Finding Biological Clues to Fear and Anxiety

“The assumption has always been that if we understand how fear works, then we will understand anxiety disorders. But I don’t think that’s the case.” Lisa Gunaydin, PhD

Searching for biomarkers for anxiety and compulsive behavior in mice, a team led by Dr. Gunaydin found neural circuits that control these symptoms of anxiety disorders. This represents an important step in the search for new treatments for these diseases, which currently affect about 40 million US adults every year. 

While researching the biological causes of fear and anxiety, Dr. Lisa Gunaydin discovered that the two emotions – although related – are quite different. 

“The assumption has always been that if we understand how fear works, then we will understand anxiety disorders,” she said. “But I don’t think that’s the case. It’s really important to look at other behavioral symptoms of anxiety disorders, like avoidance.”

So that is exactly what she did.

Dr. Gunaydin notes that avoiding a threat – such as running from a knife-wielding stranger – is essential for survival in all species. But in anxiety disorders, avoidance becomes maladaptive when threats are over-exaggerated to the point that a person avoids not only dangerous situations such as dark alleys but also safe situations such as social gatherings. 

Everyone has heard the adage that you must face your fears to overcome them. This truism captures the foundation of all exposure therapy, an extremely effective treatment for anxiety disorders because it gently exposes patients to triggers to learn that the feared situation is actually safe. Unfortunately, avoidance behavior often stops patients from getting help in the first place because they find it too scary to go see a therapist or a psychiatrist. 

The bottom line, Dr. Gunaydin says, is this: “If you're avoiding the things that trigger your anxiety, then you don't have the opportunity to correct those over‑exaggerated threat beliefs. And the more you avoid the triggers, the fewer opportunities you have to learn to overcome them.”

Searching for the neural mechanisms underlying avoidance behavior, Dr. Gunaydin and her team studied the dorsomedial prefrontal cortex, a brain region that shows altered activity in anxiety disorders. They focused on the two prefrontal circuits – the fronto-amygdala circuit implicated in fear and the fronto-striatal circuit implicated in action selection – and identified a relatively novel circuit that controls anxiety-like behavior.

“We found that when you stimulate the fronto-striatal circuit, it seems to causally decrease anxious avoidance,” she reported. “It implicates this circuit that people haven't really studied much in anxiety before.”Showing that there is a biological basis for anxiety – indeed, a specific circuit – should help erase the stigma around anxiety, she noted.  “Now we can say, `Look, they are not making it up, it’s not just in their head, it is not because they are lazy or not trying hard enough. This is the cause.’”

Much work remains to be done, but Dr. Gunaydin said she hopes this line of research will one day identify novel symptom-specific targets for stimulation-based therapies for anxiety disorders, and she is grateful for the Weill Innovation Award that helped speed the process. 

UCSF Weill Awards

Susanna Rosi, PhD; and Peter Walter, PhD
John Boscardin, PhD; Andrew Charles, MD; Steve Cummings, MD; and Amy Gelfand, MD