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December 1, 2005


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HARVARD GAZETTE ARCHIVES

Vadim Bolshakov, Ryong-Moon Shin and Keith Tully
Vadim Bolshakov (right) turned normally timid mice into daredevils by 'knocking out' one of their genes. The knockout rodents were more willing to explore unknown places and less intimidated by shocks and loud noises. With Bolshakov are research fellows Ryong-Moon Shin (left) and Keith Tully. (Staff photo Rose Lincoln/Harvard News Office)

Researchers find a gene for fear

May lead to new anxiety drugs

By William J. Cromie
Harvard News Office

A team of researchers from Harvard, Columbia, and Rutgers universities has found the seat of fear. It's located in a pea-sized area deep in the brain of all mammals, from gerbils, to lions, to humans. And it's involved in both inborn fear and the dread we acquire from dealing with people and things that hurt us.

The scientists already knew that fear forms in the amygdala (a-mig-da-la), an almond-shaped mass of gray matter. But a closer look revealed the presence of a gene that produces a protein known as "stathmin," a stimulant of fear and anxiety. The scientists' investigations were done with mice because they involved genetic engineering and surgical slicing of the brain.

"This is the first time it has been shown that the protein stathmin is linked to brain circuits that register both inborn alarm and acquired memories of fear," says Vadim Bolshakov of Harvard Medical School and Harvard-affiliated McLean Hospital. "Because it is so essential for survival, memory for fear is easily established, very resistant to extinction, and normally lasts for a lifetime."

The finding provides a deeper understanding of how learning and memory take place. It also could lead to new treatments for a variety of mental disorders including generalized anxiety, panic, phobias, obsessive-compulsive disorder, and the post-traumatic stress disorder that is being brought back from the battlefields of Iraq and Afghanistan.

Besides Bolshakov and his colleagues at McLean Hospital, the research team involved Eric Kandel and colleagues at Columbia University, and Gleb Shumyatsky and colleagues at Rutgers. Kandel won the 2000 Nobel Prize in medicine. They reported their results in the November issue of the journal Cell.

Overcoming anxiety

Once you find a protein like stathmin, you have to prove that it does what you think it does. One sure way is to remove, or knock out, the gene behind the protein and test the reaction of the mice in fearful situations.

Both the "knockouts" and a comparison group of normal mice received a mild electric shock to their feet, a jolt accompanied by a loud sound. The rodents quickly associate the sound and the shock. When they heard the sound they froze in expectation. But mice without the stathmin gene froze for a significantly shorter time than the normal ones.

Mice placed in new surroundings naturally avoid the most open or exposed areas. But those uninhibited by stathmin spent more time exploring open, unknown spaces.

Other tests were run to rule out the possibility that the gene loss left the knockouts with less pain sensitivity, enhanced locomotion, or less intelligence. Only one conclusion remained: Without the restraining effects of stathmin, mice display less fear in response to both learned (shock) and natural (open space) situations.

The fact that human brain circuits involved in fear are believed to be similar to those of mice suggests that stathmin-knockout mice can be used to further explore innate and learned dread in humans, the researchers note. "Individual human differences in inborn fear levels, as well as the ability to acquire fear, might result from different levels of gene expression," Bolshakov points out. "Thus it should be possible to determine each person's predisposition to the development of different anxiety states." In other words, how adverse an individual would be to bullying by classmates, the stress of combat, or family tragedies.

However, Bolshakov cautions, "It's important to realize that stathmin is not the only gene whose activity might regulate learned and inborn fear behaviors. The mechanisms which we have identified in our study are likely to act in concert with other mechanisms and other genes to achieve the highly efficient and lasting system of fear response."

Human questions

Among the possibilities opened up by this discovery is the opportunity to compare levels of stathmin activity in humans with different forms of anxiety. "I'm sure that medical researchers and drug companies are going to pursue this line of study, and that we'll be hearing a lot about that in the next few years," Bolshakov says.

As director of the Cellular Neurobiology Laboratory at McLean Hospital, however, he will be traveling another road. "I am personally interested in more fundamental work that could lead to better understanding of the brain changes that accompany learning and memory."

According to a long-held theory, learning takes place and memories form when the same signals travel repeatedly between specific brain cells. Communication between these cells grows stronger with repetition. Eventually, these cells no longer need to be stimulated by an outside source such as a familiar landscape or input from a teacher. "Our study of the stathmin gene and fear," notes Bolshakov, "is the first time anyone has been able to correlate a change in specific gene activity with a change in brain circuit function and with behavior, i.e., acquiring a memory."

Being born with fear and acquiring memories of it from dangerous situations is so important for survival, it's something that must have been around for millions of years. Birds, as well as snakes and other reptiles, boast amygdalae. Fish also possess a brain structure that seems to function like one. "It appears that all these animals could be conditioned to fear, and that they will demonstrate fear response, such as an increased heart rate," Balshakov says.







Copyright 2007 by the President and Fellows of Harvard College