High anxiety. Anxious monkeys show elevated activity in the amygdala (left) and anterior hippocampus (right), but the effects of heredity seem to act more on the hippocampus.

J. Oler et al., Nature, 466 (12 August 2010)

The Makings of an Anxious Temperament

In children, an anxious temperament can be a warning sign. Kids who are painfully shy and nervous are more prone to anxiety disorders and depression later in life, and they're more likely to self-medicate with alcohol and other drugs. But what causes a child to have an anxious temperament in the first place? A new study with monkeys finds that an anxious temperament is partly heritable and that it's tied to a particular brain region involved in emotion.

Children with an anxious temperament often freeze up when they meet a stranger or encounter a social situation they perceive as threatening, says Ned Kalin, a psychiatrist and neuroscientist at the University of Wisconsin, Madison. Kalin and his colleagues have found that some young monkeys do much the same thing. When a human "intruder" enters the room and approaches their cage without making eye contact, these anxious youngsters freeze in place and grow quiet. Their stress hormone levels spike, too.

In the new study, published in the 12 August issue of Nature, Kalin and colleagues studied 238 young rhesus monkeys from a family of more than 1500 lab-raised monkeys with well-documented pedigrees. By analyzing the family connections among the young monkeys, which ranged from siblings to distant cousins, the researchers found that an anxious temperament was partly heritable, accounting for about 36% of the variability in individual monkeys' responses on the human intruder test (as measured by the reduction in movement and vocalization and increase in stress hormone levels).

When the researchers used a type of positron emission tomography (PET) scan that measures metabolic activity in the brain, they found that after the intruder test anxious monkeys tended to have more activity in two brain regions: the amygdala and the anterior hippocampus. That's not surprising, Kalin says, because studies with rodents and humans have suggested that both regions rev up during anxiety-provoking situations. More surprising, he says, was the finding that the elevated responses in the hippocampus were heritable (accounting for about half of individual variability), whereas the elevated responses in the amygdala were not.

Although the amygdala is the brain region best known for regulating anxiety, Kalin says the findings suggest that the genetic influence on anxious temperament exerts itself in the anterior hippocampus instead. Which genes are involved is not known, but one way to identify candidates would be to look for genes whose activity differs between the two brain regions—a project that's already on the team's to-do list.

"It's a really well-run study with findings that are potentially important in terms of how we view the biological underpinnings of anxiety," says Stephen Suomi, a developmental primatologist at the National Institute of Child Health and Human Development in Poolesville, Maryland.

"To have PET data in over 200 related animals is really quite unique," adds Ahmad Hariri, a neuroscientist at Duke University in Durham, North Carolina. Hariri notes that the findings at first glance seem to be at odds with work he and others have done that links particular genetic variants to amygdala activity in humans. However, those studies used functional magnetic resonance imaging brain scans to investigate the brain's immediate reaction to anxiety-inducing photographs, whereas the fluorodeoxyglucose-PET scans used in the current study measure activity over a longer time scale. The two methods may be looking at different aspects of what makes a brain prone to anxiety, Hariri says. "We need to continue to use multiple approaches to understand how these areas work together to shape the expression of anxiety."