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Synaptic plasticity, memory and the hippocampus: a neural network approach to causality

A Corrigendum to this article was published on 20 November 2012

This article has been updated

Abstract

Two facts about the hippocampus have been common currency among neuroscientists for several decades. First, lesions of the hippocampus in humans prevent the acquisition of new episodic memories; second, activity-dependent synaptic plasticity is a prominent feature of hippocampal synapses. Given this background, the hypothesis that hippocampus-dependent memory is mediated, at least in part, by hippocampal synaptic plasticity has seemed as cogent in theory as it has been difficult to prove in practice. Here we argue that the recent development of transgenic molecular devices will encourage a shift from mechanistic investigations of synaptic plasticity in single neurons towards an analysis of how networks of neurons encode and represent memory, and we suggest ways in which this might be achieved. In the process, the hypothesis that synaptic plasticity is necessary and sufficient for information storage in the brain may finally be validated.

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Figure 1: Basic anatomy of the hippocampus.
Figure 2: Long-term potentiation (LTP) in vitro and in vivo.
Figure 3: A strategy for silencing a hippocampal cell assembly encoding a particular memory.
Figure 4: Thought experiments: erasing and re-installing a hippocampus-dependent memory.

Change history

  • 20 November 2012

    On page 66 of this article, there were several errors in figure 1. The tract labelled 'Temporoammonic path' should have been labelled 'Perforant path to CA1', and the tract labelled 'Perforant path' should have been labelled 'Perforant path to dentate gyrus'. The fibres from layer III cells in the lateral entorhinal cortex that were shown projecting to proximal CA1 cells should have been depicted projecting to the distal CA1 cells, and the fibres from layer III cells in the medial entorhinal cortex that were shown projecting to distal CA1 cells should have been depicted projecting to proximal CA1 cells. The layer II cells in the medial and lateral entorhinal cortex that project to the granule cells should have been depicted as continuing to the stratum lacunosum moleculare, where they contact CA3 pyramidal cells. These errors have been corrected in the online version. The authors thank J. Z. Young for pointing out the errors and M. Witter for advice in making the alterations to the figure.

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Acknowledgements

We would like to thank P. Skehel for his contribution to the ideas that have been developed here, and M. Bear, R. Morris, J. O'Keefe and J. Young for valuable discussions.

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Glossary

Contextual fear conditioning

A hippocampus-dependent form of Pavlovian conditioning in which a rodent comes to associate a context defined by polymodal sensory cues with an electrical footshock.

Cued fear conditioning

A hippocampus-independent form of Pavlovian conditioning in which a rodent comes to associate a tone cue (conditional stimulus) with an electrical footshock (unconditional stimulus). Learning is assessed by the animal's behavioural freezing.

De-depression

The selective reversal of LTD by high-frequency stimulation.

Depotentiation

The selective and time-dependent reversal of already-potentiated synapses using low-frequency stimulation. Note that depotentiation differs from LTD in that it has no affect on unpotentiated synapses and affects only recently potentiated synapses.

Episodic memory

Event-related memory: the 'what, where and when' memory system. Experiments in rodents are largely restricted to the 'what' and 'where' elements. We define hippocampus-dependent tasks such as contextual fear conditioning and the Morris water maze as requiring episodic-like memory.

EPSP-spike potentiation

(E-S potentiation). A potentiation not of synaptic transmission, as in LTP, but of the likelihood that action potentials will be generated for a given synaptic input. This phenomenon usually occurs in tandem with LTP after high-frequency stimulation.

Forgetful mouse

This is a type of genetically engineered mouse that can learn but not consolidate hippocampus-dependent memory.

Long-term depression

(LTD). The opposing process to LTP, whereby synaptic transmission is weakened by low-frequency stimulation. LTD might serve as a learning mechanism in its own right or might be a means of ensuring homeostatic stability by preventing an increase in overall activity in potentiated networks.

Long-term potentiation

(LTP). An experimental model of synaptic plasticity. In the hippocampus, high-frequency electrical stimulation of afferent-fibre pathways induces an enhancement of synaptic transmission that can last for months.

Memory mimicry

(MM) An experiment designed to test whether LTP-like plasticity alone is sufficient to support memory, by artificially installing a memory of an unexperienced event. Also called the 'Marilyn Monroe' thought experiment, because it could entail creating a false memory of a meeting with her.

Morris water maze

A spatial learning and memory task in which a rodent learns the position of an escape platform placed beneath the surface of a pool of opaque water using a set of distal visual cues.

Nictitating membrane/eyeblink conditioning

A form of classical Pavlovian conditioning in which an animal gradually modifies the timing of an eyeblink to an anticipated unconditional stimulus, using a sound or light conditional stimulus. Rabbits are traditionally used for this task owing to the presence of a third eyelid, or nictitating membrane, which is not under conscious control.

Pattern completion

The phenomenon whereby a memory can be recalled by presentation of only a subset of the cues that were available during the learning episode. There is evidence that the CA3 subregion of the hippocampus is necessary for animals to achieve pattern completion.

Pattern separation

The phenomenon whereby two similar contexts can be discriminated on the basis of subtle differences in the constituent cues. Such pattern separation allows the recall of only those memories that are relevant to one context or the other. There is evidence that the dentate gyrus is necessary for pattern separation.

Radial arm maze

Usually an eight-armed maze that can be used for various memory tasks. Here we refer to it in the context of working memory in which each arm is baited with food. Working memory can be assessed by how often the animal returns to an arm that it has already visited and emptied of food reward.

Reference memory

Long-term spatial memory that involves reference to external cues, as is needed for succesful learning of the standard form of the Morris water maze task, in which the location of the hidden platform is fixed for several days.

Spike-timing-dependent plasticity

(STDP). Plasticity in which pre- and postsynaptic cells are stimulated independently and the timing with which spikes are evoked in the two types of cell determines the direction of plasticity.

Synaptic tagging

Both long-term memory and LTP require mRNA transcription and protein synthesis. However, plasticity changes are specific to activated synapses. A mechanism, termed synaptic tagging, must exist to capture newly expressed plasticity related mRNAs or proteins specifically at activated synapses. One possible solution is the setting of labile 'tags' at activated synapses that would capture recently synthesized proteins.

Working memory

Short-term memory, used here to describe the type of memory that is needed for successful completion of a version of the Morris water maze experiment in which the position of the hidden platform is changed daily (see also radial arm maze).

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Neves, G., Cooke, S. & Bliss, T. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 9, 65–75 (2008). https://doi.org/10.1038/nrn2303

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