Where in the Brain is Long-Term Memory?

In the early 1900s, German evolutionary biologist Richard Semon first proposed the idea of the engram, loosely defined as a physical trace of a memory. The search to understand how memories are physically encoded in the brain remains one of neuroscience’s biggest mysteries.

“The question of the engram, of how we store memory, goes back to ancient Greek times—perhaps even before Plato,” says Susumu Tonegawa, director of the RIKEN Brain Science Institute at the Massachusetts Institute of Technology. “Today, in neuroscience, we understand that memory is stored in the brain. And there should be some kind of physical or chemical change underlying that memory that will last for some time. But it has been very difficult to study because in the past we didn’t have the technology to measure those changes.”

Research methods have now advanced to where scientists can observe the physical changes that take place at a molecular level when a memory is formed. These observations have given rise to a new theory: The engram for extremely long term memories, those we hold from early childhood, may be stored in the perineuronal net, the specialized extracellular matrix structure that supports synapses in the brain.

What is an engram, exactly?

New methods like optogenetics and transgenic animal models allow researchers to better measure cell-specific changes in specific brain circuits when memories are formed. Tonegawa’s work has shown the activation of neuronal ensembles in the hippocampus changes when a mouse learns a fear response–and that specific fear memory can be artificially recalled in the animal by optogenetically activating those ensembles. But is that pattern of activity all there is to an engram? Do the same mechanisms for a fear engram hold true for something more complex, like my childhood memory of my first bike or a more procedural memory like how to tie my shoes?

Perhaps not, says Sheena Josselyn, a neuroscientist at the University of Toronto. “The physical representation of a memory in the brain means different things to different people,” she says. “Research suggests the engram is probably a collection of cells and the pattern of their activity that helps facilitate the encoding and retrieving of that information. But what exactly that pattern might be, and what kind of changes are happening to make that pattern, we’re still not so sure about.”

The prevailing idea is that a memory is formed when long-term potentiation occurs—when a synapse is strengthened between two or more neurons—regardless of the type of memory. But a true engram is likely more complex than that, Josselyn says. “We’re learning that there are probably a bunch of different things that come together to make a memory. But we just haven’t figured them all out yet.”

Memory and the perineuronal net

So what about those long-term memories, those that are held from early childhood? Roger Tsien, a biochemist at the University of California San Diego (UCSD), wondered if perineuronal nets (PNNs) might act to store these long-term memories because they have much more stable proteins than synapses, offering a much more durable substrate that could maintain information over a significant period of time.

“It’s long been thought that memories are maintained by the strengthening of synapses, but we know that the proteins involved in that strengthening are very unstable. They turn over on the scale of hours to, at most, a few days,” says Sakina Palida, a graduate student in Tsien’s lab. “So Dr. Tsien became very interested in the extracellular matrix because its proteins are not subject to typical methods of degradation—they are only degraded when they need to be degraded. You can think of the PNN like a stone. So even if these synaptic proteins are coming and going, the stone remains stable. So if the memory is carved into it, the information remains as long as the substrate remains. And that makes the PNN a compelling place for these long-term memories to be stored.”

To test the idea, Palida, Tsien, and colleagues used a new method to label PNN-specific proteins in transgenic mice so they could observe specific changes to the PNN as synapses were strengthened.

“We saw that there was a reduction of proteins that formed a hole-like structure in the PNN. And that hole remains very stable over time, regardless of what synaptic proteins come and go through it,” Palida says. Furthermore, the group observed that transgenic mice who lack enzymes to make these “holes” have deficient long-term memory but their short-term memory is intact. Palida presented the results at Neuroscience 2015 in Chicago, Illinois.

“It’s surprising how stable these holes are. And that makes it an ideal substrate for the maintenance of very long-term memories over time,” she says. “It may also help us understand the kind of abnormal memory you see in Alzheimer’s, where patients often retain these very long-term memories but little else.”

The search continues

Palida cautions that their work is still preliminary and much more research is required to understand the role these PNN holes play in the engram, and then how information is both encoded into them and retrieved from them. But while it’s still early days, she thinks the PNN hypothesis is a strong one and fits well with ongoing work on engrams in the memory field.

“This work is just another piece of the puzzle,” she says. “It doesn’t negate any of the other work into memory that’s been done so far. It just adds more information about how the brain is encoding and maintaining these memories and I think that’s pretty cool.”

Tonegawa agrees. “This is a very attractive idea. It is quite possible that this perineuronal network is the mechanism for memory storage for these very long term, remote memories. It’s a little bit controversial and needs more experimental research to test the idea,” he says. “But, overall, this is a very exciting time for memory research. And these innovations and investigations that will be made will not only help us better understand the nature of human memory and the engram, but perhaps also offer more notable discoveries that can help us develop therapies to treat disorders with memory impairments like Alzheimer’s, depression, and post-traumatic stress disorder.”