Extreme gene pin-pointed

One teenager likes to snowboard off a cliff. Another prefers to read a book and wouldn't think of trading places. Why these differences exist is a mystery, but for the first time researchers have identified a possible genetic explanation behind risk-seeking behavior.

Scientists at Fred Hutchinson Cancer Research Center have found that a specific neurodevelopmental gene, called neuroD2, is related to the development of an almond-shaped area of the brain called the amygdala, the brain's emotional seat. This gene also controls emotional-memory formation and development of the fear response, according to research led by James Olson, M.D., Ph.D., associate member of the Clinical Research Division at the Hutchinson Center.

The findings will be published in the early online edition of the Proceedings of the National Academy of Sciences the week of Sept. 26.

Olson and colleagues studied mice with a single copy of the neuroD2 gene and found they had an impaired ability to form emotional memories and conditioned fear.

"Most of us are familiar with the fact that we can remember things better if those memories are formed at a time when there is a strong emotional impact -- times when we are frightened, angry or falling in love," he said. "That's called emotional-memory formation. The amygdala is the part of the brain that is responsible for formation of emotional memory."

In the brain's early development, the neuroD2 gene encodes the neuroD2 protein to transform undifferentiated stem cell-like cells into neurons, or brain cells. Under the microscope, certain areas of the amygdala were absent in mice with no neuroD2 gene. In mice with just one copy of neuroD2, researchers also found fewer nerve cells in the amygdala.

Researchers conducted experiments on mice with a single copy of the neuroD2 gene to test the theory that only having one copy of the gene impacts emotional learning and the development of traits such as fear and aggression. Long-term behavioral studies of mice with no neuroD2 genes were not possible because these mice die within a few weeks of birth.

In one experiment, mice were exposed to an adverse stimulus coupled with a non-adverse stimulus, a tone followed by a mild foot shock. Normal mice crouch down and stop moving the next time they hear the tone, a physiologic response that indicates they expected a shock. The mice remembered the experience. However, those with a single copy of the neuroD2 gene did not respond to the tone like the normal mice did, researchers found. These mice did not freeze their movements as often in anticipation of the mild shock.

To assess the level of unconditioned fear in mice with a single copy of the neuroD2 gene, researchers put them into a situation that would elicit a fear response in normal mice. They used a maze elevated 40 centimeters above a tabletop where mice had the option to walk along narrow, unprotected walkways or arms with protective walls. Half of the time the neuroD2-deficient mice chose the unprotected arms, whereas the normal mice almost always chose the protected arms, Olson said.

"All of this matches very well with previous observations that the amygdala is responsible for fear, anxiety and aggression," said Olson. "Now we're seeing that the neuroD2-deficient mice, when compared to normal littermates, show a profound difference in unconditioned anxiety levels as well as their ability to form emotional memories."

Olson noted that the dosage of neuroD2, one copy versus the normal two copies, was important for how much fear, anxiety and aggression the mice displayed.

"These findings are new to science," said Olson, who is also an associate professor in pediatrics at the University of Washington School of Medicine. "The contribution we have made is showing that neuroD2 is related to the development of the amygdala. This is the first time that a specific neurodevelopmental gene has been related to these emotional activities in the brain."

Further research is needed that one day could explain why some people react the way they do to fear, or why they take risks, Olson said.

"The question is, are there differences in the neuroD2 gene-coding sequence or differences downstream of the neuroD2 pathway during brain development that could affect either psychiatric or emotional functions in humans? It's a completely unexplored question; it is the immediate next question you would go to if you want to understand how this gene impacts human behavior."

The National Institutes of Health and the Burroughs Wellcome Career Award in the Biomedical Sciences funded the research.