A clean slate—that’s what people suffering from posttraumatic stress disorder (PTSD) crave most with their memories. Psychotherapy is more effective at muting more recent traumatic events than those from long ago, but a new study in mice shows that modifying the molecules that attach to our DNA may offer a route to quashing painful memories in both cases.
One of the most effective treatments for PTSD is exposure psychotherapy. A behavioral psychologist asks a patient to recall and confront a traumatic event; each time the traumatic memory is revisited, it becomes susceptible to editing through a phenomenon known as memory reconsolidation. As the person relives, for example, a car crash, the details of the event—such as the color and make of the vehicle—gradually uncouple from the anxiety, reducing the likelihood of a panic attack the next time the patient sees, say, a red Mazda. Repeated therapy sessions can also lead to memory extinction, in which the fears tied to an event fade away as old memories are replaced with new ones.
Yet this therapy works only for recent memories. If too much time passes before intervention, the haunting visions become stalwart, refusing to budge from the crevices of the mind. This persistence raises the question of how the brain tells the age of a memory in the first place.
Researchers at the Massachusetts Institute of Technology, led by neurobiologist Li-Huei Tsai, have now uncovered a chemical modification of DNA that regulates gene activity and dictates whether a memory is too old for reconsolidation in mice. A drug that tweaks these “memory wrinkles” gives old memories a face-lift, allowing them to be edited by reconsolidation and resulting in fear extinction during behavior therapy.
In the new study, published online this week in Cell, the researchers instilled traumatic memories in mice by placing them in an unfamiliar cage and immediately giving them an electrical shock to their feet. The rodents quickly became terrified of the cage, and when returned to the setting, they instantly froze in anticipation of a shock.
Once the researchers had instilled the fear memory, they repeatedly returned the mice to the cage without the shock, either 24 hours or 30 days later. Rodents given this behavior therapy 24 hours after the jolts eventually stopped freezing, suggesting that reconsolidation and memory extinction were erasing the anxiety connected with the cage. But if the researchers returned the animals to the cage after 30 days, the mice remained afraid, indicating that older or “remote” memories were less forgettable.
Prior work on rodents has shown that the reconsolidation update stage—the point when a recalled memory is most vulnerable to change—parallels an increase in so-called histone acetylation to DNA. DNA spools around proteins known as histones like yarn, and gene activity shuts down in the tightly wrapped regions. Acetylation, or the addition of an acetate molecule to the histone, loosens the DNA, turning these genes back on. (Such chemical modifications to DNA are known as epigenetic modifications, and they have been linked to everything from obesity to Alzheimer’s disease.) To keep the genetic material tightly bundled, a family of enzymes—called HDACs—surfs the DNA, preventing histone acetylation.
The new study reveals that one of these enzymes—HDAC2—patrols genes in the mouse hippocampus, a brain region responsible for learning and memory. However, the researchers found that HDAC2 performs this job only when older memories are being reconsolidated, not when recent memories are facing a similar update. The key difference was a biochemical change to HDAC2 called nitrosylation. HDAC2 was nitrosylated within 30 minutes of recalling recent memories, but not with remote recollections. Thus, nitrosylation appears to serve as an on-and-off switch that denotes the age of a memory.
Many studies have shown that epigenetic changes are fundamental to learning, but Tsai’s work goes a step beyond this, says Jelena Radulovic, a psychiatrist and molecular pharmacologist at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois, who was not involved with the current research. “Specific nitrosylation of HDAC2 obviously affects several genes important for reconsolidation updates—apparently as memories age, this mechanism fails.”
When Tsai’s team switched off HDAC2 with a drug, reconsolidation of remote fear memories occurred after behavior therapy. Thus, anxiety resulting from older traumas was wiped away akin to more recent memories. These findings paralleled an enhancement of neuroplasticity—genetic and structural changes in neurons—within the hippocampus, which are indicative of memory reshaping. Glucose metabolism in the hippocampus, a broad estimate of learning capacity, was also boosted in this series of experiments.
This is the first study to attenuate remote—older—fear memories in an animal model, according to the authors.
If the findings apply to humans, the potential uses of HDAC inhibitors would extend far beyond the realm of PTSD, says Kerry Ressler, a psychiatrist at Emory University in Atlanta, who was not involved with the study. “The basic idea of exposure therapy holds across a number of anxiety and fear-related disorders, including PTSD, panic disorder, and phobias like fear of heights, where fear memories are often more remote,” Ressler says. Combining psychotherapy with a drug that augments memory retrieval could access these deeply buried fear memories, while also reducing the number of sessions a patient needs to eliminate their anxiety, he says.