Gene activating drug shows promise for PTSD memories

[Wesley]

http://www.latimes.com/science/sciencenow/la-sci-sn-ptsd-epigenetics-20140116,0,3934589.story#axzz2qgrflghM

 

 

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.

 

I am somewhat ambivalent about this.

 

I feel like actually forgetting and changing the old, fear-inducing memory can lead to you not removing yourself from a potentially harmful situation (as well as other potential benefits of fear). If you do not feel the fear in response to a traumatic event, it seems like it could have negative results.

 

I also feel like if someone has gone through talk therapy and still has something deep that they can't access that is debilitating for some reason, it would provide a way out. Also, I assume this method could be at least partially done to make a PTSD situation less debilitating so that treatment becomes possible in extreme situations where it currently is not.

 

What are your thoughts?

[dsayers]

I feel pretty similarly. Just last night, I was listening to the call in show with a title about NASA and Tang. In it, a guy was talking about LSD and how it's been shown to counteract the physiology of chemical withdrawal. Anyways, before Stef was able to walk him through articulating this, he was speaking in vague statements, during which he used the word "fear" as if it inherently bad.

 

I realize that some people can be crippled by fear, that some people have irrational fears, that some fears are disproportionate, etc. However, most people's experience of fear is natural, healthy, and necessary for survival. I'm afraid that if we use one drug to blank it out, then we're going to have to add another drug to compensate the danger in somebody operating without fear, etc. I don't see a drug being superior to talk therapy except in the rare, emergency, extreme cases where an instantaneous muting of fear is necessary for the person to survive long enough to partake of safer alternatives.