Memory is the house of spirit, the hazy room in which our former self lingers stoking a persistent if invisible fire. In a new exploration of this most mysterious of mental processes, MIT neuroscientists find recollections that have disappeared as a result of amnesia can be retrieved by activating brain cells with light. This technology — one that quite literally illuminates the dark unknown — is called optogenetics.

The research, led by Dr. Susumu Tonegawa, a professor of biology and director of the RIKEN-MIT Center at the Picower Institute for Learning and Memory, springs from a familiar debate. For years, neuroscientists have disagreed whether amnesia is caused by damage to specific brain cells (causing an inability to store a memory) or by blocked access (causing an inability to recall a memory). Most scientists argue that amnesia is a storage problem, not an access problem.

The new research ends the debate once and for all. However, before answering this question, we must briefly revisit a prior model of memory.

Memory Engram Cells

Ironically, one of the most important theorists of memory is virtually unknown and seemingly forgotten.

Zoologist and biologist Richard Wolfgang Semon proposed the idea that each of our experiential memories is represented by a mneme, which he named after the Greek goddess of memory. He believed stimuli from the environment produces in an organism a “permanent record... written or engraved on the irritable substance.” Cellular material, Semon suggested, is predisposed to such inscription and a “mnemic trace” (or engram) revives whenever an element that resonates with the original complex of stimuli is encountered.

Clearly based on Semon’s 20th century theory, the contemporary concept declares the process of acquiring a memory activates an entire population of distributed neurons known as memory engram cells. Because the original activation of these neurons causes enduring physical and chemical changes in our nervous system, a simple sight or smell may trigger reactivation of the entire linked group, and we experience this as a memory.

For the current study, Tonegawa and his crew began by revisiting a 2012 optogenetics study. Using this technology, which adds proteins to neurons in order to allow them to be activated with light, the team had demonstrated for the first time ever that memory engram cells do exist in the hippocampus. Taking this 2012 study further, Tonegawa and his colleagues wanted to prove the process known as memory consolidation causes these neurons to undergo enduring changes.

One such change, long-term potentiation (LTP), involves the strengthening of synapses, the structures that allow groups of neurons to send signals to each other. How exactly does LTP work?

To find out, the researchers first identified a group of engram cells in the hippocampus of mice, and activated them using optogenetics. Here, they found the cells were capable of expressing a memory. Observing without interference, the researchers noted how the connective synapses became strengthened as the long-term memory consolidated.

Next, the researchers conducted a simple experiment to discover exactly what happens when a memory does not undergo consolidation. They administered anisomycin — a compound which blocks protein synthesis within neurons — immediately after mice had formed a new memory. By this method, the synapses were prevented from strengthening.

Returning one day later, the researchers attempted to reactivate the memory using an emotional trigger. They found no trace of it.

“So even though the engram cells are there,” Tonegawa stated in a press release, “without protein synthesis, those cell synapses are not strengthened, and the memory is lost.”

The experiment, though, did not end here. Using optogenetic tools, the researchers then reactivated the protein synthesis-blocked engram cells.

Remarkably, the mice exhibited all the signs of recalling the memory in full.

“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,” Tonegawa said. Further experiments demonstrated that memories are stored in a circuit, or “pathway” of connections between groups of engram cells. Quite like people, then, it is the group and not any individual cell that retains a complete memory.

“We are proposing a new concept, in which there is an engram cell ensemble pathway, or circuit, for each memory,” Tonegawa said. “This circuit encompasses multiple brain areas and the engram cell ensembles in these areas are connected specifically for a particular memory.”

And so, based on these findings, Tonegawa called an end to the amnesia dispute. Such memory loss is not a problem of damaged cells, he says, but a problem of impaired retrieval.

Source: Ryan TJ, Roy DS, Pignatelli M, et al. Engram Cells Retain Memory Under Retrograde Amnesia. Science. 2015.