The idea that memories should have a physical trace in the brain dates back more than a century. Pioneering experiments in the lab of Picower Professor Susumu Tonegawa have proved pivotal in pinpointing the ensembles of neurons, or “engrams,” that together encode a memory. By using techniques to label and then take control of engram cells, the lab has been able to map engrams and manipulate the memories they represent, providing strong evidence that engrams are indeed the brain’s unit of memory.

In 2012 a team in the Tonegawa lab identified the engram activated in the hippocampus region of a mouse when it formed the fearful memory: getting a little shock on the foot in an enclosure. Typically when mice return to that place, they freeze. The researchers discovered that if they engineered the engram cells they identified to be controlled with pulses of light, a technique called “optogenetics,” they could then stimulate those cells – and only those cells – to make the mouse freeze even when it was not in the enclosure where it received the shock. This proved that they had found the engram that produced the mouse’s fear memory. The next year the team took a dramatic step further. They implanted mice with a false memory by artificially reactivating the hippocampal engram of a previously experienced place while giving the mouse a little shock somewhere else. Mice later exhibited a fearful response in the location that the scientists artificially evoked the memory of, even though the rodents hadn’t ever actually experienced a shock there.

These engram mapping and manipulation experiments took place in a brain region called the hippocampus but neuroscientists had long surmised that memory could also be stored in other brain regions. Indeed, the dominant view in the field, termed the “standard model of system consolidation of memory” posited that the hippocampus plays a crucial rolein the formation and short-term storage of memory of events while the longer-term storage takes place in cortical regions like the prefrontal cortex. In 2017 the Tonegawa lab applied memory engram, optogenetics and neural circuit identifying technologies to not only the hippocampus but also the amygdala and the prefrontal cortex. Contrary to the standard model the Tonegawa lab demonstrated that the engram for a fear memory is formed immediately after foot shock in all three brain areas. However, in contrast to the hippocampus and the amygdala, the engram in the prefrontal cortex could not be reactivated immediately for natural recall, though the recall could be induced optogenetically. In other words, the prefrontal cortex engram is in a silent state and help from the hippocampus and amygdala engrams is necessary for its maturation.  Meanwhile the engram eventually becomes silent in the hippocampus and stays intact in the amygdala (SEE SILENT ENGRAMS).  This series of studies forced a significantly reconsideration of the standard model.

Tonegawa’s lab has studied memory storage in the entorhinal cortex and other regions, too, but it was not until a study in 2022 that they demonstrated just how widespread a single memory can be. After instilling a simple fear memory (as above) in mice, they examined 247 regions of the brain for signs of activation and of recall. They found that neurons in more than 100 regions including many not associated with memory before were part of what had long been hypothesized: a unified engram complex.