How do you manage fear? When did you learn it? What are psychiatrists discovering about treating anxiety disorders more effectively? (Image: Beatrice Jin)

Learning Fear

by Caitlin Hayes

All vertebrate and invertebrate species have the capacity to respond to threats, says Francis S. Lee, Psychiatry, Weill Cornell Medicine. But in humans, why do some people hold onto their fears and others let them go? Why is anxiety fleeting for some and debilitating for others?

Lee is working to elucidate the brain’s fear circuit — the mechanisms of how we learn and forget, or remember, our fears. What he has discovered is shifting paradigms in understanding which mechanisms cause anxiety, how it should be treated, and when.

Francis Lee studies the brain’s fear circuitry — the mechanisms of how we learn, forget, and remember our fears — uncovering mechanisms that cause anxiety and how to treat it. (Image: Jesse Winter)

When Do You Learn To Be Fearful?

When we’re young, there’s a period of heightened brain plasticity, Lee says, a critical period when the brain is able to learn and adapt more rapidly. “An analogy is visual plasticity,” he explains. “If you have what they call a lazy eye when you’re young, you can actually patch one eye and your visual cortex will adjust and coordinate vision again. But after about eight to 10 years of age, it becomes more difficult because you’ve passed the critical period.”

These periods have been well documented in the sensory system, but Lee wanted to know if they also existed for emotional circuits. “So we started doing very basic studies about when you learn to become fearful of things,” Lee says. “How does a juvenile versus an adolescent versus an adult, for example, regulate their fear responses?”

Amazingly, Lee says, as of 2010 that study had not been rigorously done. “So we began and found, somewhat by accident, that there is a critical or sensitive period for fear learning,” Lee says. “During adolescence, the whole fear system goes offline, which made no sense to us six years ago, and now we’re slowly putting it together. But it really suggests that brain development is not a linear process. It seems to go through waves of growth and then rearrangement and growth again. We were able to find a period of time in adolescent mice models, where they regulate fear in a very different way.”

As a result of these differences in regulation, an adolescent under stress or who experiences trauma may remember it more than an adult or child — with heightened plasticity. They will learn the fear and not be able to forget it. This outcome corresponds to Lee’s experience as a clinical psychiatrist; nearly all patients suffering from anxiety disorders can point to its origins early on in their lives.

Because the young are able to learn and adapt so quickly, there may be a great opportunity to intervene when the fear circuitry is developing. “This is our contribution,” Lee says. “That there seems to be a critical period where you can actually learn to regulate your fear in a much more plastic way.”

Anxiety Disorders — Debilitating

Lee has been inspired by his involvement at the New York-Presbyterian Youth Anxiety Center, a joint clinical and research program run by New York-Presbyterian, Weill Cornell Medicine, and Columbia University College of Physicians and Surgeons. “A quarter of American teens have a diagnosable anxiety disorder,” Lee says. “Yet we’re treating them all with therapies that have been developed for adults.”

Relative to other psychological diagnoses, Lee emphasizes the seriousness of anxiety disorders. While everyone experiences anxiety, patients with these disorders are debilitated by it. “An anxiety disorder doesn’t sound as bad as something like schizophrenia, but if you have an anxiety disorder, you actually might not finish high school or college, and then you don’t get to be a part of mainstream society,” he says. “There’s great danger that these highly severe anxiety disorders can actually stop people from reaching various milestones, and they put people at greater risk of suicide.”

Fear Learning, Anxiety, Post-Traumatic Stress, and the BDNF Protein

Lee stumbled into anxiety research when he started working with a protein not known to be associated with anxiety at all. The protein, BDNF (brain-derived neurotropic factor), had been classified as a growth factor in the brain, involved in the generation and survival of neurons. Researchers had already found that there were common genetic variations in the human BDNF gene, and Lee wanted to know what effect this variation had.

When his team made a mouse model with the human BDNF polymorphism, the result was surprising. “The mouse didn’t have Parkinson’s- or Alzheimer’s-like phenotypes as we might have expected,” Lee says. “Instead, it was an anxious mouse, and that’s when everything started.”

Lee began collaborations with former colleague at the Sackler Institute for Developmental Psychobiology B.J. Casey, who conducted parallel neuroimaging studies in humans. Together, Lee and Casey were able to show the exact circuit in the brain where this form of BDNF functions to lead to heightened anxiety and fear responses. He and Casey are co-inventors on a patent related to a BDNF single nucleotide polymorphism (SNP) and fear regulation. “Eventually, we are hoping to use the polymorphism as a biomarker to determine how patients will respond to certain treatments,” Lee says.

Lee and colleague B. J. Casey showed the exact circuit in the brain where a form of BDNF leads to heightened anxiety and fear responses; they are co-inventors on a patent related to fear regulation. (Image: Beatrice Jin; Jesse Winter)
“There seems to be a critical period where you can actually learn to regulate your fear in a much more plastic way.”

If doctors can screen for this particular polymorphism, they might have a better understanding of an individual’s patterns of fear learning. The implications for treating anxiety disorders or post-traumatic stress disorder (PTSD) could be tremendous.

In one ongoing study, Lee and Weill Cornell Medicine collaborator JoAnn Difede are screening a population of Iraq and Afghanistan War veterans to see if there’s a link between the BDNF polymorphism and PTSD. “This is not that different from the adolescent story because most people who go into the war are in their early 20s — they’re still in the window in terms of brain development,” Lee says. “We want to know whether this polymorphism will make someone more responsive or less responsive to the types of treatments we’re giving that are based on fear learning.”

In addition to BDNF, Lee has also found another polymorphism in the endocannabinoid system, the same system that is hijacked by marijuana. “If they have this cannabinoid polymorphism, it actually makes the animals less anxious and makes them extinguish fear and get rid of fear much more quickly,” Lee says.

About 30 percent of the population has the BDNF polymorphism, and 30 percent has the cannabinoid polymorphism; a smaller percentage has both. “Though very speculative, you can imagine that nature probably set this up, along with many other genetic variants, so you can have a wide range of emotional responses to fear,” Lee says. “We’re in the midst of a variety of studies to untangle the mechanisms, but ultimately we’d like to get a repertoire of anxiety genes that can help us understand anxiety and develop treatments based on genotypes.”

The Brain’s Circuitry, a Daunting Investigation

“As a psychiatrist I can say that we, as a field, know so little,” Lee says. “The brain is far more complex than many other organ systems, and there is such a variety of reactions to any one environmental stimulus. To get at underlying mechanisms for psychiatric disorders is daunting.”

The conceptual breakthrough that psychiatry has made in the last 10 years is to stop looking for a better Prozac or a silver bullet to fix psychiatric disorders. Lee continues, “Ultimately, what we’ve learned is that we’re going to be able to slowly understand these circuits.”

A focus on the circuits and the various factors that affect them will allow for more precise targeting in treatment. “The future of psychiatry will not be taking a pill and going home,” Lee says. “You might take a pill, and then get some type of psychotherapy that stimulates one type of circuit, and if it doesn’t work well, then you also get another treatment like transmagnetic stimulation in addition that also focuses just on that circuit. I think that’s going to be the future. But you can imagine what needs to be done. We have to figure out all of these circuits.

“Through our work, scientists are all trying to make bets on where the future will be,” Lee continues, “and my bet is that people will say we’ve been studying the adult circuit, when we need to be studying the developing circuit — especially around childhood and adolescence — because that is when almost all these disorders are emerging.”


Originally published on the Cornell Research website. All rights are reserved in the images. If you’d like to reproduce the text for noncommercial purposes, please contact us.

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