The organization of recent and remote memories

Key Points

  • In humans, damage to the medial temporal lobe typically produces temporally-graded retrograde amnesia — a loss of recent memories, but a relative sparing of more remote ones. This has been taken as evidence that the hippocampus has a time-limited role in the storage and retrieval of some forms of memory. This idea forms the central tenet of most contemporary views of system consolidation: the hippocampus acts as a temporary store for new information, but permanent storage depends on a broadly distributed cortical network.

  • The relationship between hippocampal damage and retrograde amnesia has been studied in animal models. The main advantage of this approach is that it allows retrograde amnesia to be studied in a prospective manner — the extent of the lesion can be controlled, as can what is learned and when. As in humans, the typical finding is that disrupting hippocampal function preferentially affects recent, rather than remote, memories.

  • These observations in humans and animal models indicate that memories are reorganized at the system level as they mature. Most contemporary models propose that experience is initially encoded in parallel in hippocampal and cortical networks. Subsequent reactivation of the hippocampal network reinstates activity in different cortical networks. This coordinated replay across hippocampal–cortical networks leads to gradual strengthening of cortico-cortical connections, which eventually allows new memories to become independent of the hippocampus and to be gradually integrated with pre-existing cortical memories.

  • By contrast, multiple trace theory proposes a more permanent role for the hippocampus in some forms of declarative memory. It posits that memories are encoded in hippocampal–cortical networks, and that retrieval of contextually rich episodic memories, as well as spatial detail, always requires the hippocampus.

  • Memory reactivation is the core mechanism in consolidation models. Reactivation of the hippocampal memory trace is thought to lead to the reinstatement of waking patterns of neural activity in the cortex, and subsequent stabilization and refinement of hippocampal–cortical circuits.

  • Gradual remodelling of hippocampal–cortical circuits depends on several rounds of synaptic modification. These changes are initiated in a reactivation-dependent manner, either during online (task-relevant) or offline (sleep or quiet wakefulness) situations, and require the expression of new genes.

  • Imaging studies in rodents have been able to characterize how circuits supporting memories are gradually reorganized over time, to identify sites of permanent storage in the cortex, and to provide evidence for network reorganization at both regional and sub-regional levels. Imaging and pharmacological and anatomical lesion studies have identified the prefrontal cortex as playing a crucial part in processing remote memories.

  • These findings indicate that the prefrontal cortex might have a dual role during recall of remote memories. First, the prefrontal cortex may be important for integrating information from many cortical modules. Second, in the case of successful recall, the prefrontal cortex may exert top-down inhibitory control over hippocampal function to minimize re-encoding of redundant information.

Abstract

A fundamental question in memory research is how our brains can form enduring memories. In humans, memories of everyday life depend initially on the medial temporal lobe system, including the hippocampus. As these memories mature, they are thought to become increasingly dependent on other brain regions such as the cortex. Little is understood about how new memories in the hippocampus are transformed into remote memories in cortical networks. However, recent studies have begun to shed light on how remote memories are organized in the cortex, and the molecular and cellular events that underlie their consolidation.

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Figure 1: Standard consolidation model.
Figure 2: Deficient cortical plasticity and memory consolidation in α-CaMKII+/− mice.
Figure 3: Time-dependent reorganisation of brain circuitry that underlies spatial discrimination memories.
Figure 4: Laminar reorganization in the parietal cortex.
Figure 5: Prefrontal cortex and remote memory.

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Acknowledgements

We thank R. Costa, T. Durkin, S. Josselyn and M. Moscovitch for discussions and comments on earlier drafts. This work was supported by a Canadian Institutes of Health Research Canada Research Chair (P.W.F.) and the Centre National de la Recherche Scientifique (B.B.).

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Correspondence to Paul W. Frankland.

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DATABASES

Entrez Gene

α-CaMKII

c-fos

Zif268

FURTHER INFORMATION

Encyclopedia of Life Sciences

learning and memory

Frankland's homepage

Bontempi's homepage

Glossary

MEDIAL TEMPORAL LOBE

(MTL). A collection of anatomically connected regions that have an essential role in declarative memory (conscious memory for facts and events). The MTL includes the hippocampal region (CA fields, dentate gyrus and subicular complex) and adjacent entorhinal, perirhinal and parahippocampal cortices. The function and organization of the MTL seems to be conserved in humans, non-human primates and rodents.

TEMPORALLY-GRADED RETROGRADE AMNESIA

A condition associated with memory loss for past events. Most often associated with damage to the medial temporal lobe, memory loss for more recent events is more pronounced than for the distant past.

FLAT

A term used to describe retrograde amnesia when both recent and remote memory are similarly impaired.

REPLAY

Recapitulation of experience-dependent patterns of neural activity previously observed during awake periods.

SLOW-WAVE SLEEP

(SWS). Stage of non-REM deep sleep that is characterized by the presence of high-amplitude, slow delta waves of brain activity.

RAPID EYE MOVEMENT

(REM). A period of sleep, during which dreaming is thought to occur. REM sleep is characterized by increased brain-wave activity, bursts of rapid eye movement, accelerated respiration and heart rate and muscle relaxation.

HIPPOCAMPAL PLACE CELLS

Cells in the hippocampus that fire in a location-specific manner. These cells are thought to form the basis of cognitive maps, which allow animals to navigate through their environment.

RIPPLES

High frequency (200 Hz) oscillations of neuronal activity which last 30–200 ms and occur in cells of the CA1 region of the hippocampus during periods of slow-wave sleep and behavioural immobility.

SPINDLES

Low frequency oscillations (7–14 Hz) of neuronal activity which last 1–4 s and occur in thalamic and neocortical networks during slow-wave sleep.

ZIF268

ZIF268 is a transcription factor that regulates the expression of many genes that have diverse cellular functions. Expression of ZIF268 correlates with neuronal firing and is, therefore, commonly used as a marker of neuronal activity.

MORRIS WATER MAZE

A task used to assess spatial memory, most commonly in rodents. Animals use an array of extra-maze cues to locate a hidden escape platform that is submerged below the water surface. Learning in this task is hippocampus-dependent.

α-CaMKII

α-calcium/calmodulin-dependent protein kinase II (α-CaMKII) is a signalling enzyme activated by Ca2+ influx through the NMDA (N-methyl-D-aspartate) receptor. It is expressed in excitatory forebrain neurons and has a crucial role in neuronal plasticity.

(14C)2-DEOXYGLUCOSE

A functional brain imaging technique that is commonly used in rodents to estimate the level of neuronal activity in specific brain regions. The glucose analogue, (14C)2-deoxyglucose, is administered to the animals and is subsequently taken up and trapped by active neurons.

CELL ASSEMBLIES

Large collections of neurons that show coordinated firing activity. Activation of any part of this network can reconstitute activity in the entire cell assembly. These cell assemblies are thought to form the basic neuronal code of representation.

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Frankland, P., Bontempi, B. The organization of recent and remote memories. Nat Rev Neurosci 6, 119–130 (2005). https://doi.org/10.1038/nrn1607

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