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Memories Can Be Edited

New advances in changing memories show the field could hold great promise for both therapy and theory of memory
PTSD therapeutics


A definitive study published early this year has now claimed memory adjustment from the domain of fiction: Researchers were able to modify the distant recollections of fear in mice, opening way to novel PTSD therapeutics in the future. 
Credit: Thinkstock

“My name is Joel Barish and I am here to erase Clementine Kruczynski,” declares Joel to Dr. Mierzwiak, the head of a local memory erasure clinic, Lacuna Inc. Joel has just been through a bad break-up with Clementine, and he was stunned to find out that she had him removed from her memory. Spiteful, Joel rushes to Lacuna to have her removed off his memory. As the procedure takes hold, Joel gets cold feet but it is too late: The memories of Clementine slowly fade away. Then one day, a new Joel with no Clementine left in mind, skips work on a whim and takes a train to a beach in Long Island. Only to meet Clementine, again, for the first time. Rinse and repeat.
 
A contorted tale of memory and love, Eternal Sunshine of the Spotless Mind leaves us with a wondrous sense of memory, one of a familiar sort: It is a strong reminder of how we obsess over memories (especially the ones that hurt) and how to rule over them. But now, with 20% of 2.3 million war veterans coping with post-traumatic stress disorder (PTSD) in the US, the engineering of traumatic memories now is more than a philosophical curiosity, but a medical priority.
 
A definitive study published early this year has now claimed memory adjustment from the domain of fiction: Researchers were able to modify the distant recollections of fear in mice, opening way to novel PTSD therapeutics in the future.
 
Be it wounds of rape, war or loss: we all know people affected by traumatic events. As intangible as it is, psychological trauma is also very real: Events of extreme stress can force the cognitive restructuring of one’s worldview, sometimes to the extent that leads to major social disability, as in the PTSD. It’s now estimated that about 1 out of every 13 people in the US will have PTSD at some point in their lives. The high prevalence naturally brings about urgency in intervention yet unfortunately there hasn’t been much in the way of eradicating trauma, especially when it comes to distant memories. One of the most effective treatment options for PTSD is a cognitive restructuring practice called exposure therapy: A patient is continuously confronted with the original memories of trauma in order to open up a window of memory updating (termed memory reconsolidation). This renders the memory susceptible to positive modification. A major drawback remains that this is only applicable to the recent memories, while the intervention is most urgently needed for patients with remote memories of trauma, which are infamously stable and resistant to modification.
 
In order to go at the distant memory challenge, Researchers utilized a rodent homologue of stress in the form of classical conditioning: First, animals received electrical foot shocks that were paired with an innocuous stimulus, say a tone. After several bouts, exposing these mice to the paired tone alone was enough to elicit a fear response (freezing) in the absence of foot shocks. Then comes the exposure therapy: The fear response was then made ‘extinct’ after several trials of playing the tone without the shock: Mice are able to overcome their fears by associating the tone with a safe environment. This approach by itself, however, had only worked on very recently formed memories. Where the study should collect the first accolade in novelty is at the timing between the fear conditioning and its extinction: For the first time in history, researchers managed to extinguish fear 30 days after it was instilled.
 
The foundation of exposure-based techniques lies in invoking “plasticity” in brain, i.e ability to rearrange a given set of neural connections. During the rectification of a previously formed memory, the neurons reorganize to accommodate the new information. This plasticity is what enables us to select, archive and connect incoming data about the world in real time. Until now, both in mice and men alike, updating distant memories have proved problematic precisely because exposure therapy-induced plasticity has never been quite enough to reanimate the needed plasticity.
 
Researchers then had to find a way to reinstate plasticity in these hoary and hardy memories. The elegant solution came from the idea that if they could access the genes that confer plasticity, they could go at the root of the problem. We cannot directly edit genes in mammals (yet), but we can manipulate their activity: How? Enter the epigenome.
 
Epigenetics is the study of molecules that interact with genes and control their activity in a given cell. These can either be GO or STOP modifications that render a particular gene active or inactive. Recent research shows that, among a constellation of cues that direct many cellular events, the epigenetic signals take the higher echelons: They have been shown to govern a long list of cellular phenomena from memory formation to addiction. Plasticity is heavily under such regulation: Remote memories are cemented due to the accumulation of epigenetic STOP signals over plasticity genes.
 
This is where the researchers were able to pick the lock on distant trauma: In addition with exposure therapy, they used an epigenetic modifier agent called CI-994, which inhibits the enzyme responsible for removing the GO signals. This was able to release the previously obscure veil over distant fear memories, leaving them susceptible to attenuation followed by positive adaptation. Similar studies have been done, in which investigators administered the epigenetic agent before the mice acquired the fear memory, which speeded its extinction weeks later. However, by nature, traumatic events are unpredictable and a treatment option that targets post-trauma symptoms, like of the one used in the current study, is more desirable.
 
Needless to say, the implications are promising for victims of PTSD and associated stress disorders. Insinuations for what this means for defining what memory is equally interesting.
 
“Topographic,” “recognition,” “procedural,” “flashbulb”… We categorize types of memory by classifications that are purely based what they “look like” (be it long- or short-term, task- or object-oriented) and not necessarily based on their underlying molecular architectures. Studies like this one, that define the distinct epigenetic landscapes of recent vs. remote memories, potentially pave way towards more empirically-informed classification systems of memory. In a way, by showing that core difference between an old and a recent memory is their epigenetic baggage, the implication is that the epigenetics might be the language to scientifically discuss the different forms of memory.

Are you a scientist who specializes in neuroscience, cognitive science, or psychology? And have you read a recent peer-reviewed paper that you would like to write about? Please send suggestions to Mind Matters editor Gareth Cook, a Pulitzer prize-winning journalist and regular contributor to NewYorker.com. Gareth is also the series editor of Best American Infographics, and can be reached at garethideas AT gmail dot com or Twitter @garethideas.

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