Researchers identify brain areas key to inherited anxiety disorder

When a child encounters strangers, it is normal for him to freeze and be quiet for a few moments. When that child's reaction lasts too long or he is too apprehensive, he may have a disorder known as anxious temperament, a risk factor for depression or other anxiety disorders that develop later in life.

Psychiatrists are able to identify the disorder, but treatments are difficult to develop because the cause of anxious temperament is unknown.

In the largest nonhuman primate neuroimaging study to date, University of Wisconsin-Madison researchers have identified brain regions that are overactive in the most anxious monkeys, and they were able to show that the response in one of those regions is likely an inherited genetic condition. The researchers hope to use their data to find the genes that predispose people to the disorder and provide a target for drug therapy, and it may help to identify children who are at-risk based on a family history of depression and anxiety.

The study appears in the current issue of the journal Nature (www.nature.com/nature/).

The impacts of the study are twofold, according to Andrew Fox, a graduate student in psychology at the University of Wisconsin-Madison and colead author of the study.

He said the size of the study — 238 young monkeys — gave researchers statistical significance that the two brain regions identified were likely to be the most important and confirmed the validity of an animal model for studying this mood disorder.

More importantly, Fox said, "because we have shown this in such a large sample of animals, and because they were from a single family, we were able to look at heritability within a single family tree."

By identifying which brain regions have an inherited component that contributes to disease development, the researchers can start to look for genes that are active specifically in that region.

"The idea is that we have tons of different genes expressed in our bodies, and if we look at everything going on everywhere we don't know where to start," Fox said.

To figure out where to start, the researchers injected monkeys with a mostly harmless radioactive variant of the sugar glucose (it is used in humans to diagnose Parkinson's, for example), then immediately challenged the animals in an "intruder" test designed to mimic a stranger approaching a child in a nonthreatening way. They assessed how the animals responded, and assigned them to a relative scale of anxious temperament based on how long the animal froze, how quiet it was, and how high its stress hormone levels were.

Next, they anesthetized the monkeys and imaged their brains, using the radioactive sugar to indicate which brain regions were the most active — and thus needed the most energy. They found that the more anxious behavior the monkey displayed, the more active its amygdala and hippocampus were.

"If you ask most neuroscientists what area of the brain would be critical in anxious temperament and emotion, most would say the amygdala," said Jonathan Oler, an associate scientist at the Health Emotions Research Institute at the University of Wisconsin-Madison and colead author of the study.

The amygdala is known to have a strong correlation with anxiety and stress responses. The hippocampus, however, was previously thought to be mostly involved with memory.

"But the data are the data, and the hippocampus and the amygdala predicted anxiety in the monkey equally," Oler said. "What was different between them was the heritability component."

"The exciting part was that the hippocampus was the region that was most affected by genes," said Ned Kalin, chairman of psychiatry at the University of Wisconsin School of Medicine and Public Health and senior author of the study.

"Now we can go and ask which genes that have to do with hippocampal function are inherited," Kalin said. "The amygdala, which has been the focus of attention for lots of reasons, is less heritable than the hippocampus."

"Mental health researchers currently are struggling to develop more effective treatments for a range of mental disorders, including mood and anxiety disorders," said Daniel S. Pine, chief of the section on development and affective neuroscience at the National Institute of Mental Health, who was not involved in the study.

"This work is one vital step toward developing coherent understanding of neural processes that cause mood and anxiety disorders."