study things like this, but it is still very early," Dr. Shumyatsky said. "This study is only a first step."

Still, it is a step that could take the study of fear in a new direction. In an e-mail message, Dr. Joseph LeDoux, a neuroscientist at New York University wrote: "While we are a long ways away, it is possible in the future that we will be able to identify amygdala-specific genes that can be used to play a role in amygdala-specific drug therapy. Studies like this are the kind we need in order to get to this point."

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