Unraveling the Mysteries of Inherited Anxiety

The National Institute of Mental Health (NIMH) estimates that roughly 18% of adults in the United States cope with anxiety disorders, a collection of troubles characterized by excess feelings of anxiety and fear. Significant research has shown that young children who tend to naturally be painfully nervous and shy, and have what’s called an anxious temperament, are much more likely to be diagnosed with an anxiety disorder as an adult. It’s also well known that children with anxious temperament often have a parent who suffers from anxiety, too. Taken together, those results suggest that anxiety is at least partly heritable. New research from the University of Wisconsin, Madison, on an extended rhesus monkey colony suggests that some aspects of anxiety are passed from generation to generation through an overactive brain circuit.

Growing up anxious

Ned Kalin, chair of psychiatry at the University of Wisconsin School of Medicine and Public Health, has spent years trying to understand the early beginnings of anxiety and depression disorders.

“These are illnesses that likely start in early childhood—and often go unrecognized or perhaps are not fully expressed in some way then,”  says Kalin, also a member of the Dana Alliance for Brain Initiatives. “So we’ve been interested in what’s called anxious temperament, feelings of intense shyness and fear that are seen both in young children and young monkeys, because when children have this, and it’s extreme, the likelihood of that child developing a significant anxiety disorder or depression is about 50%. One out of two kids with this will likely develop a significant psychiatric problem. But, the question remains, which one?”

To better answer that question, Kalin’s group is working with non-human primates, rhesus monkeys, as well with as young children, to better understand which offspring are more likely to develop psychiatric problems as an adult. They wondered if it might be related to the heritable component of anxiety.

“We don’t know how anxiety gets transmitted from the parents to the children—what the genes may be doing, what areas in the brain it may be affecting,” he says. “But if we can understand how this early anxious temperament is passed along, we may be able to think of novel ways of intervening early in life to prevent later problems.”

An extended pedigree

To better understand what brain areas were affected by anxiety’s heritability, Kalin and colleagues studied a multi-generational family of nearly 592 rhesus monkeys.

“This is a highly interrelated, multi-generational group of animals that live in remarkably consistent environments, which allowed us to really focus on the biological component,” says Andrew Fox, a post-doctoral fellow in Kalin’s lab. “We weren’t simply comparing one family to another. Because the animals were so interrelated, we could say, ‘Okay, this animal has these two half-siblings on this side and these other half-siblings on the other,” and come up with a prediction of just how anxious the animal was going to be based on the anxiety levels of the related animals.”

The researchers measured anxiety using a human intruder paradigm. A human would walk into the enclosure with an animal and not make eye contact, keeping his or her face in profile.

“If you stare at an animal, and startle them, the animal will respond to that by barking or maybe acting aggressively,” says Fox. “But in this scenario, the animal isn’t really sure if you’ve noticed them. So nearly every animal freezes for a few seconds—and they inhibit their vocalizations. But there’s large individual differences in just how long the animal will freeze.”

The more anxious animals will remain immobile and quiet for a much longer period of time, as well as show higher levels of cortisol, a stress hormone. The researchers used freezing time, vocalizations, and cortisol levels to determine an animal’s level of anxiety. But they took the study one step further:  They then scanned the animals’ brains using positron emission tomography (PET). They learned that the more anxious animals had heightened metabolism in a brain circuit involving the orbitofrontal cortex, part of the brain’s executive control center; the amygdala, seat of the “fight or flight” response; and the limbic system, the brain’s emotional processing regions. What’s more, the researchers estimated that approximately 35% of variation in anxious temperament could be explained by heritability. The results were published in July 2015 in Proceedings of the National Academy of Sciences.

“These three regions showed increased brain activity,” says Kalin. “You have to have some anxiety so you can avoid trouble. But these animals show an overactivity in this circuit. And that can be a problem that eventually leads to anxiety and depressive disorders.”

Nature and nurture

Suzanne Houston, a graduate student at the University of Southern California who studies how environment can influence the development of the brain, as well as later psychiatric problems, says this study is extremely interesting.

“This study shows us that there is no nature/nurture debate anymore. When it comes to disorders like anxiety, both nature and nurture play a role,” she says. “It’s fascinating that there may be differences in metabolism as your brain is developing and that can influence behavior later on. So these findings are important because if we can understand that some regions are more vulnerable to environment, and others to nature, we can better understand the different contributions to anxiety disorders,  and, hopefully, come up with better ways to intervene.”

Kalin agrees, and plans to follow up this work with a more in-depth look at the genetic and molecular changes in this circuit in animal models as well as do longitudinal imaging studies in human children.

“I started off by saying 50% of the kids who have anxious temperament will go on to develop a disorder. 50% won’t,” he says. “So, moving forward, if we can figure out what the genes are doing in this circuit and also naturalistically study kids that both do and do not develop these disorders so we can better understand what’s changing in the brains, we can hopefully gain insight into how we might impact the trajectory that some of these vulnerable kids have in a positive way.”