In studies of young rhesus monkeys, researchers from the University of Wisconsin Department of Psychiatry have discovered brain pathways that underlie children’s vulnerability to develop anxiety and depression later in life.

Importantly, the researchers from the UW HealthEmotions Research Institute determined that young monkeys inherit one of the pathways critical to early life anxious temperament.

The study, published today in the Journal of Neuroscience, offers insight into how anxiety develops, its underlying brain alterations, how it is transmitted from parents to children, and may provide targets for future therapies.

Ned Kalin, MD, Hedberg professor and chairman of psychiatry, and colleagues, used brain imaging techniques also used in human studies to look at the brains of hundreds of related monkeys, that vary in their levels of anxious temperament.

They found that functional connectivity between two regions of the central extended amygdala is associated with anxious temperament in pre-adolescent rhesus macaques. Extreme early-life anxiety is a significant risk factor for anxiety disorders and depression in humans, and Kalin’s group is using the monkey discoveries to guide companion studies of anxiety in preadolescent children.

“We are continuing to discover the brain circuits that underlie human anxiety, especially the alterations in circuit function that underlie the early childhood risk to develop anxiety and depressive disorders,’’ Kalin says.

“In data from a species closely related to humans, these findings strongly point to alterations in human brain function that contribute to the level of an individual’s anxiety. Most importantly these findings are highly relevant to children with pathological anxiety and hold the promise to guide the development of new treatment approaches.”

The study used functional magnetic resonance imaging (fMRI) to study the connections between brain regions (the central nucleus of the amygdala and the bed nucleus of the stria terminalis). It builds on the group’s earlier study that used positron emission tomography (PET) scans to study metabolism in the same circuitry; fMRI detects oxygenation changes in blood while PET measures neuronal metabolic activity.

Taken together, Jonathan Oler, PhD, the study’s co-lead author, says the new findings demonstrate that the degree of synchronization between these brain regions is correlated with anxious temperament.

“When we began this research, we knew so little about the brain regions involved, especially in primate species,’’ Oler says. “This study speaks to how important it is to study animals that are related to humans as they allow us to learn about the causes of human anxiety and by so doing we can potentially develop better treatment and hopefully prevention strategies.”

Oler and Kalin say their analysis suggests that the same genes that underlie the connectivity of this circuit also underlie anxious temperament. Studies underway in the Kalin laboratory are aimed at identifying gene alterations in the anxiety-related brain regions, and have the potential to lead to new treatments that are directed at the cause of anxiety rather than just the symptoms. This work also underscores the critical importance and value of studying nonhuman primates in conjunction with studies in humans suffering from anxiety.

“The way we measure this alteration in monkeys is very similar to the method that we use to measure this circuit in our studies of anxiety in human children, so this research is highly translational,’’ Kalin said. “Looking first at the monkeys has provided us with clues about which systems to focus on in our studies of at risk young children.”

Kalin is leading an ongoing brain-imaging study of risk in anxious pre-teen girls and is about to launch a second study imaging study in both boys and girls with clinically significant anxiety disorders. This study aims to use imaging in the largest sample to date of anxiety disordered children and will have additional sites at Vanderbilt University and at the National Institute of Mental Health.

The current study’s other co-lead author is Andrew Fox, PhD, a former Kalin lab member now at the University of California-Davis. Other members of the team include Rasmus Birn, PhD, and Andrew Alexander, PhD, of Wisconsin, and Alexander Shackman, PhD, a former Kalin lab member now at the University of Maryland.

The study was funded by the National Institutes of Health and the Wisconsin National Primate Research Center.