Memory engrams: Recalling the past and imagining the future
Science 03 Jan 2020:
Vol. 367, Issue 6473, eaaw4325
DOI: 10.1126/science.aaw4325
Memory engrams: Recalling the past and imagining the future
Sheena A. Josselyn, et.al.
Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada.
Department of Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Brain, Mind & Consciousness Program, Canadian Institute for Advanced Research (CIFAR), Toronto, Ontario
M5G 1M1, Canada.
RIKEN-MIT Laboratory for Neural Circuit Genetics at the Picower Institute for Learning and Memory,
Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA.
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
[paraphrase]
In 1904, Richard Semon introduced the term “engram” to describe the neural substrate for
storing memories. An experience, Semon proposed, activates a subset of cells that undergo
off-line, persistent chemical and/or physical changes to become an engram. Subsequent
reactivation of this engram induces memory retrieval. Although Semon’s contributions were
largely ignored in his lifetime, new technologies that allow researchers to image and
manipulate the brain at the level of individual neurons has reinvigorated engram research.
We review recent progress in studying engrams, including an evaluation of evidence for the
existence of engrams, the importance of intrinsic excitability and synaptic plasticity in
engrams, and the lifetime of an engram. Together, these findings are beginning to define an
engram as the basic unit of memory.
The idea that memory is stored as enduring changes in the brain dates back at least to the
time of Plato and Aristotle (circa 350 BCE), but its scientific articulation emerged in the
20th century when Richard Semon introduced the term “engram” to describe the neural
substrate for storing and recalling memories. Essentially, Semon proposed that an
experience activates a population of neurons that undergo persistent chemical and/or
physical changes to become an engram. Subsequent reactivation of the engram by cues
available at the time of the experience induces memory retrieval. After Karl Lashley
failed to find the engram in a rat brain, studies attempting to localize an engram were
largely abandoned. Spurred by Donald O. Hebb’s theory that augmented synaptic
strength and neuronal connectivity are critical for memory formation, many researchers
showed that enhanced synaptic strength was correlated with memory. Nonetheless, the
causal relationship between these enduring changes in synaptic connectivity with a
specific, behaviorally identifiable memory at the level of the cell ensemble (an engram)
awaited further advances in experimental technologies.
The resurgence in research examining engrams may be linked to two complementary studies
that applied intervention strategies to target individual neurons in an engram supporting a
specific memory in mice. One study showed that ablating the subset of lateral amygdala
neurons allocated to a putative engram disrupted subsequent memory retrieval (loss
of function). The second study showed that artificially reactivating a subset of
hippocampal dentate gyrus neurons that were active during a fearful experience (and,
therefore, part of a putative engram) induced memory retrieval in the absence of external
retrieval cues (gain of function). Subsequent findings from many labs used similar strategies
to identify engrams in other brain regions supporting different types of memory.
There are several recent advances in engram research. First, eligible neurons within a given
brain region were shown to compete for allocation to an engram, and relative neuronal
excitability determines the outcome of this competition. Excitability-based competition
also guides the organization of multiple engrams in the brain and determines how these
engrams interact. Second, research examining the nature of the off-line, enduring changes in
engram cells (neurons that are critical components of an engram) found increased synaptic
strength and spine density in these neurons as well as preferential connectivity to other
downstream engram cells. Therefore, both increased intrinsic excitability and synaptic
plasticity work hand in hand to form engrams, and these mechanisms are also implicated
in memory consolidation and retrieval processes. Third, it is now possible to artificially
manipulate memory encoding and retrieval processes to generate false memories, or
even create a memory in mice without any natural sensory experience (implantation of a
memory for an experience that did not occur). Fourth, “silent” engrams were discovered in
amnesic mice; artificial reactivation of silent engrams induces memory retrieval, whereas
natural cues cannot. Endogenous engram silencing may contribute to the change in memory
over time (e.g., systems memory consolidation) or in different circumstances (e.g., fear
memory extinction). These findings suggest that once formed, an engram may exist in
different states (from silent to active) on the basis of their retrievability. Although initial
engram studies focused on single brain regions, an emerging concept is that a given
memory is supported by an engram complex, composed of functionally connected
engram cell ensembles dispersed across multiple brain regions, with each ensemble
supporting a component of the overall memory.
The ability to identify and manipulate engram cells and brainwide engram complexes
has introduced an exciting new era of memory research. The findings from many labs are
beginning to define an engram as the basic unit of memory. However, many questions
remain. In the short term, it is critical to characterize how information is stored in an
engram, including how engram architecture affects memory quality, strength, and precision;
how multiple engrams interact; how engrams change over time; and the role of engram
silencing in these processes. The long-term goal of engram research is to leverage the
fundamental findings from rodent engram studies to understand how information is
acquired, stored, and used in humans and facilitate the treatment of human memory, or
other information-processing, disorders. The development of low- to noninvasive
technology may enable new human therapies based on the growing knowledge of engrams
in rodents.
nnnnnn