Anxiety prone? Brain scans of people with a particular genetic variant reveal a hyperactive amygdala (orange area, right) and an underactive prefrontal cortex (blue area, left).

F. Soliman et al., Science

A Frightful Genetic Twist

If you have a hard time shaking your phobias--whether they be of spiders or confined spaces--you may have a genetic quirk that alters your brain's fear circuitry. New research that links a small DNA substitution with abnormal brain activity and fear responses represents a small but encouraging step, experts say, toward understanding how genes may contribute to anxiety disorders.

Although many mental disorders run in families, tracking down the genes responsible has been tremendously difficult. It's even harder to show how those genes interfere with brain function. Complicating matters further is the uncertainty involved in assessing the mental state of mice, researchers' animal of choice for studying the genetics of psychiatric disorders.

The new study, published online today in Science, examines the role of the gene for brain-derived neurotrophic factor (BDNF). Several years of research have implicated this gene and the growth factor it encodes in mood disorders. Up to 30% of Caucasians have an alteration in the BDNF gene that causes the amino acid methionine to be substituted for valine at a particular place in the protein.

In 2006, a team led by Francis Lee at Weill Cornell Medical College in New York City reported that genetically engineered mice with this so-called Met substitution appeared to be more anxious than other mice. But studies with humans have been inconclusive, says BJ Casey, a neuroscientist at Cornell who collaborated with Lee on the new study. Having the Met variation doesn't doom someone to a life of anxiety, Casey says, but it may exert a subtle influence.

To investigate, Lee, Casey, and other colleagues led by graduate student Fatima Soliman trained both mice and people to associate either a tone (for the mice) or a colored square (for the humans) with a mild shock. They saw no difference between Met carriers and others on this standard test of fear learning: All mice froze up in fearful anticipation when they heard the tone, and all people responded to the colored square with increased skin conductance, a commonly used measure of intense emotion.

However, it was a different story when the researchers trained their human and rodent subjects to unlearn their fear. In a lab version of exposure therapy--whereby subjects are forced to confront their fears as a way to overcome them--the researchers repeatedly played the tone or displayed the square without pairing it with a shock. With time, the mice stopped freezing up and the people no longer exhibited a slight increase in skin conductance. But in both species, individuals with the Met variation maintained more of their fear responses after training.

In addition, brain-imaging experiments with the human subjects found that when Met carriers initially learned the association between shock and tone, a key fear center in their brains, the amygdala, became hyperactive. Yet the human Met carriers also exhibited impaired activity in the prefrontal cortex, a region important for extinguishing fearful associations.

To Casey, the findings suggest that people with the Met variation who suffer from phobias or other anxiety disorders may not respond as well as others to exposure therapy. Personalized medicine is still a long way off for psychiatric disorders, she says, but work on BDNF and other genes may eventually enable psychiatrists to use genetic profiles to help choose the best treatment for a given patient.

"It's a remarkable study because it shows that through genetics we can translate findings across humans and animal models developed to study human disease," says Ahmad Hariri, a neuroscientist at Duke University in Durham, North Carolina. Although it's still not clear whether the Met variant is a risk factor for clinical anxiety disorders in humans, Hariri says, the new study helps establish that this variant "does in fact bias the mechanisms that help an individual respond to stress."