Light Hides Path to Lost Memories

Researchers from the RIKEN-MIT Center for Neural Circuit Genetics have created their own "blue light special" for mice-but this one helps them recall memories that had been suppressed. Their study, published in the journal Science, also suggests something even more profound: even memories that have been assumed to be lost after traumatic injury to the brain may still exist, and be retrievable.

There is more than one way to lose your past, even from amnesia, because there is more than one variety. The type that this research impacts is retrograde amnesia: this is the variety that causes one to be unable to recall established memories. In other words at some point in life you formed the memories and they were stored, but then brain trauma made them inaccessible. Typically associated with Alzheimer's disease as well as traumatic brain injury (TBI), this kind of loss has always been assumed to be permanent.

The RIKEN team, led by Susumu Tonegawa, RIKEN director, has now established that these "lost" memories do stay in the brain of an amnesiac, and can even be found again. The secret is in the reactivation of neurological pathways that lead to them.

"Brain researchers have been divided for decades on whether amnesia is caused by an impairment in the storage of a memory, or in its recall," says Tonegawa. And while this is the same technique that researchers have used to implant false memories, optogenetics, this is a first because the memories are real and already existed.

The researchers caused amnesia in the mice by shocking their feet to "freeze" them with fear. Eventually they associated a certain location with fear and no shocks were needed to elicit the fear response. The scientists then genetically labeled neurons called "memory engram cells" that are active in memory formation in the mice so that they could be visualized and reactivated with a trigger. The labeling agent was a protein sensitive to blue light; the researchers were able to label the cells using viruses carrying the agent. Finally, they exposed the mice to the special light, triggering the fear response in a neutral setting.

Some of these mice, after they were trained, were given a chemical that inhibits memory formation, anisomycin. This drug works by preventing any increases in synaptic strength by inhibiting new protein synthesis, thus inducing retrograde amnesia. Control mice simply received saline solution. The mice who had received the drug did not freeze in the fear environment; they had forgotten the shocks. The other mice continued to freeze.

"The guys that got the drug didn't freeze to the training context-they're weren't afraid of it," says Tomas Ryan, coauthor of the study and neuroscientist at MIT.

Of course the truly remarkable part was bringing the lost memories back: "We can still retrieve the memory by directly activating it in the brain," Ryan says.

The next step in the process was to explain how this happened. The researchers suggest that the processes for recall and memory encoding may be controlled separately. This would mean that during the training period-when the mice were taught to fear-certain neurological structures may have been strengthened. This would result in a need for more synaptic strength for different memory related tasks.

"So what we think is that when we're activating engram cells, we're able to activate a whole engram circuit," Ryan says. Even the use of an amnesia-inducing drug severs the circuit needed to retrieve the memory, but the blue light has a powerful effect on the circuit, giving it enough of a jump start to work again.

"Our conclusion," says Tonegawa, "is that in retrograde amnesia, past memories may not be erased, but could simply be lost and inaccessible for recall. These findings provide striking insight into the fleeting nature of memories, and will stimulate future research on the biology of memory and its clinical restoration."