Researchers led by BBRF Scientific Council member and 2017 Distinguished Investigator Stephen Maren, Ph.D., report they have demonstrated in animal experiments the ability to retrieve and weaken or even erase fear memories that are indirectly associated in the brain with specific cues or contexts.

The results have potential translational value in developing novel treatments for PTSD and addiction in people.

As explained by Dr. Maren and colleagues at the Institute for Neuroscience at Texas A&M University in a paper recently appearing in Nature Neuroscience, currently used behavioral therapies used to treat PTSD—notably, prolonged exposure therapy—seek to extinguish fear memories. They often work quite well for a while, but fail to prevent long-term relapse in about 50% of patients.

In exposure therapy, an individual is re-exposed to cues or contexts that they automatically associate in memory with the trauma or shock that they fear. Performed in a safe environment, the therapy is driven by the idea of de-conditioning the individual, by effectively separating fear-triggering cues and contexts (for example, loud noises like the backfire of a truck) from harmful outcomes (such as battlefield traumas) which, in the context of therapy, do not occur.

Knowing that this therapeutic strategy fails to prevent relapses in many patients, Dr. Maren and colleagues have designed innovative experiments in rodents to test the possibility of disrupting the original fear memory itself—the memory formed, or "consolidated," at the moment of trauma or shock, or in the 4- to 6-hour window (of "memory consolidation") that follows.

They specifically aimed at what scientists call "re-consolidation"—the narrow window in time during which original fear memories are recalled by individuals when they are prompted by a contextual cue—the truck backfire, for example, that triggers the battlefield fear memory and causes behavioral changes such as freezing in place or taking cover under a table.

Triggering fear memories in this way is called "indirect retrieval." While exposure therapy relies upon indirect retrieval of the traumatic memory, it does not attempt to manipulate the original memory, only the individual's response to it.

In their rodent experiments, Dr Maren's team used a novel method called backward conditioning to induce rodents to indirectly retrieve a conditioned, context-dependent fear memory (in this case, of a mild foot shock)—but to do so without the rodents being conscious of the process.

Having accomplished this, they turned to two questions. One was whether they could use sophisticated neural tracing technology to identify specific brain circuits that were activated in this process. The other was to see if they could intervene in such circuitry to alter the process of memory "reconsolidation"—in such a way as to weaken or eliminate the fear memory and its potential to negatively impact behavior.

The team succeeded in associating fear memory reconsolidation with circuitry in a part of the brain's hippocampus called the dentate gyrus.

Then, using a technology called DREADD (which enables scientists to activate or deactivate specific neurons via surface receptors that they have designed) the team switched on cells in the identified hippocampal fear memory circuit, causing rodents to exhibit previously fear-conditioned "freezing" behavior.

In a final phase of the experiments, the team used a drug called rapamycin to disrupt this specific circuit involved in the rodents' conditioned fear memory. The drug (widely used in people as an antibiotic) interfered with the ability of neurons to generate proteins needed for functioning of the circuit. The effect was to weaken the animals' freezing behavior during a time window when their contextual fear memory was being indirectly reactivated.

In other words, the team appears to have succeeded in intervening in a circuit to modify an original fear memory, in turn generating therapeutic behavioral effects.

These experiments are hopeful steps toward the development of clinical interventions to alter neural representations in the brain that drive specific context-linked pathological fear. A similar approach might conceivably be taken in developing novel therapies for addiction, for instance in modifying the role of environmental or behavioral cues that can trigger relapse after the conclusion of successful behavioral therapy.

The team makes clear that the methods used in the rodent experiments cannot at this point be directly translated into people with PTSD or addiction. There are other brain areas, for instance the amygdala, that are also involved in memory consolidation and retrieval, and it is not known how they might be involved or affected by strategies such as those used in the experiments. As noted in a commentary in Nature Neuroscience, Amy L. Milton, Ph.D., of the University of Cambridge (UK), also notes that "it remains unknown whether older, more remote, or more extensively trained memories would also become unstable following indirect reactivation."

These will be among the subjects of future studies by Dr. Maren's team.