Study Identifies Gene In Mice That May Control Risk-taking Behavior In Humans

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

The findings will be published in the early online edition of theProceedings of the National Academy of Sciences the week of Sept. 26.Olson and colleagues studied mice with a single copy of the neuroD2gene and found they had an impaired ability to form emotional memoriesand conditioned fear.

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

In the brain's early development, the neuroD2 gene encodes the neuroD2protein to transform undifferentiated stem cell-like cells intoneurons, or brain cells. Under the microscope, certain areas of theamygdala were absent in mice with no neuroD2 gene. In mice with justone copy of neuroD2, researchers also found fewer nerve cells in theamygdala.

Researchers conducted experiments on mice with a single copy of theneuroD2 gene to test the theory that only having one copy of the geneimpacts emotional learning and the development of traits such as fearand aggression. Long-term behavioral studies of mice with no neuroD2genes were not possible because these mice die within a few weeks ofbirth.

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

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

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

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

"These findings are new to science," said Olson, who is also anassociate professor in pediatrics at the University of WashingtonSchool of Medicine. "The contribution we have made is showing thatneuroD2 is related to the development of the amygdala. This is thefirst time that a specific neurodevelopmental gene has been related tothese emotional activities in the brain."

Further research is needed that one day could explain why some peoplereact the way they do to fear, or why they take risks, Olson said. "Thequestion is, are there differences in the neuroD2 gene-coding sequenceor differences downstream of the neuroD2 pathway during braindevelopment that could affect either psychiatric or emotional functionsin humans? It's a completely unexplored question; it is the immediatenext question you would go to if you want to understand how this geneimpacts human behavior."