Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Squire, L. R. & Kandel, E. R. Memory: From Mind to Molecules (W. H. Freedman & Co., New York, 1999).

    Google Scholar 

  2. Lechner, H. A., Squire, L. R. & Byrne, J. H. 100 years of consolidation — remembering Müller and Pilzecker. Learn. Mem. 6, 77–87 (1999).

    CAS  PubMed  Google Scholar 

  3. Müller, G. E. & Pilzecker, A. Experimentelle Bieträge zur Lehre vom Gedächtnis. Z. Psychol. Ergänzungsband 1, 1–300 (1900).

    Google Scholar 

  4. Dudai, Y. The neurobiology of consolidations, or, how stable is the engram? Annu. Rev. Psychol. 55, 51–86 (2004).

    Article  PubMed  Google Scholar 

  5. Ledoux, J. E. Synaptic Self (Viking, New York, 2001).

    Google Scholar 

  6. Ribot, T. Diseases of Memory (Appleton-Century-Crofts, New York, 1882).

    Google Scholar 

  7. Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurochem. 20, 11–21 (1957).

    CAS  Google Scholar 

  8. Penfield, W. & Milner, B. Memory deficit produced by bilateral lesions in the hippocampal zone. AMA Arch. Neurol. Psychiatry 79, 475–497 (1958).

    Article  CAS  PubMed  Google Scholar 

  9. Salmon, D. P., Lasker, B. R., Butters, N. & Beatty, W. W. Remote memory in a patient with circumscribed amnesia. Brain Cogn. 7, 201–211 (1988).

    Article  CAS  PubMed  Google Scholar 

  10. Beatty, W. W., Salmon, D. P., Bernstein, N. & Butters, N. Remote memory in a patient with amnesia due to hypoxia. Psychol. Med. 17, 657–665 (1987).

    Article  CAS  PubMed  Google Scholar 

  11. Rempel-Clower, N. L., Zola, S. M., Squire, L. R. & Amaral, D. G. Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J. Neurosci. 16, 5233–5255 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Squire, L. R., Slater, P. C. & Chace, P. M. Retrograde amnesia: temporal gradient in very long term memory following electroconvulsive therapy. Science 187, 77–79 (1975).

    Article  CAS  PubMed  Google Scholar 

  13. Squire, L. R. & Alvarez, P. Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin. Neurobiol. 5, 169–177 (1995). This important paper provides a description of the standard view of system consolidation.

    Article  CAS  PubMed  Google Scholar 

  14. McClelland, J. L., McNaughton, B. L. & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457 (1995). This landmark paper provides a thorough overview of connectionist models of learning and memory, focusing especially on the role of hippocampal– cortical interactions during the formation and consolidation of memories. The complementary concepts of the hippocampus as a fast learner and the cortex as a slow learner are developed.

    Article  PubMed  Google Scholar 

  15. Corkin, S. What's new with the amnesic patient H.M.? Nature Rev. Neurosci. 3, 153–160 (2002).

    Article  CAS  Google Scholar 

  16. Scoville, W. B. The limbic lobe in man. J. Neurosurg. 11, 64–66 (1954).

    Article  CAS  PubMed  Google Scholar 

  17. Gabrieli, J. D., Corkin, S., Mickel, S. F. & Growdon, J. H. Intact acquisition and long-term retention of mirror-tracing skill in Alzheimer's disease and in global amnesia. Behav. Neurosci. 107, 899–910 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Squire, L. R., Stark, C. E. & Clark, R. E. The Medial Temporal Lobe. Annu. Rev. Neurosci. 27, 279–306 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Gaffan, D. Recognition impaired and association intact in the memory of monkeys after transection of the fornix. J. Comp. Physiol. Psychol. 86, 1100–1109 (1974).

    Article  CAS  PubMed  Google Scholar 

  20. Hirsh, R. The hippocampus and contextual retrieval of information from memory: a theory. Behav. Biol. 12, 421–444 (1974).

    Article  CAS  PubMed  Google Scholar 

  21. Nadel, L. & O'Keefe, J. in Essays on the Nervous System (eds Bellairs, R. & Gray, E. G.) 367–390 (Clarendon, Oxford, 1974).

    Google Scholar 

  22. Squire, L. R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. O'Kane, G., Kensinger, E. A. & Corkin, S. Evidence for semantic learning in profound amnesia: an investigation with patient H.M. Hippocampus 14, 417–425 (2004).

    Article  PubMed  Google Scholar 

  24. Bayley, P. J. & Squire, L. R. Failure to acquire new semantic knowledge in patients with large medial temporal lobe lesions. Hippocampus (in the press).

  25. Sagar, H. J., Cohen, N. J., Corkin, S. & Growdon, J. H. Dissociations among processes in remote memory. Ann. NY Acad. Sci. 444, 533–535 (1985).

    Article  CAS  PubMed  Google Scholar 

  26. Nadel, L. & Moscovitch, M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol. 7, 217–227 (1997). This paper introduces the basic tenets of the multiple trace theory, challenges the standard model of system consolidation and provides original arguments to account for observations of flat retrograde amnesia gradients.

    Article  CAS  PubMed  Google Scholar 

  27. Bayley, P. J., Hopkins, R. O. & Squire, L. R. Successful recollection of remote autobiographical memories by amnesic patients with medial temporal lobe lesions. Neuron 38, 135–144 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Manns, J. R., Hopkins, R. O. & Squire, L. R. Semantic memory and the human hippocampus. Neuron 38, 127–133 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Rosenbaum, R. S., McKinnon, M. C., Levine, B. & Moscovitch, M. Visual imagery deficits, impaired strategic retrieval, or memory loss: disentangling the nature of an amnesic person's autobiographical memory deficit. Neuropsychologia 42, 1619–1635 (2004).

    Article  PubMed  Google Scholar 

  30. Viskontas, I. V., McAndrews, M. P. & Moscovitch, M. Memory for famous people in patients with unilateral temporal lobe epilepsy and excisions. Neuropsychology 16, 472–480 (2002).

    Article  PubMed  Google Scholar 

  31. Teng, E. & Squire, L. R. Memory for places learned long ago is intact after hippocampal damage. Nature 400, 675–677 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Rosenbaum, R. S. et al. Remote spatial memory in an amnesic person with extensive bilateral hippocampal lesions. Nature Neurosci. 3, 1044–1048 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Nadel, L., Ryan, L., Hayes, S. M., Gilboa, A. & Moscovitch, M. in Limbic and Association Cortical Systems — Basic, Clinical and Computational Aspects (eds Ono, T. et al.) 1250, 215–234 (Elsevier Science/Excerpta Medica International Congress Series, Amsterdam, 2003).

    Google Scholar 

  34. Anagnostaras, S. G., Maren, S. & Fanselow, M. S. Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. J. Neurosci. 19, 1106–1114 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bolhuis, J. J., Stewart, C. A. & Forrest, E. M. Retrograde amnesia and memory reactivation in rats with ibotenate lesions to the hippocampus or subiculum. Q. J. Exp. Psychol. B 47, 129–150 (1994).

    CAS  PubMed  Google Scholar 

  36. Cho, Y. H., Beracochea, D. & Jaffard, R. Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal cortex lesions in mice. J. Neurosci. 13, 1759–1766 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cho, Y. H. & Kesner, R. P. Involvement of entorhinal cortex or parietal cortex in long-term spatial discrimination memory in rats: retrograde amnesia. Behav. Neurosci. 110, 436–442 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Clark, R. E., Broadbent, N. J., Zola, S. M. & Squire, L. R. Anterograde amnesia and temporally graded retrograde amnesia for a nonspatial memory task after lesions of hippocampus and subiculum. J. Neurosci. 22, 4663–4669 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Debiec, J., LeDoux, J. E. & Nader, K. Cellular and systems reconsolidation in the hippocampus. Neuron 36, 527–538 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Gaffan, D. Additive effects of forgetting and fornix transfection in the temporal gradient of retrograde amnesia. Neuropsychologia 31, 1055–1066 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Glenn, M. J., Nesbitt, C. & Mumby, D. G. Perirhinal cortex lesions produce variable patterns of retrograde amnesia in rats. Behav. Brain Res. 141, 183–193 (2003).

    Article  PubMed  Google Scholar 

  42. Kim, J. J. & Fanselow, M. S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Kim, J. J., Clark, R. E. & Thompson, R. F. Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses. Behav. Neurosci. 109, 195–203 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Maviel, T., Durkin, T. P., Menzaghi, F. & Bontempi, B. Sites of neocortical reorganization critical for remote spatial memory. Science 305, 96–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Mumby, D. G. & Glenn, M. J. Anterograde and retrograde memory for object discriminations and places in rats with perirhinal cortex lesions. Behav. Brain Res. 114, 119–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Mumby, D. G., Astur, R. S., Weisend, M. P. & Sutherland, R. J. Retrograde amnesia and selective damage to the hippocampal formation: memory for places and object discriminations. Behav. Brain Res. 106, 97–107 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Ramos, J. M. Retrograde amnesia for spatial information: a dissociation between intra and extramaze cues following hippocampus lesions in rats. Eur. J. Neurosci. 10, 3295–3301 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Riedel, G. et al. Reversible neural inactivation reveals hippocampal participation in several memory processes. Nature Neurosci. 2, 898–905 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Shimizu, E., Tang, Y. P., Rampon, C. & Tsien, J. Z. NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation. Science 290, 1170–1174 (2000). Genetic disruption of NMDAR function in the CA1 region of the hippocampus immediately following training blocks memory consolidation. This study is consistent with the idea that hippocampal replay drives memory consolidation, and shows that NMDAR-mediated mechanisms have a central role.

    Article  CAS  PubMed  Google Scholar 

  50. Sutherland, R. J. et al. Retrograde amnesia after hippocampal damage: recent vs. remote memories in two tasks. Hippocampus 11, 27–42 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Takehara, K., Kawahara, S., Takatsuki, K. & Kirino, Y. Time-limited role of the hippocampus in the memory for trace eyeblink conditioning in mice. Brain Res. 951, 183–190 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Takehara, K., Kawahara, S. & Kirino, Y. Time-dependent reorganization of the brain components underlying memory retention in trace eyeblink conditioning. J. Neurosci. 23, 9897–9905 (2003). Using a trace eyeblink conditioning protocol, this study is the first to identify an important role for the prefrontal cortex in processing remote memory.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Thornton, J. A., Rothblat, L. A. & Murray, E. A. Rhinal cortex removal produces amnesia for preoperatively learned discrimination problems but fails to disrupt postoperative acquisition and retention in rhesus monkeys. J. Neurosci. 17, 8536–8549 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang, H. et al. Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain. Proc. Natl Acad. Sci. USA 100, 4287–4292 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wiig, K. A., Cooper, L. N. & Bear, M. F. Temporally graded retrograde amnesia following separate and combined lesions of the perirhinal cortex and fornix in the rat. Learn. Mem. 3, 313–325 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Winocur, G. Anterograde and retrograde amnesia in rats with dorsal hippocampal or dorsomedial thalamic lesions. Behav. Brain Res. 38, 145–154 (1990).

    Article  CAS  PubMed  Google Scholar 

  57. Winocur, G., McDonald, R. M. & Moscovitch, M. Anterograde and retrograde amnesia in rats with large hippocampal lesions. Hippocampus 11, 18–26 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Zola-Morgan, S. M. & Squire, L. R. The primate hippocampal formation: evidence for a time-limited role in memory storage. Science 250, 288–290 (1990). Using circumscribed lesions of the hippocampal formation, this is the first study to provide evidence for graded retrograde amnesia in non-human primates.

    Article  CAS  PubMed  Google Scholar 

  59. Quillfeldt, J. A. et al. Different brain areas are involved in memory expression at different times from training. Neurobiol. Learn. Mem. 66, 97–101 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Izquierdo, I. et al. Sequential role of hippocampus and amygdala, entorhinal cortex and parietal cortex in formation and retrieval of memory for inhibitory avoidance in rats. Eur. J. Neurosci. 9, 786–793 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Clark, R. E., Broadbent, N. J. & Squire, L. R. The hippocampus and remote spatial memory in rats. Hippocampus (in the press).

  62. Martin, S. J., de Hoz, L. & Morris, R. G. Retrograde amnesia: neither partial nor complete hippocampal lesions in rats result in preferential sparing of remote spatial memory, even after reminding. Neuropsychologia (in the press). References 61 and 62 show that hippocampal lesions produce a flat retrograde amnesia for spatial (water maze) memories, which indicates that the expression of detailed spatial memories in rats always depends on hippocampal function.

  63. Maren, S., Aharonov, G. & Fanselow, M. S. Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav. Brain Res. 88, 261–274 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Salmon, D. P., Zola-Morgan, S. M. & Squire, L. R. Retrograde amnesia following combined hippocampus-amygdala lesions in monkeys. Psychobiology 15, 37–47 (1987).

    Google Scholar 

  65. Remondes, M. & Schuman, E. M. Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory. Nature 431, 699–703 (2004). This paper shows that lesioning the temporoammonic input from the entorhinal cortex to the CA1 region of the hippocampus allows hippocampal memories to form normally, but prevents them from becoming consolidated in cortical networks.

    Article  CAS  PubMed  Google Scholar 

  66. Laurent-Demir, C. & Jaffard, R. Temporally graded retrograde amnesia for spatial information resulting from afterdischarges induced by electrical stimulation of the dorsal hippocampus in mice. Psychobiology 25, 133–140 (1997).

    Google Scholar 

  67. Gaskin, S., Tremblay, A. & Mumby, D. G. Retrograde and anterograde object recognition in rats with hippocampal lesions. Hippocampus 13, 962–969 (2003).

    Article  PubMed  Google Scholar 

  68. Fanselow, M. S. Contextual fear, gestalt memories, and the hippocampus. Behav. Brain Res. 110, 73–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Galef, B. G. Jr. Food selection: problems in understanding how we choose foods to eat. Neurosci. Biobehav. Rev. 20, 67–73 (1996).

    Article  PubMed  Google Scholar 

  70. Eichenbaum, H. Hippocampus; cognitive processes and neural representations that underlie declarative memory. Neuron 44, 109–120 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Anagnostaras, S. G., Gale, G. D. & Fanselow, M. S. The hippocampus and Pavlovian fear conditioning: reply to Bast et al. Hippocampus 12, 561–565 (2002).

    Article  PubMed  Google Scholar 

  72. Winocur, G., Moscovitch, M., Fogel, S., Rosenbaum, R. S. & Sekeres, M. Preserved spatial memory following hippocampal lesions: effects of extensive experience in a complex environment. Memory Disorders Research Society, New York, Oct 10 2004.

  73. Whishaw, I. Q. & Maaswinkel, H. Rats with fimbria-fornix lesions are impaired in path integration: a role for the hippocampus in 'sense of direction'. J. Neurosci. 18, 3050–3058 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Marr, D. A theory for cerebral neocortex. Proc. R. Soc. Lond. B 176, 161–234 (1970).

    Article  CAS  PubMed  Google Scholar 

  75. Marr, D. Simple memory: a theory for archicortex. Philos. Trans. R. Soc. Lond. B 262, 23–81 (1971).

    Article  CAS  Google Scholar 

  76. Cipolotti, L. et al. Long-term retrograde amnesia... the crucial role of the hippocampus. Neuropsychologia 39, 151–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Addis, D. R., Moscovitch, M., Crawley, A. P. & McAndrews, M. P. Recollective qualities modulate hippocampal activation during autobiographical memory retrieval. Hippocampus 14, 752–762 (2004).

    Article  PubMed  Google Scholar 

  78. Gilboa, A., Winocur, G., Grady, C. L., Hevenor, S. J. & Moscovitch, M. Remembering our past: functional neuroanatomy of recollection of recent and very remote personal events. Cereb. Cortex 14, 1214–1225 (2004).

    Article  PubMed  Google Scholar 

  79. Ryan, L. et al. Hippocampal complex and retrieval of recent and very remote autobiographical memories: evidence from functional magnetic resonance imaging in neurologically intact people. Hippocampus 11, 707–714 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Maguire, E. A. & Frith, C. D. Lateral asymmetry in the hippocampal response to the remoteness of autobiographical memories. J. Neurosci. 23, 5302–5307 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mednick, S. C. et al. The restorative effect of naps on perceptual deterioration. Nature Neurosci. 5, 677–681 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Walker, M. P., Brakefield, T., Morgan, A., Hobson, J. A. & Stickgold, R. Practice with sleep makes perfect: sleep-dependent motor skill learning. Neuron 35, 205–211 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Stickgold, R., James, L. & Hobson, J. A. Visual discrimination learning requires sleep after training. Nature Neurosci. 3, 1237–1238 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Gais, S. & Born, J. Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proc. Natl Acad. Sci. USA 101, 2140–2144 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fenn, K. M., Nusbaum, H. C. & Margoliash, D. Consolidation during sleep of perceptual learning of spoken language. Nature 425, 614–616 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Wagner, U., Gais, S., Haider, H., Verleger, R. & Born, J. Sleep inspires insight. Nature 427, 352–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Walker, M. P. & Stickgold, R. Sleep-dependent learning and memory consolidation. Neuron 44, 121–133 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Vertes, R. P. Memory consolidation in sleep; dream or reality. Neuron 44, 135–148 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Maquet, P. et al. Experience-dependent changes in cerebral activation during human REM sleep. Nature Neurosci. 3, 831–836 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Huber, R., Ghilardi, M. F., Massimini, M. & Tononi, G. Local sleep and learning. Nature 430, 78–81 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Peigneux, P. et al. Are spatial memories strengthened in the human hippocampus during slow wave sleep? Neuron 44, 535–545 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Hoffman, K. L. & McNaughton, B. L. Coordinated reactivation of distributed memory traces in primate neocortex. Science 297, 2070–2073 (2002). This study provides the first evidence that coordinated replay occurs in multiple cortical regions and supports the idea that offline reactivation of distributed cortical traces is crucial for cortical consolidation.

    Article  CAS  PubMed  Google Scholar 

  93. Ribeiro, S. et al. Long-lasting novelty-induced neuronal reverberation during slow-wave sleep in multiple forebrain areas. PLoS Biol 2, E24 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Siapas, A. G. & Wilson, M. A. Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep. Neuron 21, 1123–1128 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Lee, A. K. & Wilson, M. A. Memory of sequential experience in the hippocampus during slow wave sleep. Neuron 36, 1183–1194 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Louie, K. & Wilson, M. A. Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep. Neuron 29, 145–156 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Wilson, M. A. & McNaughton, B. L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Skaggs, W. E. & McNaughton, B. L. Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science 271, 1870–1873 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Kudrimoti, H. S., Barnes, C. A. & McNaughton, B. L. Reactivation of hippocampal cell assemblies: effects of behavioral state, experience, and EEG dynamics. J. Neurosci. 19, 4090–4101 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dave, A. S. & Margoliash, D. Song replay during sleep and computational rules for sensorimotor vocal learning. Science 290, 812–816 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Wilson, M. A. Hippocampal memory formation, plasticity, and the role of sleep. Neurobiol. Learn. Mem. 78, 565–569 (2002).

    Article  PubMed  Google Scholar 

  102. Sutherland, G. R. & McNaughton, B. Memory trace reactivation in hippocampal and neocortical neuronal ensembles. Curr. Opin. Neurobiol. 10, 180–186 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Qin, Y. L., McNaughton, B. L., Skaggs, W. E. & Barnes, C. A. Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles. Philos. Trans. R. Soc. Lond. B 352, 1525–1533 (1997).

    Article  CAS  Google Scholar 

  104. Cirelli, C., Gutierrez, C. M. & Tononi, G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron 41, 35–43 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Jones, M. W. et al. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nature Neurosci. 4, 289–296 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Lee, J. L., Everitt, B. J. & Thomas, K. L. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 304, 839–843 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Ribeiro, S., Goyal, V., Mello, C. V. & Pavlides, C. Brain gene expression during REM sleep depends on prior waking experience. Learn. Mem. 6, 500–508 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ribeiro, S. et al. Induction of hippocampal long-term potentiation during waking leads to increased extrahippocampal zif-268 expression during ensuing rapid-eye-movement sleep. J. Neurosci. 22, 10914–10923 (2002). This elegant series of studies (references 107 and 108) shows that the plasticity-related gene Zif268 is induced in cortical regions during sleep following either behavioural exploration or induction of LTP in the dentate gyrus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wittenberg, G. M. & Tsien, J. Z. An emerging molecular and cellular framework for memory processing by the hippocampus. Trends Neurosci. 25, 501–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Cui, Z. et al. Inducible and reversible NR1 knockout reveals crucial role of the NMDA receptor in preserving remote memories in the brain. Neuron 41, 781–793 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nature Rev. Neurosci. 3, 175–190 (2002).

    Article  CAS  Google Scholar 

  112. Elgersma, Y., Sweatt, J. D. & Giese, K. P. Mouse genetic approaches to investigating calcium/calmodulin-dependent protein kinase II function in plasticity and cognition. J. Neurosci. 24, 8410–8415 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Frankland, P. W., O'Brien, C., Ohno, M., Kirkwood, A. & Silva, A. J. α-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Frankland, P. W., Bontempi, B., Talton, L. E., Kaczmarek, L. & Silva, A. J. The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881–883 (2004). This paper combines cellular imaging, mouse genetic and pharmacological inactivation approaches to establish a crucial role for the anterior cingulate cortex in processing remote contextual fear memories.

    Article  CAS  PubMed  Google Scholar 

  115. Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Hayashi, M. L. et al. Altered cortical synaptic morphology and impaired memory consolidation in forebrain-specific dominant-negative PAK transgenic mice. Neuron 42, 773–787 (2004). Together with reference 113, this study shows that mice with abnormal cortical plasticity are unable to form enduring, hippocampus-independent memories.

    Article  CAS  PubMed  Google Scholar 

  117. Hall, J., Thomas, K. L. & Everitt, B. J. Cellular imaging of zif268 expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: selective activation of hippocampal CA1 neurons during the recall of contextual memories. J. Neurosci. 21, 2186–2193 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bontempi, B., Laurent-Demir, C., Destrade, C. & Jaffard, R. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671–675 (1999). Using regional brain imaging approaches in mice, the results of this paper show that the hippocampus has a transitory role in memory storage. In addition, this study was the first to identify possible sites of permanent storage in the cortex.

    Article  CAS  PubMed  Google Scholar 

  119. Chklovskii, D. B., Mel, B. W. & Svoboda, K. Cortical rewiring and information storage. Nature 431, 782–788 (2004). This excellent review contrasts mechanisms underlying weight and wiring plasticity, and proposes that the latter may play a crucial role in cortical memory consolidation.

    Article  CAS  PubMed  Google Scholar 

  120. Benowitz, L. I. & Routtenberg, A. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 20, 84–91 (1997).

    Article  CAS  PubMed  Google Scholar 

  121. Miller, R. Neural assemblies and laminar interactions in the cerebral cortex. Biol. Cybern. 75, 253–261 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Hebb, D. O. The Organization of Behavior (Wiley, New York, 1949).

    Google Scholar 

  123. Haist, F., Bowden Gore, J. & Mao, H. Consolidation of human memory over decades revealed by functional magnetic resonance imaging. Nature Neurosci. 4, 1139–1145 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Ridderinkhof, K. R., Ullsperger, M., Crone, E. A. & Nieuwenhuis, S. The role of the medial frontal cortex in cognitive control. Science 306, 443–447 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Lashley, K. S. In search of the engram. Symp. Soc. Exp. Biol. 4, 454–482 (1950).

    Google Scholar 

  126. Uylings, H. B., Groenewegen, H. J. & Kolb, B. Do rats have a prefrontal cortex? Behav. Brain Res. 146, 3–17 (2003).

    Article  PubMed  Google Scholar 

  127. Morris, R. G. et al. Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos. Trans. R. Soc. Lond. B 358, 773–786 (2003).

    Article  CAS  Google Scholar 

  128. Miyashita, Y. Cognitive memory: cellular and network machineries and their top-down control. Science 306, 435–440 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Ungerleider, L. G. Functional brain imaging studies of cortical mechanisms for memory. Science 270, 769–775 (1995).

    Article  CAS  PubMed  Google Scholar 

  130. Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 24, 167–202 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Tomita, H., Ohbayashi, M., Nakahara, K., Hasegawa, I. & Miyashita, Y. Top-down signal from prefrontal cortex in executive control of memory retrieval. Nature 401, 699–703 (1999).

    Article  CAS  PubMed  Google Scholar 

  132. Moody, S. L., Wise, S. P., di Pellegrino, G. & Zipser, D. A model that accounts for activity in primate frontal cortex during a delayed matching-to-sample task. J. Neurosci. 18, 399–410 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. O'Reilly, R. C. & Rudy, J. W. Computational principles of learning in the neocortex and hippocampus. Hippocampus 10, 389–397 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Lisman, J. & Morris, R. G. Memory: why is the cortex a slow learner? Nature 411, 248–249 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Trachtenberg, J. T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Willshaw, D. J. & Buckingham, J. T. An assessment of Marr's theory of the hippocampus as a temporary memory store. Philos. Trans. R. Soc. Lond. B 329, 205–215 (1990).

    Article  CAS  Google Scholar 

  137. Genoux, D. et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418, 970–975 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Villarreal, D. M., Do, V., Haddad, E. & Derrick, B. E. NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay. Nature Neurosci. 5, 48–52 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Feng, R. et al. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32, 911–926 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. Fortin, N. J., Wright, S. P. & Eichenbaum, H. Recollection-like memory retrieval in rats is dependent on the hippocampus. Nature 431, 188–191 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Day, M., Langston, R. & Morris, R. G. Glutamate-receptor-mediated encoding and retrieval of paired-associate learning. Nature 424, 205–209 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Bourtchouladze, R. et al. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn. Mem. 5, 365–374 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Kida, S. et al. CREB required for the stability of new and reactivated fear memories. Nature Neurosci. 5, 348–355 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Shadmehr, R. & Holcomb, H. H. Neural correlates of motor memory consolidation. Science 277, 821–825 (1997).

    Article  CAS  PubMed  Google Scholar 

  145. McBride, S. M. et al. Mushroom body ablation impairs short-term memory and long-term memory of courtship conditioning in Drosophila melanogaster. Neuron 24, 967–977 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Menzel, R. Searching for the memory trace in a mini-brain, the honeybee. Learn. Mem. 8, 53–62 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Gale, G. D. et al. Role of the basolateral amygdala in the storage of fear memories across the adult lifetime of rats. J. Neurosci. 24, 3810–3815 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sokoloff, L. et al. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 28, 897–916 (1977).

    Article  CAS  PubMed  Google Scholar 

  149. Laroche, S., Davis, S. & Jay, T. M. Plasticity at hippocampal to prefrontal cortex synapses: dual roles in working memory and consolidation. Hippocampus 10, 438–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. Dutar, P., Bassant, M. H., Senut, M. C. & Lamour, Y. The septohippocampal pathway: structure and function of a central cholinergic system. Physiol. Rev. 75, 393–427 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul W. Frankland.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1607

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing