Researchers identify the brain’s on-off switch for fear

Harvard researchers at McLean Hospital have identified a particular protein in the brain that serves as a trigger for the body’s innate fear response. This discovery suggests a potential target for the development of new medications aimed at treating anxiety, particularly generalized anxiety disorder, a condition that afflicts millions.

In a paper published in the current issue of Cell, Vadim Bolshakov, director of the Cellular Neurobiology Laboratory at McLean and associate professor of psychiatry at Harvard Medical School, and his colleagues report that mice lacking the transient receptor potential channel 5 (TRPC5) gene showed diminished fear levels in response to stimuli that they normally would fear innately, compared with normal mice.

“This is the first demonstration that this protein is implicated in fear-related behaviors,” said Bolshakov. “By identifying this trigger, we now have a greater likelihood of developing medications that will turn off the fear switch in the brain, and therefore significantly reduce anxiety.”

The study is the collaborative effort of Bolshakov’s laboratory and that of David Clapham, the Aldo R. Castanada Professor of Cardiovascular Research at Children’s Hospital Boston, and professor of neurobiology and pediatrics at HMS.

In the study, the researchers looked at the neurons in the amygdala of mice lacking the TRPC5 gene and discovered that they did not fire as well as those in the brains of normal mice. At the same time, neurons in the same region of the brain of the mice missing the TRPC5 gene were not as sensitive to the neuropeptide cholecystokinine, commonly released in the brain during situations of innate fear or anxiety, explained Bolshakov.

According to Clapham, though the identified protein is found throughout the brain, it is highly concentrated in the amygdala, the region of the brain implicated in emotional responses.
“Many of our emotional responses are integrated in and emerge from the amygdala, including learned and innate fear,” said Clapham. “What we found with our work was that the mice who did not have the TRPC5 protein no longer showed fear-related behaviors when faced with situations that would typically cause them anxiety.”

Bolshakov explained that the mice lacking the gene, for example, would show no fear in exploring places where they normally would fear to tread. The mice also were not as fearful of new social interactions with other mice. 

“This is the first time this gene has been implicated in anxiety-related behaviors,” he said. “We have learned something at the level of fundamental science, but, at a practical level, it suggests some new potential molecular targets for treatments, some new kinds of treatments.”

Perhaps a new drug could be developed to block the function of this protein or the pathway through which the protein travels in the brain cells, he said.

“This could give us a nice tool with which to treat anxiety,” he added.

Generalized anxiety disorder is a condition characterized by chronic anxiety and/or exaggerated worry and tension, even when there is little or nothing obvious to provoke it. The condition affects an estimated 6.8 million Americans, and about twice as many women as men, according to the National Institute of Mental Health.