Review Article | Published:

Finding the engram

Nature Reviews Neuroscience volume 16, pages 521534 (2015) | Download Citation

Abstract

Many attempts have been made to localize the physical trace of a memory, or engram, in the brain. However, until recently, engrams have remained largely elusive. In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram. Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times. We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram.

Key points

  • An engram is the physical trace of a memory in the brain. Although many attempts have been made to localize engrams, the engram has remained largely elusive until now.

  • Here, we develop four defining criteria for engram identification and apply these criteria to recent capture studies that have attempted to observe, erase and artificially express engrams in rodents.

  • Capture studies (allocate-and-manipulate or tag-and-manipulate) allow neurons that were active at the time of learning (engram encoding) to be captured and permanently tagged for later visualization and/or manipulation.

  • Observation studies have established that neurons active at the time of encoding are reactivated when the corresponding memory is retrieved.

  • Erasure studies have shown that silencing of engram neurons prevents memory expression, and thus establish that activation of these neurons is necessary for successful retrieval.

  • Conversely, stimulation of these engram neurons has been used effectively to induce artificial memory recovery, and thus establish that activation of engram neurons is sufficient for retrieval.

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Acknowledgements

This project was supported by Canadian Institutes of Health Research grants to P.W.F. (MOP-86762), S.A.J. (MOP-74650) and S.K. (MOP-93644). The authors thank A. Santoro for artwork, and N. Insel for comments on earlier drafts of the manuscript.

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Affiliations

  1. Program in Neurosciences & Mental Health, The Hospital for Sick Children (SickKids), 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.

    • Sheena A. Josselyn
    •  & Paul W. Frankland
  2. Department of Psychology, University of Toronto, 100 St. George Street, Toronto, Ontario M5S 3GM, Canada.

    • Sheena A. Josselyn
    •  & Paul W. Frankland
  3. Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.

    • Sheena A. Josselyn
    •  & Paul W. Frankland
  4. Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.

    • Sheena A. Josselyn
    •  & Paul W. Frankland
  5. Brain and Mind Institute, University of Western Ontario, Natural Sciences Centre, London, Ontario N6A 5B7, Canada.

    • Stefan Köhler
  6. Department of Psychology, University of Western Ontario, London, Ontario N6A 5C2, Canada.

    • Stefan Köhler

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The authors declare no competing financial interests.

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Glossary

Neuronal ensembles

Collections of neurons that show coordinated firing activity, equivalent to the cell assembly defined by Hebb.

Consolidation

The transformation of engrams from an initially labile state (in which they are vulnerable to disruption) to a more permanent state (in which they are resistant to disruption).

Replay

Recapitulation of experience-induced patterns of neuronal activity that occur during sleep or awake rest periods following an experience.

Sharp wave–ripple

High-frequency neural oscillations that occur in the hippocampus during periods of slow-wave sleep and behavioural immobility.

Functional connectivity

Task-specific coordination of activity between different elements (for example, neuronal ensembles) within neural systems.

Cued fear conditioning

A form of Pavlovian conditioning in which an initially neutral conditioned stimulus is paired with an aversive unconditioned stimulus. Subsequent presentation of the conditioned stimulus alone induces a conditioned fear response.

Contextual fear conditioning

A one-trial learning paradigm that is hippocampus and amygdala dependent, in which animals are placed in a specific context and administered one or a series of footshocks.

Cyclic AMP-responsive element-binding protein

(CREB). A transcription factor that, when activated, results in the expression of downstream proteins thought to be important for long-term memory.

Designer receptors exclusively activated by designer drugs

(DREADDs). Engineered G protein-coupled receptors that are no longer activated by the endogenous ligand but are instead activated by otherwise inert drug-like small molecules, used to control G protein signalling in vivo.

Opsins

Light-sensitive proteins that change their conformation from a resting state to a signalling state upon light absorption, used to excite or inhibit neuronal populations using light (that is, optogenetics).

Graph theory

Graph theory is a branch of mathematics used to compare both global (for example, 'small worldness') and local ('hubs') properties of networks.

Pattern completion

The ability of a network to retrieve stored information on the basis of partial or degraded input patterns.

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https://doi.org/10.1038/nrn4000

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