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      Memory engrams: Recalling the past and imagining the future

      research-article
      1 , 2 , 3 , 4 , 5 , * , 6 , 7 , *
      Science (New York, N.Y.)

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          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.

          Graphical Abstract

          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).

          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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          Most cited references187

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          Synaptic plasticity and memory: an evaluation of the hypothesis.

          Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.
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            Optogenetic stimulation of a hippocampal engram activates fear memory recall

            A specific memory is thought to be encoded by a sparse population of neurons 1,2 . These neurons can be tagged during learning for subsequent identification 3 and manipulation 4,5,6 . Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, a critical question of sufficiency remains: can one elicit the behavioral output of a specific memory by directly activating a population of neurons that was active during learning? Here we show that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behavior. We labeled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) 7,8 and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear conditioned mice with cells labeled by EYFP instead of ChR2. Finally, activation of cells labeled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context-specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.
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              Pattern separation in the dentate gyrus and CA3 of the hippocampus.

              Theoretical models have long pointed to the dentate gyrus as a possible source of neuronal pattern separation. In agreement with predictions from these models, we show that minimal changes in the shape of the environment in which rats are exploring can substantially alter correlated activity patterns among place-modulated granule cells in the dentate gyrus. When the environments are made more different, new cell populations are recruited in CA3 but not in the dentate gyrus. These results imply a dual mechanism for pattern separation in which signals from the entorhinal cortex can be decorrelated both by changes in coincidence patterns in the dentate gyrus and by recruitment of nonoverlapping cell assemblies in CA3.
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                Author and article information

                Journal
                0404511
                7473
                Science
                Science
                Science (New York, N.Y.)
                0036-8075
                1095-9203
                10 October 2020
                03 January 2020
                21 October 2020
                : 367
                : 6473
                : eaaw4325
                Affiliations
                [1 ]Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
                [2 ]Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada.
                [3 ]Department of Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
                [4 ]Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
                [5 ]Brain, Mind & Consciousness Program, Canadian Institute for Advanced Research (CIFAR), Toronto, Ontario M5G 1M1, Canada.
                [6 ]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.
                [7 ]Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                Author notes
                [* ]Corresponding author. sheena.josselyn@ 123456sickkids.ca (S.A.J.); tonegawa@ 123456mit.edu (S.T.)
                Article
                PMC7577560 PMC7577560 7577560 nihpa1636529
                10.1126/science.aaw4325
                7577560
                31896692
                c2482c68-4845-4cea-a948-6f87da3d72fb
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