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Prefrontal and medial temporal lobe interactions in long-term memory

Nature Reviews Neurosciencevolume 4pages637648 (2003) | Download Citation



Cognitive neuroscience has made considerable progress in understanding the involvement of the medial temporal and frontal lobes in long-term memory. Whereas the medial temporal lobe has traditionally been associated with the encoding, storage and retrieval of long-term memories, the prefrontal cortex has been linked with cognitive control processes such as selection, engagement, monitoring and inhibition. However, there has been little attempt to understand how these regions might interact during encoding and retrieval, and little consideration of the anatomical connections between them. Recent advances in functional neuroimaging, neurophysiology, crossed-lesion neuropsychology and computational modelling highlight the importance of understanding how the medial temporal and frontal lobes interact to allow successful remembering, and provide an opportunity to explore these interactions.

Key Points

  • Much progress has been made by cognitive neuroscientists in understanding the separate roles of the medial temporal and prefrontal lobes in memory, but the way in which these regions interact in the processes of remembering has been neglected. This review provides a synthesis of evidence from human and animal neuropsychology, functional neuroimaging, neurophysiology and computational modelling, through which the functional interactions between prefrontal and medial temporal cortices can be better understood.

  • Since the first reports of patients with amnesia, evidence has converged on a role for the medial temporal lobes in the encoding, storage and retrieval of long-term memories. Controversies include whether there is differential involvement of regions such as the hippocampus and perirhinal cortex in processes of recollection and familiarity, and the long-term role of these regions in consolidation of memories from the past.

  • The prefrontal cortex is considered to support processes of cognitive control that are important for memory function. Accordingly, frontal lobe damage is often associated with particular memory impairments. Regional distinctions are evident within the frontal lobes, with left/right lateralization on the basis of material type and medial/lateral differentiation between reward-based mapping and goal-directed mnemonic control, respectively. Within lateral prefrontal cortex, there is a further distinction between ventral (specification and maintenance) and dorsal (monitoring and manipulation) regions.

  • Recent advances in primate crossed-lesion neuropsychology, human functional effective connectivity, single-cell electrophysiology and computational modelling highlight the importance of interactions between prefrontal cortex and medial temporal lobe in remembering. These new insights indicate that an understanding of these interactions will be crucial if we are to move closer to a full account of how memory is supported in the brain.

  • At encoding, information is processed by a hierarchy of unimodal and polymodal cortical areas, resulting in a bound representation of associated features in the medial temporal lobe. Through interactions with different regions of prefrontal cortex, top-down control of the encoding process is provided, modifying, elaborating and organizing medial temporal lobe representations in a goal-dependent manner, and ensuring that they are sufficiently discrete to be amenable for long-term storage.

  • During retrieval, the prefrontal cortex and medial temporal lobes interact in the specification of retrieval cues, searching the long-term store using those cues, reactivating stored information, and monitoring, disambiguation and verification of retrieved information. If a retrieval attempt is not sufficiently successful, the retrieval cue might be modified and further search interactions undertaken.

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We are very grateful to M. Baxter, S. Becker, N. Burgess, J. Gimpel, R. Henson, M. Rugg and D. Schacter for valuable comments on an earlier draft. J.S.S. is supported by a Wellcome Trust grant and H.J.S. by the Alzheimer's Research Trust.

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  1. Institute of Cognitive Neuroscience, University College London, Alexandra House, 17 Queen Square, London, WC1N 3AR, UK

    • Jon S. Simons
  2. Medical Research Council Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge, CB2 2EF, UK

    • Hugo J. Spiers


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A major input/output of the hippocampus, connecting it to prefrontal cortex and a range of subcortical structures.


Recognition of previously presented items based on a feeling of familiarity in the absence of recollection of the earlier study episode.


A task in which an object/item is presented and following a delay, presented again along with a new item, and the participant is required to choose the new item.


A degenerative neuropathological condition that results in the progressive loss of semantic knowledge as revealed through naming, description and non-verbal tests of semantic knowledge, resulting from disease of the anterior and lateral aspects of the temporal lobes.


Axon connections between pyramidal cells in the CA3 region of the hippocampus.


A process by which overlapping neural representations are separated to keep episodes independent of each other in memory.


A process by which a stored neural representation is reactivated by a cue that consists of a subset of the stored pattern.


Memory for events and episodes, which are uniquely characterized by a specific time and place.


Short-lasting memory associated with active maintenance and rehearsal of information.


Multivariate analysis of activity in different regions to model the influence that regions exert over each other.

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