Lost and found: reactivating memories with light

In a paper, recently published in the journal Science, a group from MIT reveal how to reactivate memories that could not otherwise be retrieved by directly stimulating the specific neurons associated with a memory using light.

Neuroscientists have long debated whether retrograde amnesia – following traumatic injury, stress or disease – is caused by damage to the memory storage itself or if access to that memory has somehow become blocked.

Susumu Tonegawa, the Picower Professor in MIT’s Department of Biology and Director of the RIKEN-MIT centre at the Picower Institute for Learning and Memory (and corresponding author for the study), said: “The majority of researchers have favoured the storage theory, but we have shown in this paper that this majority theory is probably wrong. Amnesia is a problem of retrieval impairment.”

Cell discovery

In 2012, Professor Tonegawa’s group used optogenetics to show that a population of neurons known as memory engram cells exist in the hippocampus, part of the brain heavily associated with memory.

These neurons are activated during memory acquisition, causing enduring physical or chemical changes. If these neurons are later reactivated by some form of trigger (e.g. a certain sight, smell or sound) the entire memory is recalled.

However, no one has previously shown that these neurons undergo the lasting changes associated with memory consolidation. Long-term potentiation (LTP) is one of these changes that involves the strengthening of synapses, the structures that enable communication between neurons.

Illuminating the memory consolidation process

To observe whether synapse strengthening occurs in engram cells, the researchers created light-sensitive cell populations in the hippocampus and then stimulated them with light to induce firing and recall a memory. Recorded activity after optogenetic stimulation showed that the synapses had been strengthened.

They then tested the consequence of interrupting the consolidation process. Administration of the compound anisomycin, which stops protein synthesis in neurons, prevented the synapses from strengthening upon activation.

Twenty-four hours later the researchers attempted to retrieve the memory using an emotional cue without success showing that protein synthesis is necessary for synaptic strengthening. However, when the researchers directly activated the engram cells with light the mice exhibited signs of recalling the memory in full.

Professor Tonegawa said: “If you test memory recall with natural recall triggers in an anisomycin-treated animal, it will be amnesiac, you cannot induce memory recall. But if you go directly to the putative engram-bearing cells and activate them with light, you can restore the memory, despite the fact that there has been no LTP.”

Further experiments demonstrated that memories are not stored in the synapses themselves but in a circuit, or “pathway” of groups of engram cells and their connections.

According to Tomas Ryan, one of the lead authors of the paper, this research dissociates the mechanisms of memory storage from memory retrieval. He said: “The strengthening of engram synapses is crucial for the brain’s ability to access or retrieve those specific memories, while the connectivity pathways between engram cells allow the encoding and storage of the memory information itself.”

These findings mean that it may be possible to retrieve memories in patients with retrograde amnesia by restoring the ability to retrieve the memory.

Paper reference

Ryan T.J., Roy D.S., Pignatelli M., Arons A., Tonegawa S. Engram cells retain memory under retrograde amnesia Science, 348:6238 1007-1013 (2015) doi: 10.1126/science.aaa5542