[Paleopsych] NYT: Timid Mice Made Daring by Removing One Gene

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Timid Mice Made Daring by Removing One Gene
http://www.nytimes.com/2005/11/18/science/18brave.html
[Thanks to W. David for this.]

    By [3]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."