Epigenetic and exposure therapy

The brain on epigenetic therapy: Metabolic activity (green and red colors), a sign of learning capacity, was much higher in the hippocampus of mice that underwent extinction training in combination with epigenetic therapy (left). (Johannes Graff / Cell)

A combination of exposure therapy and gene stimulation may be the best way to alter fear-provoking memories that are the persistent core of post-traumatic stress and anxiety disorders, a new study suggests.

Using fear-conditioned mice, researchers found they could essentially wipe out a fear response to distant memory by stimulating expression of genes that open a window of opportunity for learning in the brain’s hippocampus, a region crucial for memory processing and consolidation.

The mice didn’t just "forget" their conditioned fear in this double-barreled approach. Neurons associated with memory were physically altered and appeared healthier and more active, according to the study published online Thursday in the journal Cell.

"We can see that this treatment can markedly increase synaptic density, and synapses are the basic unit for the communication between neurons," said study author Li-Huei Tsai, a neurobiologist and director of Picower Institute for Learning and Memory at MIT.

The researchers were looking for a biochemical answer to a clinical puzzle. Therapy centered on deliberate recall of traumatic memory has been relatively successful at opening a window for patients to overcome the crippling effects of fear. But such therapy has been less successful for older, or "remote," memory.

Laden with intense emotion, those memories can become a lifelong battle for some 29% of patients, according to a recent study.

Previous research has shown that neurons in the hippocampus can undergo significant changes after short-term memories are induced, but not after recall of distant memories. That so-called neuroplasticity is mediated by genes, and those genes can be primed by an enzyme that affects the way DNA is packaged and sorted.

Trainers used Pavlovian conditioning to get mice to associate a tone or a setting (a cage) with a shock. They then used the rodent equivalent of exposure therapy – exposing them repeatedly to the tone or context without the subsequent shock, until they no longer froze in response to that stimulus. Some underwent this so-called extinction training in one long session, while others received short sessions over four days, a therapy timing thought to have greater effect among humans.

Among mice retested a day after the extinction training, fear responses to the conditioned stimulus were greatly reduced. But for mice tested much later, fear responses persisted.

"We showed that new fear memories can be modified or extinguished through exposure therapy, but for old memories, the exposure-based therapy is not very effective," Tsai said.

Inside the brains, these different behavioral outcomes were matched by chemical differences. A chemical process that enhances gene expression was far more evident among the mice that lost their fear response. It appeared that the epigenetic window to rewiring memory in the hippocampus was closed for remote memory.

Researchers, however, overcame this chemical shortcoming with a compound called a histone deacetylase inhibitor. They administered it after the exposure to the conditioned stimulus, but before each of the extinction training regimes, and the mice’s fear response was reduced, even for the relatively distant memories. (By itself, the inhibitor had no such effect.)

Significantly, the fear-conditioned mice that no longer responded fearfully to a context after the multi-session extinction training still responded fearfully to a tone – a hint that the original memory wasn't being replaced so much as reassociated.

At the genetic level, the inhibitor applied with exposure therapy appeared to increase the activity of 199 genes that improve the function and even the form of neurons.

The researchers believe the data show that new learning occurred during the mouse equivalent of exposure therapy administered during the critical time period when the brain was epigenetically primed for change. That learning, they suggest, is not a new memory, but a new association for the original memory – substituting safety for fear.

It is unclear yet whether epigenetic therapies such as this can be applied to humans without causing harm, Tsai cautioned. The team plans to explore effects on other parts of the brain, as well as non-pharmaceutical ways to stimulate gene expression, such as using light, known as optogenetics.