Mice with amnesia could recall specific training after having their memories jogged by blue lights — the first time researchers have been able to suppress a memory and then restore it in an animal. And while that technical feat is impressive, what's more important is what the study in Science suggests: in some cases, memories that are lost due to brain trauma may still be present in the human brain.
The kind of memories that are often never recovered
Amnesia comes in many forms. In some cases, people have trouble forming memories after sustaining a brain injury; others are unable to recall the events that led up to a brain injury. The latter is called "retrograde amnesia," and it’s this particular form of memory loss that the researchers looked into. They wanted to see if they could retrieve lost memories — the kind that are often never recovered.
To do this, researchers at MIT trained two groups of mice to associate a mild electrical shock to the foot with a specific environment, called Chamber A. The foot shock caused the mice to freeze in fear; eventually, just placing the mice in Chamber A triggered this response without the shock. During this training phase, the researchers also identified which neurons — in this case, cells in the brain that the researchers call "memory engram cells" — were active while the mice learned to fear Chamber A. The scientists labeled these cells with a protein that's sensitive to blue light, smuggled into the cells using a virus designed to seek them out. When the researchers shined a blue light on the engram cells, they activated the memory — causing the mice to freeze again, even though they were in a neutral environment.
This use of blue light to activate certain cells is called "optogenetics." It’s the same technique that was used a few years, by the same group of researchers, to implant false memories in mice. But using it to recover a memory that had already been formed is completely new.
"We can still retrieve the memory by directly activating it in the brain."
Here's how the scientists did it. Once the two groups of mice were adequately trained, the researchers injected one group with a drug called anisomycin — a drug that inhibits memory formation. The second group was injected with a saline solution. Then, the researchers returned both groups to Chamber A. "The guys that got the drug didn’t freeze to the training context — they're weren’t afraid of it," explains Tomas Ryan, a neuroscientist at MIT and a co-author of the study. The mice that got the saline, on the other hand, kept freezing in Chamber A.
At this point, the researchers were certain that the mice in the first group were displaying retrograde amnesia; they had lost the memory of the training. So, the scientist decided to activate the neurons once more, using blue light. Remarkably, it worked. The amnesiac mice froze in a neutral environment, just as they had before. And the memory that returned in these mice was as strong as the one in the saline-treated mice.
The memory that’s lost because of retrograde amnesia isn’t destroyed in the mice. "We can still retrieve the memory by directly activating it in the brain," Ryan says — an idea that has never been demonstrated experimentally in animals before.
"I can't think of what they could have improved," says Yave Lozano, a neuroscientist at University College London. Nonetheless, the work showed that it's possible to "reactivate the fear memory that had been blocked."
Why was the memory retrieved?
The researchers didn’t stop there. The wanted to find out why the mice had been able to retrieve the memory. So the scientists went back to the engram cells. By looking at brains of trained mice, they found that the connections between the engram cells in the hippocampus — a seahorse-shaped brain region that's associated with memory — had been strengthened thanks to the training and the labeling of the cells. That made the memory far easier to retrieve after light activation.
Engram cells create a network across multiple brain areas
Still, this didn't explain where the memory had been stored in the meantime. The researchers began to wonder if it might be encoded in the way their targeted cells interacted, Ryan says. They guessed that engram cells might create a network that’s distributed throughout many brain areas, so they started to look beyond the region of the brain that they had labelled.
Eventually, their search lead them to figure out that the engram cells in one part of the hippocampus were strongly connected to another part of the hippocampus, and it was this pattern of connectivity that survived the drug treatment. When they extended the search further, they realized that other regions of the brain, including the amygdala, where where fear-based memories can be found, were also involved in this network. The researchers were therefore able to retrieve the memories because other connections in the brain — connections that were unaffected by the drug, but inaccessible without the light treatment — were storing information related to the shock treatment as well.
"So what we think is that when we're activating engram cells, we're able to activate a whole engram circuit," Ryan says. The drug used to cause amnesia severs the circuit somehow. But with blue light, the researchers can give the circuit a powerful kick that reactivates it and makes the memory accessible once more.
The blue light gives the memory circuit a powerful kick
"We have strong reason now to believe that memory storage — that is, the storage of the memory information itself — is encoded through connectivity patterns of engram cells throughout the brain," Ryan says.
If the finding holds up in future studies, it's bound to have a large impact on memory research going forward. But this work isn't going to help people who suffer from retrograde amnesia or Alzheimer's disease any time soon. "It's very difficult to be doing this in humans, partly for the ethical reasons — the work is invasive — but also because we tag the memories in the brain before they're learned," Ryan says. This means that if the researchers wanted to help someone recover a memory, they would have to be present when the memory was formed.
That isn't to say that this isn't useful information. The study provides important information regarding the mechanisms behind retrograde amnesia — and perhaps even a bit of hope for those who suffer from it. "If you have had significant retrograde amnesia for a particular event due to brain trauma, it's quite possible that those memories are still present," Ryan says. What that means is that scientists can begin asking a new question: how to find them.