Peter, aged 3, was scared of rabbits. So Mary Cover Jones kept bringing him rabbits.
At first, she’d take a caged rabbit up to Peter, while he ate some candy and played with other children. At first, Peter was terrified by the mere presence of a rabbit in the same room. But soon, he allowed the animal to get closer—12 feet, then four, then three. Eventually, Peter was happy for rabbits to nibble his fingers. “The case of Peter illustrates how a fear may be removed under laboratory conditions,” Cover Jones wrote in 1924.
Cover Jones is now recognized as the "mother of behavioral therapy." Her observations laid the groundwork for what would become known as exposure therapy—the practice of getting people to overcome their fears by facing them in controlled settings.
A century later, neuroscientists can watch how the act of facing one’s fears actually plays out inside the brain. Using gene-engineering tools, they can label the exact neurons in a mouse’s brain that store a specific fearful memory. Then, they can watch what happens when the rodent recalls those experiences.
By doing this, Ossama Khalaf from the EPFL in Lausanne showed that the extinction of fear depends on reactivating the neurons that encode it. A mouse has to re-experience a deep-rooted fear if it is to lose it.
When someone encounters a new experience—say, a terrifying rabbit—groups of neurons in their brain fire together, the connections between them become stronger, and molecules accumulate at the places where neurons meet. Many scientists believe that these preserved patterns of strengthened connections are the literal stuff of memories—the physical representations of the things we remember. These connected neuron groups are called engrams.
When people bring up old memories, the engram neurons fire up again. They also enter a brief period of instability, when the molecules that preserved the connections between them disappear and must be remade. This process, known as reconsolidation, means that humans are partly reconstructing our memories every time they bring them to mind. And it means that the act of recollection creates a window of time in which memories can be updated, and fears can be unlearned.
“That was the theory,” says Daniella Schiller from the Icahn School of Medicine at Mount Sinai. “It’s been speculated, but [this new study] is one of the most direct demonstrations so far.”
Khalaf and his team, led by Johannes Gräff, worked with a special strain of engineered mice that are completely normal as long as they can eat a drug called doxycycline. If you remove the drug from their meals, a series of genes kicks into action, and drops a distinctive molecule into any active neuron. In this way, the rodents automatically label their own engrams. Whenever they learn something new, or recall an old memory, the buzzing networks of neurons in their heads get tagged.
The team made good use of this feature in a simple experiment. They trained the mice to fear a small box, by putting them inside and giving them some mild electric shocks. A month later, the team took the rodents off doxycycline and put them back in the same box. They froze—a clear sign that they were remembering their old distress. Meanwhile, they were labeling all the neurons that fired during this moment of recollection—the fear engram.
Later, Khalaf put the mice through exposure therapy, repeatedly returning them to the scary box without any accompanying shocks. As these sessions continued, their fear started to subside. But here’s the crucial bit: The more closely they reactivated the neurons from their original fear engram, the more thoroughly they shook off their fear.
Without the former, the latter doesn’t happen. Khalaf showed this by chemically silencing the rodents’ labeled neurons, and preventing them from reactivating their fear engrams. When he did this, the mice responded less well to their rounds of exposure therapy. But if Khalaf instead boosted the activity of the engram neurons during the rodents’ therapy sessions, they lost their fears faster than before.
“It’s an important advance, in that it suggests, for the first time, that extinction of fear involves the modification of the original fear-inducing memory,” says Jelena Radulovic from Northwestern University.
But memory-labeling techniques are still new, and as with all leading-edge methods, it can be tricky to interpret their results. For example, these techniques often show that the neurons that are reactivated when memories are recalled only partly overlap with those that encoded the original memory. “The observed effects [in Khalaf’s study] could be attributed to a novel neuronal population that is not necessarily involved in processing of the original memory,” Radulovic says.
Still, “in many respects, these findings confirm what any accomplished therapist already knows—that, to a large degree, patients with anxiety disorders must relive their trauma to overcome it,” write Paul Frankland and Sheena Josselyn from The Hospital for Sick Children in a related commentary. “Exposure therapy is the only known successful treatment for traumatic memories,” says Khalaf.
But it isn’t always successful, and “sometimes, the fears resurface, forcing the patient to return to their psychiatrist.” Perhaps that’s because instead of changing how they remember the original fearful memory, patients are simply papering over it with new ones. An accumulation of safe and reassuring memories could blot out the original fear, but it’s still under there. “Re-engaging the original fear could be more useful than suppressing it,” Khalaf adds.
That’s still hypothetical, though. The team showed that reactivating fear engrams is important for quelling those fears, but does it stop them from returning later? The team also focused only on the neurons in one part of the brain—the dentate gyrus, which is involved in the creation of new memories. What about other regions, like the amygdala, which influences emotions, and the prefrontal cortex, which governs decision-making and other complex behaviors?
By answering these questions, the team hopes to find ways of working out when exposure therapies are most likely to succeed, and perhaps developing more effective ways of helping people to face their fears.