A newly published review describes the rapid progress scientists have been making over the last dozen years in identifying, characterizing and even manipulating engrams, as well as the major outstanding questions of the field.

Although German zoologist and evolutionary biologist Richard Semon introduced the concept of the engram 115 years ago to propose a neural basis for memory, direct evidence for engrams has only begun to accumulate recently as advanced technologies and methods have become available.

Experiments in rodents have revealed that engrams exist as multiscale networks of neurons. An experience becomes stored as a potentially retrievable memory in the brain when excited neurons in a brain region such as the hippocampus or amygdala become recruited into a local ensemble.

Engram Complexes

These ensembles combine with others in other regions, such as the cortex, into an engram complex. Crucial to this process of linking engram cells is the ability of neurons to forge new circuit connections, via processes known as synaptic plasticity and dendritic spine formation.

Importantly, experiments show that the memory initially stored across an engram complex can be retrieved by its reactivation but may also persist silently even when memories cannot be naturally recalled, for instance in mouse models used to study memory disorders such as early stage Alzheimer’s disease.

“More than 100 years ago Semon put forth a law of engraphy. Combining these theoretical ideas with the new tools that allow researchers to image and manipulate engrams at the level of cell ensembles facilitated many important insights into memory function. For instance, evidence indicates that both increased intrinsic excitability and synaptic plasticity work hand in hand to form engrams and that these processes may also be important in memory linking, memory retrieval, and memory consolidation,"

write Sheena Josselyn, Professor of Psychology and Physiology at the University of Toronto and Senior Fellow in the Brain, Mind & Consciousness Program at the Canadian Institute for Advanced Research, (CIFAR) and Susumu Tonegawa, Picower Professor of Biology and Neuroscience at the RIKEN-MIT Laboratory for Neural Circuit Genetics at MIT and Investigator of the Howard Hughes Medical Institute.

Unanswered Questions

For as much as the field has learned, Josselyn and Tonegawa say, there are still important unanswered questions and untapped potential applications.

For example, how do engrams change over time? How can engrams and memories be studied more directly in humans?

And can applying knowledge about biological engrams inspire advances in artificial intelligence, which in turn could feedback new insights into the workings of engrams?

Support for the work came from the Canadian Institute of Health Research, the Natural Science and Engineering Research Council (NSERC), the Canadian Institute for Advanced Studies, the NIH, RIKEN’s Center for Brain Science, Howard Hughes Medical Institute (HHMI), and the JPB Foundation.

Sheena A. Josselyn, Susumu Tonegawa. Memory engrams: Recalling the past and imagining the future. Science 03 Jan 2020: Vol. 367, Issue 6473, eaaw4325 DOI: 10.1126/science.aaw4325

Image: Memory engram cells labeled green and red in the prefrontal cortex of a mouse. Credit: Takashi Kitamura

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