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Published in Proceedings of the National Academy of Sciences, the findings give insight into what areas of the brain can be targeted to help treat anxiety disorders.

While behavioral therapies can reduce pathological fear, says Stephen Maren, professor of psychology at Texas A&M University, “relapse of fear is a major problem in the treatment of disorders of fear and anxiety in humans, with a large percentage of individuals exhibiting a return of fear after behavioral therapies to reduce it.”

Using a genetically modified line of rats known as the “Venus rat,” scientists were able to see the physical connections in the brain—the specific synaptic connections between neurons―that are responsible for fear relapse in the rats.

“We trained the rats to fear a tone by pairing it with a mild shock to the feet,” Maren says. “We then trained the animals that the tone was safe by using an extinction procedure in which the tone was presented alone a number of times in a new place.”

The rats learned not to have fear in the new place that was free of shocks. “But extinction (lack of shock) does not erase the fear memory,” explains Maren. “Fear returns or relapses when the tone is encountered outside of the safe place.”

The Venus rats, developed by an international team of scientists led by Ewelina Knapska and Leszek Kaczmarek at Poland’s Nencki Institute, have been modified to release a fluorescent protein so the scientists can see and trace what connections in the rat’s brain are activated when fear returns.

“The results revealed that connections between brain areas involved in memory and emotion were involved in fear relapse,” Maren says. “Specifically, synaptic connections from the hippocampus and prefrontal cortex, which are important for memories of when and where events happen, to the amygdala (a brain area involved in emotion) were active during the relapse of fear.”

Fear returns because while the animal knows a stimulus is safe in one place, it isn’t so sure when that same stimulus is encountered in a new place―and that uncertainty causes relapse. “It appears that the hippocampus and cortex are responsible for detecting this uncertainty and informing the amygdala, if you will, to produce fear,” he says.

So how does this relate to fear in humans?

Maren uses the example of arachnophobia, the fear of spiders, to illustrate fear relapse in humans.

“A spider phobic who is completely capable of controlling their fear of spiders in the safety of the therapist’s office is very likely to relapse outside of that context and shriek at the sight of a spider crawling on the floor of the garage when they return home,” he says.

The research findings on rats could open the door for new medicines to treat such fear relapse in humans, Maren says.

“This work sheds light on the specific brain circuits involved in this relapse of fear, and these findings hold promise for novel pharmacotherapies to reduce the prospect for fear relapse after treatment.”

Researchers at Massachusetts Institute of Technology and at the Nencki Institute of Experimental Biology and the International Institute of Molecular and Cell Biology, both in Warsaw, Poland, contributed to the study.

Source: Texas A&M