Memory engrams: Recalling the past and imagining the future
The neural substrate of memory
The ability to form memory is an essential trait that allows learning and the accumulation of knowledge. But what is a memory? There has been a long history of searching for the neuronal substrate that forms memory in the brain, and the emerging view is that ensembles of engram cells explain how memories are formed and retrieved. In a Review, Josselyn and Tonegawa discuss the evidence for engram cells as a substrate of memory, particularly in rodents; what we have learned so far about the features of memory, including memory formation, retrieval over time, and loss; and future directions to understand how memory becomes knowledge.
Science, this issue p. eaaw4325
Structured Abstract
BACKGROUND
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.
ADVANCES
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.
OUTLOOK
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.
An engram cell alongside a nonengram cell.
Within the hippocampus, dentate gyrus cells were filled with biocytin (white) to examine morphology. Engram cells active during context fear conditioning were engineered to express the red fluorescent protein mCherry, which appears pink owing to overlap with biocytin signals. Axons of the perforant path (green) express the excitatory opsin channelrhodopsin 2 and a fluorescent marker (enhanced yellow fluorescent protein). The upper blade of the dentate gyrus granule cell layer is revealed by the nuclear stain 4′,6-diamidino-2-phenylindole (DAPI, blue).
CREDIT: ADAPTED FROM T. J. RYAN ET AL., SCIENCE 348, 1007 (2015).
Abstract
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.
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Volume 367 | Issue 6473
3 January 2020
3 January 2020
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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Published in print: 3 January 2020
Acknowledgments
We thank our many colleagues for interesting conversations that shaped this review. In particular, we would like to acknowledge the contributions of Y. Dudai, P. Frankland, S. Köhler, M. Pignatelli, and S. Waddell, as well as J. Lau (for figure preparation) and D. Roy and J. Yu (for a sorted publication list); and the members of the Josselyn, Tonegawa, and Frankland labs for helpful discussions. Funding: Supported by the Canadian Institute of Health Research (CIHR, FDN-388455), the Natural Science and Engineering Research Council (NSERC) Discovery Grant, the Canadian Institute for Advanced Studies (CiFAR) Grant, and the NIH (NIMH, 1 R01 MH119421-01) (to S.A.J); and by RIKEN’s Center for Brain Science, Howard Hughes Medical Institute (HHMI), and JPB Foundation (to S.T.). Competing interests: The authors declare no competing interests.
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NIMH: 1 R01 MH119421-01
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RE: physiological basis 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)" (Josselyn and Tonegawa). In fact, Aristotle (350 B.C.E.) articulated the "actuality" prescient of Gibsons "affordance".
Furthermore, "the causal relationship between [the] enduring changes in synaptic connectivity with a specific, behaviorally identifiable memory at the level of the cell ensemble (an engram) await further advances in experimental technologies". (Josselyn & Tonegawa, 2019).
Gibson addressed Lashley's engram. But Gibson also noted "At the very end of the paper, however, Lashley sounded another note. He suggested that 'the learning process must consist of the attunement of the elements of a complex system in such a way that a particular combination or pattern of cells responds more readily than before the experience. No one knows how this might occur, and the suggestion is vague, but note that this idea is novel" (Gibson citing Lashley).
So where does that leave us now?
Josselyn & Tonegawa (2019) assert "Although recent engram studies have offered important insights into memory, several key questions remain": (a) do all engrams (engrams representing different types of memories such as episodic, semantic, or even procedural or motor memories, with different valence) change over time, gradually engaging more cortical regions? (b) Is there a role for top-down (mPFC to hippocampal) processing in the dematuration of hippocampal engrams and a possible role of silent hippocampal engrams in remote memory recall? (c) do all engrams (engrams representing different types of memories such as episodic, semantic, or even procedural or motor memories, with different valence) change over time, gradually engaging more cortical regions? (d) how can we leverage our knowledge of engrams in rodents to better understand human memory?
Gibson foresaw this conundrum. His theory of direct-perception and affordances , investigared in ecological-psychology laboratories that include the University of Connecticut and the University of Cincinnati, support the resolution that "If learning is a kind of resonance in the nervous system, a turning of the system to certain inputs, then it is not any sort of storage of engrams or depositing of traces" (Gibson citing Lashley).
References
Aristotle. (350 B.C.E.). On the soul. (Translated by J. A. Smith). Retrieved from http://classics.mit.edu/Aristotle/soul.html.
Gibson, J. J. (1966). The problem of temporal order in stimulation and perception. The Journal Of Psychology, 62(2), 141–149. https://doi.org/10.1080/00223980.1966.10543777.
Josselyn & Tonegawa. (2020 Jan 03). Memory engrams: Recalling the past and imagining the future. Science, 367(6473). doi: 10.1126/science.aaw4325. Retrieved from https://science.sciencemag.org/content/367/6473/eaaw4325.
Lashley, K. S. (1950). In search of the engram. In Physiological Mechanisms in Animal Behaviour (Symp. Soc. Exper. Biol., No. 4). New York: Academic Press.