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Engram mechanisms of memory linking and identity

Nature Reviews Neuroscience (2024)Cite this article

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Abstract

Memories are thought to be stored in neuronal ensembles referred to as engrams. Studies have suggested that when two memories occur in quick succession, a proportion of their engrams overlap and the memories become linked (in a process known as prospective linking) while maintaining their individual identities. In this Review, we summarize the key principles of memory linking through engram overlap, as revealed by experimental and modelling studies. We describe evidence of the involvement of synaptic memory substrates, spine clustering and non-linear neuronal capacities in prospective linking, and suggest a dynamic somato-synaptic model, in which memories are shared between neurons yet remain separable through distinct dendritic and synaptic allocation patterns. We also bring into focus retrospective linking, in which memories become associated after encoding via offline reactivation, and discuss key temporal and mechanistic differences between prospective and retrospective linking, as well as the potential differences in their cognitive outcomes.

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Fig. 1: Sufficiency of engram cells for memory recall.
Fig. 2: Associative learning and prospective memory linking.
Fig. 3: A somato-synaptic model for dynamic memory linking and identity preservation.
Fig. 4: Retrospective linking through offline reactivation.
Fig. 5: Mechanisms and characteristics of prospective versus retrospective memory linking.

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Acknowledgements

This work was supported by the JSPS KAKENHI (grant numbers JP18H05213, JP23H05476), the Core Research for Evolutional Science and Technology (CREST) programme (JPMJCR23N2) of the Japan Science and Technology Agency (JST) and the Takeda Science Foundation to K.I., and by the Grant-in-Aid for AMED (grant number JP23gm6510028), the JSPS KAKENHI Scientific Research(B) (grant numbers 20H03554, 23H02785), the Takeda Science Foundation and the Tamura Science and Technology Foundation to M.N.

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Authors and Affiliations

  1. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Ali Choucry, Masanori Nomoto & Kaoru Inokuchi

  2. Research Center for Idling Brain Science, University of Toyama, Toyama, Japan

    Ali Choucry, Masanori Nomoto & Kaoru Inokuchi

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Ali Choucry

  4. CREST, Japan Science and Technology Agency (JST), University of Toyama, Toyama, Japan

    Masanori Nomoto & Kaoru Inokuchi

  5. Japan Agency for Medical Research and Development (AMED), Tokyo, Japan

    Masanori Nomoto

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Glossary

Behavioural tagging

A phenomenon in which memories for non-salient experiences are strengthened when they are immediately followed or preceded by an event of greater salience. As a result, weak events that would otherwise only elicit short-term memories are stored as long-term memories.

Dendritic compartmentalization

The non-linear segregation of dendrites by various mechanisms, such as dendritic spikes and intrinsic excitability, as well as their anatomical configuration. Synaptic potentiation or depression can thus be restricted within those compartments.

Dendritic spikes

Spatially restricted spikes in potential occurring in a localized area of the dendrite when synaptic inputs are temporally or spatially clustered. Such localized spikes may occasionally propagate to the soma and can trigger axonal action potentials. As such, dendritic spikes underlie dendritic non-linearities and compartmentalization.

Immediate early genes

(IEGs). A subset of neuronal genes that are rapidly and selectively upregulated in response to neuronal stimulation by a wide variety of stimuli. IEGs are implicated in synaptic plasticity, learning and memory.

Inferential reasoning

The ability to deduce relationships among events that were never co-presented, through common intermediaries. Using such intermediaries allows one to infer the whole hierarchy of events, from highest to lowest, on an arbitrary scale.

Long-term depression

(LTD). A synaptic plasticity mechanism in which there is a decrease in the strength of synaptic efficacy, following low-frequency stimulation.

Long-term potentiation

(LTP). A synaptic plasticity mechanism in which there is an increase in the strength of synaptic efficacy, following high-frequency stimulation. Together with LTD, LTP is believed to have a major role in various forms of learning and memory.

Memory engram

A group of neurons that are activated by an event, resulting in enduring cellular changes, and whose reactivation results in the recollection of the memory of that event.

Memory replay

The offline reinstatement of the cellular activity patterns that encoded a particular event. This replay is often observed during subsequent rest or sleep periods in a compressed manner, and is thought to have a key role in memory consolidation.

Network reverberation

A mechanism by which neuronal circuits maintain patterns of activity after an initial stimulus has ceased, by forwarding the signal from one neuron to another within a specific circuit or ensemble. This signal may coincide with a new input converging on the same ensemble, which may create an association.

Pavlovian conditioning

Behavioural and physiological changes that occur when an animal learns that a naturally neutral stimulus predicts a biologically salient event. In the original studies conducted by Pavlov, dogs salivated in response to the ticking of a metronome (a neutral stimulus), because this sound immediately preceded food delivery (a salient event) on previous occasions.

Plasticity-related proteins

(PRPs). Proteins that are synthesized in response to synaptic stimulation and are required for maintenance of the ensuing synaptic plasticity. The diffusion and capture of these proteins by weakly activated or inhibited synapses may stabilize their synaptic plasticity, according to the synaptic tagging and capture hypothesis.

Synaptic clustering

The grouping of synapses with similar response and/or input properties within relatively short stretches of the dendritic branch.

Synaptic engrams

A subset of synapses in engram cells with altered synaptic plasticity following learning.

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Choucry, A., Nomoto, M. & Inokuchi, K. Engram mechanisms of memory linking and identity. Nat. Rev. Neurosci. (2024). https://doi.org/10.1038/s41583-024-00814-0

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