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Drug Tweaks Epigenome to Erase Fear Memories

A hurricane, a car accident, a roadside bomb, a rape — extreme stress is more common than you might think, with an estimated 50 to 60 percent of Americans experiencing it at some point in their lives. About 8 percent of that group will be diagnosed with post-traumatic stress disorder, or PTSD. They will have flashbacks and nightmares. They will feel amped up, with nerves on a permanent state of high alert. They won’t be able to forget.

One of the only effective treatments for PTSD is ‘exposure therapy,’ in which people are repeatedly exposed to their fear — such as a painful memory — in a safe context. This treatment works partly because of how our brain encodes memories. Whenever we actively recall a memory, it transforms into a pliable molecular state and becomes vulnerable to modification.

About half of people who get exposure therapy for PTSD get better. But that still leaves a lot of people who don’t. A mouse study published last week in Cell throws the spotlight on a drug that acts in concert with exposure therapy to help extinguish fear memories. The drug works by changing the epigenome, the chemical markers that attach to DNA and can turn genes on and off.

“It’s remarkable,” says Li-Huei Tsai, a neuroscientist at the Massachusetts Institute of Technology who led the work. “If we inject a single dose of this drug it actually is sufficient to reactivate neuroplasticity.”

The drug works by changing the way DNA is expressed in the brain.

DNA wraps around proteins called histones. Image via Wikipedia

In order to fit into the nucleus of each cell, DNA wraps tightly around spherical proteins called histones. (You can see how in this animation.) Histones are littered with chemical groups, such as methyl and acetyl, that influence how nearby genes get turned on and off.

For many years, Tsai has been studying enzymes called histone deacetylases, or HDACs, which switch off genes by removing acetyl groups from histones. In 2012, she showed that one such enzyme, dubbed HDAC2, is overactive in a mouse model of Alzheimer’s disease and shuts down genes related to learning. In that study she also showed that blocking HDAC2 led to dramatic gains in the animals’ memory.

“HDAC2 is a master regulator of the expression of neuroplasticity genes,” Tsai says. “And HDAC inhibitors seem to be very beneficial for memory formation.”

In the new study, Tsai’s team investigated whether this enzyme is also involved in the way that fear memories cement themselves into brain circuits.

Mice don’t get PTSD, but they can acquire fear memories. Using so-called Pavlovian fear conditioning, researchers train the animals to fear a particular cue, such as a sound or smell, by pairing it with a mild shock to the foot. After a few trials, the animal freezes at the cue alone.

There’s also a mouse version of exposure therapy. After a mouse learns to fear, say, a certain tone, researchers can extinguish that fear by repeatedly playing the tone without a shock. Gradually the animal learns to associate the tone with the safer context.

But in mice (and, importantly, in some people with severe PTSD), this extinction therapy only works for recently acquired fear memories. If a fear memory is old, then no amount of retraining will erase the animal’s fear. “One of the major challenges in developing treatments for PTSD is that traumatic memories can persist for a lifetime,” notes Matt Lattal, a neuroscientist at Oregon Health and Science University who was not involved in the new study. “It is therefore critical that laboratory models of PTSD include this long interval between traumatic experience and testing.”

Tsai and her colleagues trained mice to fear a tone and then gave them extinction therapy either a day later or 30 days later. When extinction training happened a day later, the HDAC2 enzyme was inactivated in brain cells, the study found. With HDAC2 quiet, acetyl groups stayed latched on to histones and various memory genes stayed on. Presumably, this window of plasticity allowed the mice to un-learn the fear memory. In contrast, when extinction training happened 30 days later, the HDAC2 enzyme was active. It removed those acetyl groups, effectively shutting off neuroplasticity genes.

But here’s the exciting part. The animals were able to un-learn the fear memory 30 days after it was formed when the researchers paired extinction therapy with a drug that inhibits HDAC2, dubbed “CI-994.” It only took one dose, and the researchers saw no side effects, Tsai says. “We did a lot of control experiments to show that this mechanism doesn’t wipe out other memories. It really is very specific to the training condition.”

HDAC inhibitors are becoming a hot class of drugs. In 2012, Yossef Itzhak and his colleagues at the University of Miami reported that giving a different HDAC inhibitor to mice before they acquire the fear memory accelerates the extinction of the memory weeks later. “Hypothetically speaking, HDAC inhibitors may be useful prophylactics against the persistence of fear memory,” says Itzhak, who was not involved in the new study.

Researchers are investigating HDAC inhibitors for all sorts of other conditions, too, including heart disease, HIV, and cancer. Because HDAC enzymes are expressed all over the body, though, some experts are worried about their translation into the clinic.

“HDAC inhibitors have a wide spectrum of biological effects, and only when they will be targeted for the treatment of a specific malady [will] their therapeutic value be of great importance,” Itzhak says. “The goal is to identify specific HDAC inhibitors which target specific brain circuits and genes.”

42 thoughts on “Drug Tweaks Epigenome to Erase Fear Memories

  1. Good to point out that there are a lot of HDAC enzymes, and alot of HDAC inhibitors, some which aren’t too specific. The anticonvulsant valproate and the experimental anticancer drug vorinostat both are HDAC inhibitors, for example. (Thanks for the Twitter mention, Ginny.)

  2. I wonder if this can be used to encode whole new sequences not possible with low plasticity. And, how would this help Alzheimer’s patients?

    [Jim — Tsai’s earlier study found that a mouse model of Alzheimer’s disease has over-active HDAC2 enzyme, and that shutting down HDAC2 improved the animals’ memory. It’s preliminary animal work, of course, but still tells a consistent story about how these drugs might work. –Ginny]

  3. If a person has PTSD and it is Years Old can this therapy help them?

    [This is a mouse study, so it’s far too early to say whether and how these drugs might affect people with PTSD. IF they work in humans as they do in mice, then yes, it would seem that very old memories could be tweaked. –Ginny]

  4. If this translates into a drug that can be given to soldiers before they enter battle, or to adults to finally erase the trama of childhood sexual abuse, this type of drug may be one of the greatest quality-of-life enhancers ever developed

  5. Would these be an ultimate prescription for anxiety/ agorophobia. .. .. I hsvd usex a similar concept but with just consistent exposure. It worked but the capability of doing this within days is so much harder with no help.

  6. Some thinking I did :

    Perception determines your mindset and thus influences directly your biology at cell level which means;

    if you are in fear, being in fear thus running/fighting and/or in stress, it weakens your immune system and potential of growth making survival possible… because you are in a protection mode…being too long in this mode creates changes even at biological level that can lead to illness and eventually can even lead to death…

    if you are not in fear but at easy and in love and feeling loved, love mode, defences are down, you can relax and then the immune system becomes active again and strong, reinforces and you can grow and literary become more intelligent, smart..

    in our modern day we can achieve that by meditation, mindset and effective passive protection by looking up environments which provide the right external stimulus to your senses, receptors which are connected into your biology thus cell level…that way the right genes will be activated and even changed when needed..

    environments means physical places and substances, ( radiation, toxins, sun light etc) healthy or not, but also meme and thoughts and literary good and bad habits and in between…

    bad unhealthy habits, specially the ones you got programmed with, even before being born and as a child, can be changed…reversed and positively changed, this only can be done with the subconscious mind…you need to reach your subconscious mind…

  7. Hope this’ll work. Husband was AWFUL when we dated. I had gotten bad PTSD from years of various abuse types from not just him. He eventually grew up and stopped and is a model husband and father 11 years later but no matter how gentle and patient and understanding he is about what all the trauma and behavioral conditioning did, I just can’t feel safe around people. It offends friends who try very hard not to trigger me. Most of all I feel like I will never again truly love my husband because every time I start to feel lovey dovey my thought process goes into panic overdrive and I spaz and push everyone away. I want to stop living in reaction based fear. I KNOW not every raised hand is going to hit me. I KNOW not every surprise touch will end up a rape. But try telling that to my nervous system.

  8. EMDR is also a non-drug treatment option for ptsd. Though it is still yet to be heavily studied to the extent of some other therapies.

  9. So, if the animals were able to unlearn their fear memories thirty days after they were formed, when the extinction therapy was combined with the HDAC inhibitor, are we to conclude that a 30 day period is considered a “long-term” fear memory and are we then, also concluding that this provides hope to some people that have older formed fear memories? It seems like this is the conclusion that we are led to believe. I think, however, that 30 days should be considered short-term fear memories. After quoting: “traumatic memories can persist for a lifetime” it seems unrealistic that one could predict when a person would need the HDAC inhibitor unless you are talking about using it for men/women whom you know are going to experience a traumatic event such as war. So, are these HDAC inhibitors made for super soldiers without fear? In what other circumstances would someone know that they are going to experience trauma and form fear memories?

    [Katie — Well, it’s unclear how this research will or won’t apply to people. That said, remember that a mouse only lives a couple of years, so 30 days is actually quite a long time. And even in people, long-term memories seem to form on the order of hours. So I think it’s not far-fetched to think that if something worked on 30-day-old memories it would work on much older ones as well. We don’t know that yet, of course. 🙂 –Ginny ]

  10. Another study from LeDoux lab showed that if you shut down global protein translation and then try to remember a particular fear memory , then you specifically erase that memory. This means that recycling of a certain protein at synapse is important after the memory is recalled. Since mRNAs are already poised at the synapse, this process of reinstegating the memory you recall is pretty fast. Modifying epigenome must have reduced the amount of mRNA that should be recycled or something that is important in the recycling process. I think pinning down the protein involved in this process is also need of the hour.

  11. I agree with Chris, EMDR is a much better and natural method. No drugs, just go to a licensed EMDR practitioner. It really works, bad memories and the associated feeling and trauma will go away.

  12. Maybe im just being the devil’s advocate here – but does nobody else see the danger in this? I understand that the HDAC inhibitor apparently won’t affect tangible memories, but from what I understand, the drug has a direct and immediate influence on conditioned response – which is not always a negative thing.

    Example: The “fear” induced by being hijacked means that I automatically go into super-safe aware mode whenever I see somebody dodgy-looking wondering around an intersection. Intellectually I was always aware of the risk, but living through a traumatic experience made me ultra-aware on an involuntary level – something that has done me good since.

    I understand the obvious benefits of the drug, but how far will it go in humans that they cannot test in rats? Our neural response mechanisms are much more complex – Taken to it’s extreme conclusion, this theory implies separation of all conditioned hard-wired response mechanisms.

    – It just seems like a massive gamble. Think of a baby touching a hot stove for the first time. The reaction that follows is a conditioned fear that will be essential for the rest of the child’s life. Do we really want to be messing with our hard-code?

    [Darren — I think you’re asking really important questions. There is always risk when new treatments are being translated from animal research into clinics. Researchers should wade carefully into this testing, just as they should for any experimental drug. –Ginny]

  13. If this drug relates specifically to neuroplasticity then I immediately wonder if it can be used as an aide to accelerate the learning process in adults rather than just treat PTSD.

  14. If this drug relates specifically to neuroplasticity then I immediately wonder if it can be used as an aide to accelerate the learning process in adults rather than just treat PTSD.

  15. I have PTSD and went through EMDR therapy ( Eye Movement Desensitization and Reprocessing) It was awful! I went through it for months and all it did was force me to live through the horrible things that happened to me, the things that caused the PTSD. It didn’t make me better, it didn’t help. It made me worse and turned me into this sad, angry person who my family ended up disliking. People with PTSD can be angry any way and this therapy sure ampt up that part of the PTSD. A drug like that would be wonderful if it worked in humans and didn’t have horrible side effects like most drugs do. Most of the time you end up switching one ailment for another that is almost just as bad but in its own way. The meds I’m on now help with my depression and a touch of the anxiety, but I’m still paranoid, still freak out when even a fly flies too close or even a bird’s shadow crosses my path when its flying overhead. Thanks to the meds, I now have an added lack of motivation and don’t care about squat in my life. They really need to do more research and focus on helping those not only with PTSD but with other mental illnesses. Perhaps this is a start.

    [Thanks so much for sharing your experience, Katie. Hope things go better for you in the future. –Ginny]

  16. I’ve PTSD since a home jacking took place. My son also has it. I’m not going into any details from that night we had to experience. It’s hard having a normal life now. Panic attacks, insomnia, paranoia etc, etc. Hope this treatment can help a lot of people like us having ptsd

    [Thanks so much for sharing your experience, Kenneth. I wish you and your son better times to come. –Ginny]

  17. I have PTSD was well and I am 57 my attacks etc. happened when I was 9 thru the age of 16 they were a long time ago. I have worked thru all the horror that happened, still I will have episode’s of PTSD just depends on what triggers it. The therapy there talking about sounds to emotionally painful. The new treatment sounds scary, I need to know to be protected by my instincts I am afraid the treatment may take that away. NOT THAT I WILL BE PRIVEY TO ANY IN MY LIFETIME!!!!!!

    [Thanks for sharing, Deirdre. Glad to hear you’ve gotten better over the years. As for whether the treatment will be available in your lifetime, you never know. This particular area of science seems to be moving very quickly. –Ginny]

  18. Yes Manely, it is so easy to meditate and reach your subconcious after someone witnesses their friends’ blown up and have to help clean up their body parts form a roadside IED. Or perhaps being brutally raped. Please do tell how this is so easy.

  19. My daughter is an addictions counselor and she told me about this. It has been tested on people and there were good results. If I were in need of it I would search for it on the internet to find studies or more research. I am not comfortable telling you the next part, but I can hear the desperation in your words. My daughter told me that the drug is ecstasy, which means there is some care to be taken ingesting that, and knowing the name might help the research. I think it must be obvious that taking ecstasy wont do anything for you without the proper medical guidance. In fact, it can cause a lot of harm, and you also don’t know the proper dosage for this proceedure.

    [Thanks for this, Catherine. This particular drug isn’t ecstasy, but you’re right that other researchers are experimenting with ecstasy treatment for PTSD. –Ginny]

  20. I was diagnosed with PTSD in March 2010 after trauma experienced during a procedure that was performed on me in a hospital. My anxiety levels are still too high for CBT almost 4 years later, so I would be very grateful if this worked. Sick of being sick and tired and also sick of treatment and meds – but it would be awesome if this could work. Using it as a preventative measure though – no. Absolutely not. My deepest love to all PTSD sufferers, and sending angels to all who have commented here. xx

    [Thanks so much for sharing, Retha. –Ginny]

  21. Fascinating of course, but one thing occurs to me: Removing the memory of trauma may induce the victim of childhood assault to be no longer motivated to help track down the perpetrator.

  22. In a video on plant intelligence — the roots reach out in an oscillating format , unless the end of the root is cut, and then the roots grow straight out — now for humans , and our very sensitive nerves , which have nerve endings past the actual nerves , can learn to tune into this oscillating energy with helpers , teachers, words , sounds , light , and meditation , even if your nerves are cut , your beautiful sense of feeling into the future still exists .

  23. Obesity is rampant in our society and there is some speculation that certain genes can be influence in a way to cause a precursor for obesity in people. While curious about the question I intend to ask of this forum, I do consider that eating healthy and exercise are key to living well and being fit. Having said that, could the above research be used to help suppress the gene that gives a predisposition to obesity and help the person achieve and maintain a healthy life? In essence, giving the person with the predisposition an opportunity to combat obesity both on the environmental front as well as on the genetic front?

  24. Ginny,when would this theory probably go to the clinic? Can you give me some hope,please? I need this. God bless you!

  25. Remarkable Post. I enjoy your creating style a great deal. I trimmed this post to Evernote and will review that again shortly! Keep up the favorable work.


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