Without Gene, Timid Mice Turn Into Daredevils

Stefan Lovgren
for National Geographic News

November 29, 2005

Normally cautious mice can be turned into daredevils by removing a gene in their brain that regulates fear, a new study has found.

Scientists say stathmin, a gene that is normally present in high levels in a part of mammals' brains called the amygdala, controls both innate and learned fear. Switching off the gene makes a fearful mouse courageous.

The discovery provides important information on how fear is experienced and processed. It could have important implications for the study of anxiety disorders in humans, and may aid in the development of gene-based therapies to treat such diseases.

"Because stathmin controls both instinctive and learned fear, it provides genetic means to study how these two types of fear work and interact to govern our emotions," said Gleb Shumyatsky, a genetics professor at Rutgers University in New Brunswick, New Jersey.

Shumyatsky is the lead author on the study, which was reported in the November 18 issue of the science journal Cell.

Among 5,000 Genes

Stathmin had been considered a fairly obscure gene, known mostly for its role in brain development and leukemia. But scientists knew the gene functions primarily in the amygdala, a key region of the brain that acts as a major responder to danger for all mammals.

Shumyatsky and his fellow researchers, including Nobel laureate Eric Kandel of Columbia University and Vadim Bolshakov of Harvard Medical School, began their work by looking at the 5,000 genes that are highly active in the amygdala.

They zeroed in on the lateral nucleus, the portion of the amygdala that receives information from the rest of the body about fearful stimuli.

The team found two genes—gastrin-releasing peptide (GRP) and stathmin—that were much more active there than in a part of the brain not thought to be involved in fear.

The scientists first studied GRP and discovered that it controls learned, but not innate, fear. Their study of stathmin revealed that it controls both types of fear.

"Both GRP and stathmin are highly concentrated in the amygdala, and this anatomic location hinted on their potentially important role in fear," Shumyatsky said.

"Therefore, our earlier and current work provide a first glimpse at how genes may regulate instinctive and learned fear based on their anatomic locations in the neural circuits of fear."

Danger Signal

To test their theory, Shumyatsky and his colleagues bred genetically modified mice stripped of the stathmin gene. The mice were then tested to assess their inborn and learned fears.

One experiment tested an instinctive mouse fear—that of open spaces. Researchers placed the rodents on a maze-like platform that had walls on one end and an open area at the other. The mice lacking the stathmin gene were very comfortable in the open area. But the unaltered mice remained in the closed area of the maze or close to the walls.

Another experiment tested a learned fear. Scientists paired a soft sound with a mild electrical shock. Normal mice quickly learned that the sound was a danger signal, and responded by freezing. The mutant mice, on the other hand, had diminished responses.

The researchers found that the stathmin gene encodes a protein that inhibits the formation of microtubules, building blocks that help connect neurons. Without the gene, mice could not rebuild the microtubules to update their ability to recognize fear.

Anxiety Disorders

The study could help scientists understand how the inborn response to fear develops and how the brain takes fearful experiences and logs them into its memory.

The brain system that regulates fear is similar in all mammals. As a result, the new findings may have important implications for the study of anxiety disorders in humans.

The discovery may help in the development of potential drugs to treat phobias, post-traumatic stress syndrome, fear-related behaviors, and social abnormalities in autism and anxiety-related illnesses.

The research suggests that the amygdalae of people with anxiety disorders may have high levels of stathmin protein. If scientists can manipulate the production of stathmin, they could possibly change the level of anxiety.

"Our findings pave the way for future fundamental and clinical studies, which will eventually optimize the treatments for anxiety disorders," said Bolshakov, who directs the cellular neurobiology laboratory at McLean Hospital in Belmont, Massachusetts.

However, scientists are only beginning to discover all the genes that control the brain. It is likely that stathmin is just one of several genes that regulates fear.

"The gene identified in our study is likely to act together with other genes to provide an adequate fear response," Bolshakov said.

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