Winter 2018

To Fear or Not to Fear

Tufts researchers find an underlying neurological mechanism for mediating fear response.

By Kim Thurler

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Photo: Chris Dale/Getty Images

A child may reach for a honeybee buzzing around a bright flower—but a child who has previously been stung by a bee may shrink from the insect. This is because humans, like all mammals, have dedicated circuits in their brains for expressing learned fearful behavior and for suppressing such fear.

When an experience proves threatening or painful, nerve cells in the brain’s basolateral amygdala (BLA) store that memory. Later, in similar circumstances, the cells can trigger fear-based behavior. If future experience repeatedly proves similar situations are not dangerous after all, then the original fear memory will typically be suppressed over time in a process called extinction learning. But people suffering from post-traumatic stress disorder (PTSD) or other anxiety disorders may experience disabling recurrences of fear. By uncovering the precise mechanisms underlying fear memories and their suppression, researchers hope to find more effective treatments for such conditions.

Now Leon Reijmers, an assistant professor of neuroscience, and his colleagues at Tufts University School of Medicine, have published findings in the journal Nature Neuroscience demonstrating that a particular type of BLA nerve cell, the PV interneuron, plays a key role in suppressing the neurons that store fear memories after fear extinction learning has occurred.

The researchers were able to home in on the PV interneurons’ role by treating genetically modified mice— which had undergone fear extinction learning—with a chemogenetic agent that turned off these interneurons. Without functioning PV interneurons, the mice displayed fear behavior that had previously been extinguished.

That finding confirmed a hypothesis proposed in Reijmers’ earlier work, but the researchers also made another, unexpected discovery: PV interneurons regulate an ongoing tug of war between a neural circuit that expresses fear memories and a competing circuit that extinguishes fear memories.

“When we recorded electrical activity in the BLA of our test mice, we saw brainwaves—or oscillations—at two different frequencies, each with a different relationship to fear expression. Oscillations around 4 Hz correlated with more fear behavior while oscillations around 8 Hz correlated with less fear,” Reijmers said. “Silencing the PV interneurons after fear extinction learning increased the activation of the fear-associated 3 to 6 Hz oscillation as well as increased the activation of the fear neurons. Our findings suggest that oscillatory activity could be a useful target for therapies to address disorders such as PTSD.”

First author on the paper is Patrick Davis, a fifth-year student in the combined M.D./Ph.D. degree program offered by the Sackler School in conjunction with the School of Medicine, through a Medical Scientist Training Program grant from the National Institutes of Health. Other authors are Yosif Zaki, a Northeastern University undergraduate who was an intern in Reijmers’ lab, and Jamie Maguire, an assistant professor of neuroscience at Tufts.

“We need a far better understanding of the basic mechanisms at work in the brain before we can start to apply them to treat disease,” said Davis. “While this type of work is many years away from being clinically beneficial, I firmly believe that collectively the neuroscience community can help patients who suffer from anxiety disorders.”

Kim Thurler is former executive director of the Office of Public Relations at Tufts University.

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