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Traumatic experiences create long-lasting memories that can negatively impact our lives in a myriad of ways. A common treatment to overcome fear is called exposure therapy, or fear extinction, where patients are repeatedly confronted with the source of the fear. This typically is effective at dampening the fearful response, however, the original fear tends to relapse outside of the clinic, limiting the effectiveness of the treatment. Anthony F. Lacagnina and fellow researchers at the University of Texas at Austin wanted to know how the brain changes to adapt to extinction training, and what happens when relapse occurs. To answer these questions, he and his colleagues got to work and shared their findings in a study, titled: Distinct Hippocampal Engrams Control Extinction And Relapse Of Fear Memory, recently published in the Journal of Nature Neuroscience.

“I've always been interested in the nature of memories; how they are formed, how they change over time, and so on,” Lacagnina told us. “Memories also have an emotional component to them, and so I've always wondered if it's possible to overcome our fears by understanding how they were formed and what happens when we are actively suppressing them. I realized there isn't a lot of research about what's happening in the brain when an animal is successfully suppressing it's fear (recalling the extinction memory), or about what happens when the original fear memory relapses (during spontaneous recovery).”

Russian physiologist, Ivan Petrovich Pavlov, was the first to describe that extinction memories tend to relapse over time, which he named spontaneous recovery, Lacagnina explained. This led to the idea that extinction learning does not erase the original memory, but instead creates a distinct memory trace that either inhibits or competes with the original one. Recent studies have shown that in the hippocampus, neurons active during the time of a fearful event can be reactivated at a later time point, showing that some component of the memory was stored in those cells. Lacagnina and his colleagues hypothesized that extinction learning might generate a new memory trace in this brain region, and that distinct populations of hippocampal neurons would represent the 'fearful' and 'safe' (or extinguished) memory.

To test out their theory, researchers placed mice in a chamber and delivered a mild foot shock, which causes them to form a fearful memory of the chamber. Later, researchers returned them to the same chamber day after day, never shocking them again, to show them that the chamber was no longer dangerous, which led to a reduction in fear. The mice were genetically altered to allow researchers to tag the population of neurons in the hippocampus that were active during either the day of their traumatic memory was formed, or when they were no longer expressing any fear. Using a technique called optogenetics, researchers could either stimulate or silence those populations of neurons. If the two memories existed in unique populations of neurons, researchers should expect to see different effects on behavior by manipulating them.

“We found that a new population of neurons, what we called ‘extinction neurons’, emerged after the extinction training,” Lacagnina told us. “The activity of these neurons were needed for the animal to continue to suppress their fear. If we silenced them, the original fear would emerge. Moreover, if we stimulated them, we could block natural forms of fear relapse, such as spontaneous recovery. Manipulating the fear neurons had the opposite effect - stimulating them could cause an animal to behave in a fearful way, while silencing them reduced the amount of fear relapse. We concluded that the hippocampus creates two unique and opposing memories of the experience; one to remember that the chamber was fearful, and one to remember that it was safe. We think that these two memories compete with one another to determine whether you will overcome your fear or succumb to it.”

Lacagnina told us that a couple of things were surprising to him and his fellow researchers. For one, the mechanisms of fear relapse are not well understood, so they were surprised to find that the neurons of the hippocampus involved in the initial traumatic experience played an important role in the phenomenon of spontaneous recovery. Second, they were surprised they were able to block fear relapse by activating the extinction neurons. Extinction learning is thought to be a weaker form of learning, Lacagnina explained, so it was unexpected that reminding the animal of the safe context was able to override the natural tendency to be afraid.

“There is still a lot more to learn about how both fear and extinction representations in the hippocampus compete for reactivation,” Lacagnina told us. “Why does the fearful representation win out during times of relapse, for instance. But if since we demonstrated that they exist in two populations of neurons, this gives us a useful target, to either strengthen the connections of the neurons related to the extinction memory, or weaken those related to the fear memory. We hope that this research and those like it will give us better insight into treating disorders like Post Traumatic Stress Disorder, anxiety, and phobias.”