Scientists Face the Fear Gene

Discovery could lead to treatments for anxiety disorders, experts say

THURSDAY, Nov. 17, 2005 (HealthDay News) -- If you're scared of heights, flying or the neighbor's dog, new research suggests you can blame one particular gene.

The gene in question, called stathmin, appears to control the ability to learn and remember frightening experiences and recognize threatening situations. Such basic skills are considered critical to survival.

The discovery in mice "firms up the ground from which we can continue to explore the how, when and why of fear conditioning," said Mahzarin Banaji, a Harvard University professor of psychology.

Banaji, who was not involved in the study, said "it gives us new confidence to explore how human beings may both over-respond and under-respond with fear to events in their world. And it creates a stronger bond between the genetics of fear and the psychological and social consequences of fear learning."

Aiming to help people who suffer from anxiety disorders, a research team from Harvard Medical School, Columbia University, Rutgers University, and the Albert Einstein College of Medicine found that mice genetically engineered to go without stathmin had a reduced ability to react with anxiety in situations in which they would normally have been expected to be fearful.

The finding may open doors to anti-anxiety treatments that target the stathmin gene.

"This is the tip of the iceberg, and these things take a lot of time, but I think there's no question that this has the potential for therapy," said 2000 Nobel prizewinner and study co-author Dr. Eric Kandel, of the Howard Hughes Medical Institute Center for Neurobiology and Behavior at Columbia University in New York City.

"There aren't good drugs for the treatment of anxiety, and it's possible that this will provide a new set of targets for all kinds of problems, ranging from stage fright and phobias to post-traumatic stress disorders," Kandel added.

Stathmin genes are found in high levels in an almond-shaped section of the brain known as the amygdala, a center for the regulation of emotions.

In a series of experiments with mice, Kandel and his colleagues found that the normal presence of stathmin genes controlled a process of cellular breakdown and rebuilding that gives the brain the necessary flexibility to rapidly form neural connections critical to normal learning and memory processes.

Reporting in the Nov. 18 issue of Cell, the researchers found this process was both overactive and less flexible in mutant mice bred without stathmin. This deficiency stripped their brains of critical neural "scaffolding," and short-circuited their ability to learn new fear or to rely on instinctive fear when placed in typically anxiety-inducing situations.

For example, stathmin-deficient mice were less likely than normal mice to freeze in fear 24 hours after being exposed to a harmless sound previously linked to an electric shock.

As well, mutant mice showed less immediate anxiety than normal mice when given the option to enter and explore unprotected open areas in a series of maze experiments.

However, mice missing stathmin were not found to be any less sensitive to pain than normal mice. In addition, the mutant mice were as adept as their normal counterparts at spatial reasoning and movement.

The researchers believe the animal study may be a model for research into drugs to help control anxiety disorders.

But this type of research faces hurdles, too. According to the investigators, previous studies have uncovered at least one more amygdala-centered fear gene, and anxiety disorders are likely to have complex molecular origins. Research in this area could mean years spent developing highly tailored drugs aimed at a host of disorders, they said.

"Because our findings suggest that anxiety is not one disorder but a number of disorders with unique molecular characteristics, pharmacological approaches for the treatment of different subclasses of anxiety disorders will have to be different," said study co-author Vadim Bolshakov, an associate professor and director of the Cellular Neurobiology Laboratory at the McLean Hospital Department of Psychiatry at Harvard Medical School. "But identifying a gene that controls fear behavior is a major discovery."

"This is really exciting because what we've needed in psychiatry in general are new targets," added Dr. Thomas R. Insel, director of the National Institute of Mental Health. "What we haven't known are the key players in the anatomy, and here's one we haven't heard of before, and it beautifully labels what we know of the anatomy of anxiety. So this is going to open up a whole area for investigation."

More information

For more on anxiety disorders, check out the The National Institute of Mental Health.

SOURCES: Eric Kandel, M.D., Howard Hughes Medical Institute Center for Neurobiology and Behavior, Columbia University, New York City; Vadim Bolshakov, Ph.D., associate professor and director, Cellular Neurobiology Laboratory, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, Mass.; Thomas R. Insel, M.D., director, National Institute of Mental Health, Bethesda, Md.; Mahzarin Banaji, Ph.D., professor, psychology, Harvard University, Cambridge, Mass.; Nov. 18, 2005, Cell
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