In a remarkable feat achieved earlier this year, a team of French neuroscientists manipulated memories in sleeping mice, using electrodes inserted into the brain to turn neutral memories into positive ones.
Now, neuroscientists at the Massachusetts Institute of Technology’s Tonegawa Lab have taken another major step forward in the science of memory manipulation. In a study published this week in the journal Nature, the researchers describe how they succeeded in reversing depression-like behavior in mice by artificially reactivating happy memories.
The findings — the first of their kind — could have major implications down the road for the treatment of depression in humans. If scientists are able to manipulate the brain cells where memories are housed, it may one day be possible to develop pharmaceutical therapies for depression that are more targeted than antidepressants, which work across the entire brain.
“Once you identify specific sites in the memory circuit which are not functioning well, or whose boosting will bring a beneficial consequence, there is a possibility of inventing new medical technology where the improvement will be targeted to the specific part of the circuit, rather than administering a drug and letting that drug function everywhere in the brain,” said senior author Dr. Susumu Tonegawa, a professor of biology and neuroscience at MIT.
While this type of intervention is not yet feasible in humans, “there is hope that knowledge obtained from this type of animal model study could be taken advantage of, in the future, when it is combined with less invasive technology,” Dr. Tonegawa told the BBC.
Hotwiring the memory
Dr. Tonegawa, who was awarded the 1987 Nobel Prize in Medicine, has been at the forefront of some of the most important advances in memory science in recent history.
In 2012, Dr. Tonegawa and MIT colleagues Steve Ramirez, a doctoral student, and Dr. Xiu Li, a former postdoc, demonstrated for the first time ever that it was possible to label and reactivate clusters of brain cells that store specific memories, which they called engrams. A short time later the team made another groundbreaking discovery, showing that they could actually plant false memories and switch the emotional associations of a particular memory (from positive to negative, and vice versa) by manipulating certain clusters of engrams.
The tool that allows the MIT team to explore and manipulate the brain is called optogenetics — a process whereby researchers insert the DNA of a light-sensitive protein into specific neurons, allowing them to switch those particular neurons on and off using flashes of light. The technique, which developed over the past decade, has shown tremendous potential to help researchers understand brain function and treat brain disorders, because unlike electrical stimulation or pharmacological methods, it allows for very precise activation and deactivation of neurons. It’s this precision that has allowed Dr. Tonegawa’s team to carry out their groundbreaking experiments. In addition to learning and memory, optogenetics has been used to study sleep, pain, addiction and social behavior, and has been highlighted as a technology crucial to the success of the White House’s new BRAIN initiative.
In this latest study, the researchers built on their past work with optogenetics to determine whether their ability to reactivate existing memories could be exploited to treat depression.
First, the researchers exposed the mice to positive social experiences, which allowed them to isolate the brain cells that held the happy memory of the experience. Then, they marked those brain cells with a light-sensitive protein that activates the neuron in response to blue light. Some time after the social interactions passed, the researchers were able to reactivate the positive memories by shooting a beam of light into the brain cells where they were stored.
Then, the researchers induced depression-like symptoms — such as giving up easily on a challenging task and losing pleasure in enjoyable activities — by exposing the mice to ongoing stress.
When the brain cells were reactivated with a beam of light, the mice experienced a complete reversal of the depressive symptoms, displaying renewed motivation and ability to experience pleasure for the duration of time that the memory was activated. In contrast, reactivating neutral- or negative-tagged memory neurons did not have this effect.
Notably, the researchers also found that allowing the mice to engage in pleasurable social experiences after becoming depressed did not improve their symptoms nearly as much as reactivating an old memory — so in other words, the memory gave them more pleasure than the experience itself.
A new treatment for depression?
So does this mean that simply thinking about happy memories can help reduce symptoms of depression? Probably not. As the researchers explain, a common symptom of depression is the inability to derive pleasure from positive memories or even to recall them in the first place.
“People who suffer from depression have those positive experiences in the brain, but the brain pieces necessary to recall them are broken. What we’re doing, in mice, is bypassing that circuitry and forcing it to be jump-started,” Ramirez said. “We’re harnessing the brain’s power from within itself and forcing the activation of that positive memory, whereas if you give a natural positive memory to the person or the animal, the depression that they have prevents them from finding that experience rewarding.”
However, the findings do offer a potential biological explanation for the success of certain psychotherapies in which patients are trained to recall pleasant experiences or repeatedly exposed to pleasant imagery. “In some way this depression state suppresses the ability to recall positive experiences, and what the psychiatrist is doing is trying to override that and help them to recall those memories,” he said. The
What’s most exciting about the results, the researchers said, is that they support the possibility of developing entirely new approaches to treating depression, and potentially other brain diseases. If scientists could develop a noninvasive way to stimulate specific brain circuits, they might be able to achieve the same effects seen in this study using optogenetics. One way to accomplish this could be a more targeted form of deep-brain stimulation, which requires implantation of a brain pacemaker that sends electrical impulses to specific parts of the brain. Deep-brain stimulation is sometimes used to treat Parkinson’s disease, depression, and obsessive-compulsive disorder, among other diseases.
The problem right now “is that deep-brain stimulation is crude and activates a large chunk of the brain,” explains Ramirez. “You could imagine in the future that if you could target deep-brain stimulation not to patches of brain but to specific sets of cells that we think are holding onto a positive memory, then it offers a new therapeutic avenue.” Targeted pharmaceutical therapies may also be able to achieve the same outcomes, he added.
Ramirez hopes that scientists will one day find a way to prevent depressive symptoms from occurring in the first place by artificially stimulating positive memories prior to stressful exposures. In the study, the researchers found that repeatedly stimulating brain cells to recall positive memories — instead of reactivating them only once — protected the mice from developing symptoms of depression, even without reactivating the memory cells after the mice were exposed to the depression-inducing stimuli. In other words, repeated exposure to positive memories may increase resilience to adversity, indicating a potential preventive mechanism.
The authors concluded the article with a special dedication to Dr. Liu, their former colleague and co-investigator who passed away before the study was published: “We dedicate this study to the memory of Xu Liu, who made major contributions to memory engram research.”