REVIEWSTHE ORGANIZATION OF RECENT
AND REMOTE MEMORIESPaul W. Frankland*‡ and Bruno Bontempi §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 thecortex, and the molecular and cellular events that underlie their consolidation.

*Programs in Integrative
Biology and Brain &Behaviour, Hospital for Sick
Children, 555 University
Avenue, Toronto, Ontario,
Canada M5G 1XB.
‡
Department of Physiology
and Institute of Medical
Science, University ofToronto, Toronto, Canada.
§
Laboratoire deNeurosciences Cognitives,
CNRS UMR 5106,
Université de Bordeaux 1,
Avenue des Facultés,
33405 Talence, France.
Correspondence to P.W.F.
e-mail:paul.frankland@sickkids.ca
doi:10.1038/nrn1607

Our memories of everyday life — of people, places andevents — define who we are1. However, these records oflife experience are not formed instantaneously. Rather,
new memories are gradually transformed from an
initially labile state (in which they are vulnerable todisruption) to a more permanent state (in which they
are resistant to disruption). Müller and Pilzecker first
adopted the term ‘consolidation’ to describe these
post-experience processes of memory stabilization2,3.
Consolidation involves reorganization at both thesynaptic and system levels4 (BOX 1). Synaptic consolidation is complete within hours of training, and involves
the stabilization of changes in synaptic connectivity inlocalized circuits (for example, the growth of newsynaptic connections as well as the restructuring ofexisting ones)1,4,5. By contrast, system consolidation is amore prolonged process and involves gradual reorganization of the brain regions that support memory. For
example, this may involve a time-dependent shift in thecircuits that support memory recall1,4.
The French psychologist Ribot was the first to suggestthat memories might be gradually reorganized overtime6. Ribot described how memory loss following
brain insult was often related to the age of the memory:the effect on more recent memories was typicallygreater than that on remotely acquired memories. Thisdissociation suggested that there is a time-dependent
process of memory reorganization, and became known
as Ribot’s law (or Ribot’s gradient). It was only in the
mid-twentieth century that a more precise relationship

NATURE REVIEWS | NEUROSCIENCE

between the locus of brain damage and the gradient wasestablished. In these classic studies7,8, Penfield, Milner andScoville characterized memory loss in patients withlesions of the MEDIAL TEMPORAL LOBE (MTL) and provided
the first anecdotal evidence that MTL damage preferentially affects recent, but not remote, memories. Later
studies that used quantitative methods to characterize
memory loss in patients with more circumscribed lesions
established that hippocampal damage, in particular, istypically associated with TEMPORALLY-GRADED RETROGRADE
9–12
AMNESIA.
Such examples of temporally-graded retrograde
amnesia have been taken as evidence that the hippocampus has a time-limited role in the storage andretrieval of some forms of memory. This idea forms thecentral tenet of most contemporary views of system consolidation: the hippocampus functions as a temporary
store for new information, but permanent storage
depends on a broadly distributed cortical network13,14.
Although we have a good understanding of the mechanisms that underlie the formation of new hippocampusdependent memories, we know much less about how
these memories are transformed into lifelong, or
remote, memories in cortical networks. In this review,
we begin by describing neuropsychological studies thathave established a crucial role for the hippocampus indeclarative memory. We then shift our focus to how
these memories become consolidated in the cortex.
Recent studies that use imaging and mouse genetic
approaches, alongside traditional pharmacological and
VOLUME 6 | FEBRUARY 2005 | 1 1 9

REVIEWS

Box 1 | Synaptic versus system consolidation
Neurobiologists distinguish between two types of memory consolidation — one fast,
one slow — and their different kinetic properties reflect qualitatively distinct underlying
processes. For example, morphological changes are necessary for the initial stabilizationof memories in hippocampal circuits. These changes, which include the growth of newsynaptic connections as well as the restructuring of existing synaptic connections, takeplace in the first few hours that follow learning1,4,5. They depend on a cascade that is
initiated by synaptic activation, which leads to the recruitment of second messenger
systems, activation of transcription factors and, ultimately, synthesis of new proteinsrequired for the structural changes. Any manipulation, whether it be behavioural (forexample, retroactive interference), pharmacological (for example, protein synthesis
blockers142) or genetic (for example, genetic disruption of cAMP responsive elementbinding protein143) that interferes with any part of this cascade will block memory
formation. Just as the dictionary definition implies (that is, to consolidate is tostrengthen or to secure), similar treatments applied outside the period of consolidation
fail to disrupt the memory. The application of molecular biological approaches has beensuccessful in identifying many of the molecular components of this cascade that arenecessary for synaptic consolidation. These studies have shown that the molecularbuilding blocks for memory are highly conserved across species (from Aplysia
californica to Drosophila melanogaster to mice) and different memory systems1.
However, consolidation can also occur at a system level. Consolidation, in this case,refers to a gradual (and usually slower) process of reorganization of the brain regionsthat support memory. System consolidation seems to be a feature of different types ofmemory: both declarative7 and non-declarative144 memories in humans show timedependent reorganization at a system level, although their timescales are markedly
different. Similar time-dependent reorganization is observed in invertebrates: memories
for courtship conditioning in flies145 and olfactory conditioning in bees146 are both
initially dependent on the antennal lobes, but with time the dependence shifts to themushroom bodies. These examples indicate that system consolidation might be a
general organizing principle across species as well as memory systems. As performancedoes not necessarily change over time, these changes might serve other purposes (suchas memory stabilization).

anatomical lesion approaches, have begun to identify the
network of cortical regions that support remote memory
and the molecular events that are important for theirconsolidation. It is becoming clear from these analyses
that the prefrontal cortex might have a privileged role inprocessing remote memory.
MEDIAL TEMPORAL LOBE

(MTL). A collection of
anatomically connected regionsthat have an essential role indeclarative memory (conscious
memory for facts and events).
The MTL includes the
hippocampal region (CA fields,
dentate gyrus and subicularcomplex) and adjacententorhinal, perirhinal andparahippocampal cortices. The
function and organization of the
MTL seems to be conserved inhumans, non-human primatesand rodents.
TEMPORALLY-GRADEDRETROGRADE AMNESIA

A condition associated withmemory loss for past events.
Most often associated withdamage to the medial temporal
lobe, memory loss for more
recent events is more
pronounced than for the distantpast.

The hippocampus and declarative memory

Anterograde amnesia. In humans, MTL damage produces persistent anterograde amnesia — an inability toform new memories. In the most well-known case,patient H.M.15 had parts of the MTL removed to alleviate
a severe form of epilepsy16. This surgery successfully
reduced the frequency of H.M.’s seizures. However,
H.M.’s ablity to form new declarative memories —the type of memories that can be readily brought toconscious recollection — was profoundly impaired7.
This impairment included an inability to form lasting
memories of events (episodic memory) or to acquire newgeneral knowledge or facts normally (semantic memory).
In stark contrast, many other forms of mnemonic processing seemed to be largely spared. For example, he
could acquire new visuomotor skills, and retain thesefor up to a year17. These, and other examples of spared
non-declarative memory (for example, perceptual
learning and repetition priming)15,18 in patients such as
H.M., who have damage to the MTL system, have led tothe concept that memory is not a unitary phenomenon.

1 2 0 | FEBRUARY 2005 | VOLUME 6

As specific memory deficits are associated with specificpatterns of brain damage, these neuropsychologicalapproaches have led to the concept that there are several
anatomically distinct memory systems19–22. Although
there is a consensus that MTL damage profoundly disrupts the formation of new declarative memories, there
is considerable debate as to whether all forms of declarative memory are equally affected23,24. While some sparingof semantic learning following MTL damage indicatesthat this form of declarative learning might also dependon brain regions outside the MTL23, a recent report indicates that patients with almost complete bilateral MTL
lesions fail to acquire new semantic knowledge24.
Retrograde amnesia. H.M.’s surgery also produced
retrograde amnesia — a loss of the declarative memories that were acquired during the period that led up tohis operation. However, the retrograde amnesia was notcomplete: although H.M. lost more recent memories,
he retained memories from his early childhood7.
Subsequent analyses revealed that H.M.’s retrograde
amnesia extends back approximately 11 years25. The
discovery that retrograde amnesia following MTL
damage was incomplete indicated that the MTL might
have a time-limited role in the storage and retrieval of
declarative memories, and that, over time, memories
might be permanently stored elsewhere.
This important finding has subsequently been characterized in detail in many patients with similar brain
lesions13,18,26. In these case studies, there is considerable
variation in the length of the gradient, which ranges
from several months to several years (or even decades).
At least two factors might account for this variability.
First, the length of the gradient seems to be related to theextent of the MTL damage13. For example, in twopatients where damage was limited to the CA1 region of
the hippocampus, retrograde amnesia only extended
back 1–2 years11. By contrast, in patients with more
extensive MTL damage (including the entire hippocampus and parts of the entorhinal cortex) retrograde
amnesia covered at least 15 years11. In cases where damage
extends beyond the MTL, retrograde amnesia can be
FLAT, possibly because sites for permanent memory storage are also affected13. Second, the length of the gradientmight be related to the particular type of declarative
memory being tested26,27–31. For example, althoughdetailed remote memories might be preserved inpatients with MTL damage27, in some reports they are
not always as vivid when compared with healthy individuals30,32. To some, this indicates a dissociation
between semantic and episodic memories — with anintact hippocampus always necessary for episodic(including contextual or spatial) details26,33.
Modelling retrograde amnesia in animals. In humans,
MTL damage produces temporally-graded retrograde
amnesia for at least some forms of declarative memory.
However, there are difficulties in studying retrograde
amnesia in patients with brain damage. Because thesestudies rely on retrospective tests, it is difficult tocompare performance across time points. In addition,www.nature.com/reviews/neuro

REVIEWS

Box 2 | Two behavioural models of system consolidation in rodentsabTraining

Demonstrator

Food
Exchange of information

Testing
Preference test

100

Freezing (%)

75

50

25

0

Familiar food eaten (%)

100

Control
HPC lesion

75

50

25
1

7

14

28

Training–surgery delay (days)

1

10

30

Training–surgery delay (days)

Contextual fear conditioning (panel a) is a form of Pavlovian conditioning where animals
learn an association between a distinctive place (context) and an aversive event (shock)68.
When placed back into the same context (but not dissimilar contexts), rodents show arange of conditioned fear responses, including freezing. An attractive feature ofcontextual fear conditioning is that a single training experience is enough to produce a
memory that can last for a lifetime147. Freezing behaviour is thought to be adaptive
because, in the wild, absence of movement would reduce the likelihood of detection by a
predator. Electrolytic lesions of the hippocampus (HPC) produce a temporally-gradedretrograde amnesia for contextual fear memories in rats42.
In the socially-acquired food preference task (panel b), animals learn about potential
food sources by sampling those sources on the breath of littermates. During training
rodents interact with a ‘demonstrator’ rodent that has recently sampled a new, flavoured
food. After some delay, when given the choice between two foods, rodents show apreference for the food that they smelled on the breath of the demonstrator rodent. Thispreference lasts for up to several weeks38, which makes this task appropriate for studies ofsystem consolidation. This type of learning might be adaptive as it allows rodents to learn
about the safety of different food sources69. Complete electrolytic lesions of the
hippocampus (including the subiculum) produce a temporally-graded retrograde
amnesia for socially-acquired food preference in rats 38. Panel a adapted, with permission,from REF. 42  (1992) American Association for the Advancement of Science. Panel b
adapted, with permission, from REF. 38  (2002) Society for Neuroscience.

FLAT

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

the extent of the damage varies from one case toanother, and lesions are rarely confined to the hippocampus13. To address some of these issues, animalmodels have been developed to enable researchers to
study the relationship between hippocampal damage
and retrograde amnesia. The main advantage of thisapproach is that it allows retrograde amnesia to be

NATURE REVIEWS | NEUROSCIENCE

studied in a prospective manner — the extent of thelesion can be controlled, as can what is learned andwhen. More than 30 studies34–67 have directly investigated
the impact of disrupting function in the hippocampus
and related structures on recent and remote memories(online supplementary information TABLE 1). In thesestudies, several behavioural models have been used toassess memory, including contextual fear conditioning68
and socially-acquired food preference (a form of nonspatial learning)69 (BOX 2). Although there are manydifferences between these tasks in terms of stimulus
properties, motivation and performance demands, theyshare some unifying features with human declarative
memory. All these tasks require animals to represent
complex relations among stimuli and/or to form memories that integrate contextual, spatial or temporal
information70.
Typically, these studies show that disrupting hippocampal function preferentially affects recent, rather
than remote, memories. Temporally-graded retrograde
amnesia has now been shown across a wide range of
species, in a broad range of protocols, using a varietyof lesion methods (including pharmacological44,48,59,60
or genetic49,54 approaches) and following extensive
hippocampal lesions (including the subiculum)34,38, as
well as entorhinal36,37 and perirhinal41,53 cortex lesions.
In these studies, the length of the gradient varies from a
few days to several weeks, which is much shorter thanthat seen in humans. Although systematic studies havenot been carried out, the length of the gradient probably depends on factors such as species, complexity of
behavioural task, amount of training and the type,extent and location of lesion. It should be noted that, as
in humans, temporally-graded retrograde amnesia is
not always observed. In some of these cases, failure toobserve a gradient is probably confounded by poor
performance of control animals in the remote memory
test35,41,67. In others, extra-hippocampal damage, possibly
affecting sites of permanent storage, might account for
deficits at remote, as well as recent, time points71. Finally,in more demanding spatial memory tests, the hippocampus might always be necessary for topographicaldetails62,72 or navigational (path integration61,62,73)
aspects of task performance.
Models of system consolidation

Examples of temporally-graded retrograde amnesia inboth humans and animals have led to system-basedmodels of consolidation. Marr74,75 formulated the firstmodel to account for system consolidation. He proposed that the hippocampus rapidly stores the day’s
events before the information is transferred to the cortex for subsequent reorganization and reclassification.
Marr further proposed that the transfer processdepended on REPLAY of waking patterns of neural activity
during sleep.
The ideas that the hippocampus is a temporary
repository, that waking patterns of neural activity arereinstated or replayed during sleep, and that the cortex
is important in extracting statistical structure (semantic
knowledge) form the bases of contemporary models of

VOLUME 6 | FEBRUARY 2005 | 1 2 1

REVIEWS

Memory reactivation

Cortical modules

Hippocampus

Time

Figure 1 | Standard consolidation model. Encoding of perceptual, motor and cognitive
information initially occurs in several specialized primary and associative cortical areas. The
hippocampus integrates information from these distributed cortical modules that represents
the various features of an experience, and rapidly fuses these features into a coherent
memory trace70,127. Successive reactivation of this hippocampal–cortical network leads toprogressive strengthening of cortico-cortical connections (for example, by strengthening
existing cortico-cortical connections or establishing new ones). Incremental strengthening ofcortico-cortical connections eventually allows new memories to become independent of the
hippocampus and to be gradually integrated with pre-existing cortical memories13,14. A key
feature of this model is that changes in the strength of the connections between the
hippocampal system and the different cortical areas are rapid and transient, whereas changes
in the connections between the cortical areas are slow and long-lasting13,14.

REPLAY

Recapitulation of experiencedependent patterns of neuralactivity previously observed
during awake periods.
SLOW-WAVE SLEEP(SWS). Stage of non-REM deep
sleep that is characterized by thepresence of high-amplitude, slow
delta waves of brain activity.
RAPID EYE MOVEMENT(REM). A period of sleep, during
which dreaming is thought tooccur. 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 thatfire in a location-specific manner.
These cells are thought to form
the basis of cognitive maps,
which allow animals to navigate
through their environment.
RIPPLESHigh 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 ofslow-wave sleep and behaviouralimmobility.

memory formation13,14 (FIG. 1). According to these models,
experience is initially encoded in parallel in hippocampal and cortical networks. Subsequent reactivationof the hippocampal network reinstates activity indifferent cortical networks. This coordinated replay
across hippocampal–cortical networks leads to gradualstrengthening 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. In these models,memories are assumed to decay more rapidly in the
hippocampus than in the cortex.
An alternative view is based on two observations.
First, MTL damage can produce ungraded retrograde
amnesia for some types of declarative memory, such as
autobiographical/episodic30,76 and detailed spatial
memories32,62. Second, the recall of detailed, remote autobiographical/episodic memories engages the hippocampus77–80. To account for these observations, themultiple trace theory (BOX 3) proposes that, althoughexperience is initially encoded in distributed hippocampal–cortical networks, the hippocampus is always
required for rich contextual or spatial detail26. This
theory predicts that complete hippocampal lesions
should produce temporally-graded retrograde amnesia
for only semantic (and not episodic) memories33.
However, the finding that patient E.P., who has extensive
bilateral MTL lesions, has excellent autobiographicaland spatial memories from his youth31 is inconsistent
with this prediction. At present, there is some debate
about whether spared remote memories in patients like
E.P. are as vivid and detailed as in healthy subjects32.

1 2 2 | FEBRUARY 2005 | VOLUME 6

Cellular correlates of memory reactivation. Memory
reactivation is the core mechanism in consolidation
models. Reactivation of the hippocampal memory traceis thought to lead to the reinstatement of experiencedependent patterns of neural activity in the cortex,
and subsequent stabilization and refinement of cortical traces. This iterative process is proposed to lead,
eventually, to storage and recall becoming completelydependent on the cortex, and independent of the
hippocampus. Memories can be reactivated during
either ‘online’ states (such as task-relevant situations) or‘offline’ states (such as during sleep or quiet wakefulness/day dreaming).
Indirect evidence for the idea that memory replay
during sleep contributes to consolidation comes fromhuman studies documenting the beneficial effects
of sleep on memory. For example, brief naps or overnight sleep improve various forms of non-declarative
memory including motor skills, visual and texture
discrimination learning81–83, and some forms of declarative memory 84. Furthermore, overnight sleep can
restore ‘lost’ memories85 and even enhance ‘insight’86.
However, the relative contributions of different sleep
phases (for example, SLOW-WAVE SLEEP (SWS) and RAPID
EYE MOVEMENT (REM) sleep) to the consolidation ofdeclarative and non-declarative memory remain
uncertain87,88.
More direct evidence comes from demonstrations
that patterns of brain activity that are associated withearlier learning are selectively replayed during subsequent sleep in humans89–91 and other species such as
non-human primates92, rodents93–99 and songbirds100. In
a series of important experiments, McNaughton,
Wilson and colleagues showed that coordinated replay
occurs in the hippocampus and in both hippocampal–
cortical and cortico-cortical networks101,102. When theactivity of HIPPOCAMPAL PLACE CELLS was recorded during
spatial exploration in rats, cells that were co-active
during exploration showed correlated firing patterns
during SWS97. Along with other examples, this study
shows that replay of hippocampal CA1 firing patterns
can occur in subsequent rest or sleep states. Furthermore, hippocampal replay retains the original temporalorder, and occurs preferentially during high frequency
bursts of activity known as sharp-wave RIPPLES93–99.
Although this high frequency oscillatory activity
might promote strengthening of synaptic connectionsin the hippocampus, it is also thought to coordinate
memory consolidation in target cortical regions.
Consistent with this, hippocampal ripple activity
occurs in temporal correlation with cortical slow-wave
94
SPINDLES recorded in the medial prefrontal cortex .
Such coordinated replay of experience-dependent
activity during SWS in hippocampal–cortical94,103 andcortico-cortical92 networks could promote the gradual stabilization of memory in the cortex. Futurestudies might further strengthen the link between
experience-dependent replay in sleep and memory
consolidation by showing that blocking this activity
impairs memory.

www.nature.com/reviews/neuro

REVIEWS

Box 3 | Multiple trace theoryb Multiple trace theory

100

100

Memory score

100

Memory score

Memory scorea Standard model

0

0

0

RecentmemoryRemotememoryRecentmemorySemantic or episodic
information
Controls (sham)

RemotememorySemantic information

Partial HPC lesion

RecentmemoryRemotememoryEpisodic information

Complete HPC lesion

Multiple trace theory (MTT)26 was proposed in 1997 as an alternative to standard
consolidation models. At the heart of the debate is how to account for instances where
MTL damage produces extensive retrograde amnesia. Although one argument is thatflat gradients are associated with extensive damage to extra-hippocampal regions,which affect possible sites of permanent storage13,18, Nadel and Moscovitch argued thatthe length of the gradient depended on the extent of hippocampal damage as well as thetype of memory being probed. In particular, they noted that when damage included thewhole hippocampal formation, retrograde amnesia for autobiographical (episodic)
information was extensive, spanning much of a subject’s lifetime. These observations
led to the formulation of MTT. HPC, hippocampus.

memory circuits. One gene that is regulated in anexperience-dependent manner during sleep is ZIF268.
ZIF268 is a transcription factor that regulates long-term
plasticity and stabilization of retrieved memories105,106.
For example, after rats had explored a novel environment, upregulation of ZIF268 was observed, during
subsequent sleep, in the hippocampus as well as invarious cortical regions such as the piriform and frontal
cortices107. Similarly, the induction of long-term potentiation (LTP) in the dentate gyrus in awake, behaving
rats led, during subsequent sleep, to upregulation of
ZIF268 in various cortical regions, including theentorhinal, auditory, somatosensory and frontal
cortices108. Importantly, tetracaine-induced inactivationof the hippocampus prior to the onset of REM sleep
blocks the upregulation of ZIF268 in these corticalregions. This indicates that gene expression in the cortex
might be under the control of the hippocampus and,
therefore, that cortical remodelling might depend on
hippocampal activity — at least in the first few hours
after training108. In these studies, upregulation of ZIF268
expression occurred during REM sleep. As replay
predominantly occurs during SWS, this supports a
two-stage model in which sustained high frequency
activity during SWS leads to structural changes in cortical networks that are stabilized during subsequent
REM sleep93.

The main features of the multiple trace theory• Memories are encoded in hippocampal–cortical networks• Memory reactivation leads to the generation of multiple traces in the hippocampus,
which are linked to cortical networks• Traces in the hippocampus provide spatial and temporal context• Traces in the cortex are context-free (or semantic) in nature• Retrieval of contextually rich episodic memories always depends on
hippocampal–cortical networks• Retrieval of remote semantic memories is possible in the absence of a functional
hippocampus
According to this model, there are two conditions in which hippocampal damage
might be associated with temporally-graded retrograde amnesia. Incomplete
hippocampal lesions should preferentially affect recent rather than remote episodic orsemantic memories, as trace proliferation should render older memories more resistant
to hippocampal damage. Complete hippocampal lesions should abolish all episodic
memories, regardless of their age. Furthermore, semantic components of remotememories might be spared even after complete hippocampal lesions. Predictions ofstandard models (a) and MTT (b) are contrasted above.
This theory shares one important assumption with standard consolidation models —that is, reactivation of memories initiates a process of reorganization. Where it differs isin terms of the locus of this reorganization. Although standard models predict that
reorganization occurs in cortical networks, MTT predicts that reactivation should also
lead to the generation of new traces within the hippocampus.

SPINDLES

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

Molecular correlates of memory reactivation. Successive
reactivations are thought to promote gradual remodelling of the hippocampal–cortical circuits that support
memory. Around 100 known genes (and ~400 unidentified genes) have been shown to be upregulated during
sleep, independent of circadian time104. It is likely that atleast some of these genes are involved in stabilizingchanges in synaptic strength and structure in reactivated

NATURE REVIEWS | NEUROSCIENCE

Mouse genetic studies. Data from these studies indicatethat the gradual remodelling of hippocampal–corticalcircuits depends on many rounds of synaptic modification. These changes are initiated in a reactivationdependent manner (either during online or offline
situations) and require expression of new genes. The
idea that recurrent reactivation-dependent synaptic
modifications in hippocampal and cortical networks
are essential for the consolidation of memory109,110 has
been tested using genetic approaches in mice. To
address the importance of maintaining the integrityof the hippocampal trace in the days after training,mice were generated in which the NR1 subunit of the
NMDA (N-methyl-D-aspartate) receptor (NMDAR)
in CA1 can be deleted in an inducible manner49. Micewith normal NMDAR function were trained in two
hippocampus-dependent learning tasks: the MORRISWATER MAZE and contextual fear conditioning. Suppressing NMDAR function in the week immediately
after training blocked the formation of remote memories, although suppressing NMDAR function at latertime points did not. Similarly, overexpression of adominant-negative form of α-calcium/calmodulin
kinase II (α-CaMKII)111 in the forebrain in the week
immediately after training, but not thereafter, blocks
the formation of remote contextual fear memories54.
These results are consistent with the idea that hippocampal replay is vital for memory consolidation incortical networks. They identify a crucial week-longwindow during which normal hippocampal activity
is important for memory consolidation. This time
window is consistent with the observation that hippocampal lesions in the first week after training, but not

VOLUME 6 | FEBRUARY 2005 | 1 2 3

REVIEWSa LTP

b Memory
CA1

Late-LTP in CA1
70

Wild typeα-CaMKII+/–

60

175
200
150
125
100

50
40
30

100

20

0

75
–10

0

10

20

30

40

50

60

–30

0

30

Time after TBS (min)60

90

120 150 180 210

3240Time after TBS (min)Visual cortex

10

17

Delay (days)

Temporal cortex

140

100

Contextual

130

130

75

120

Freezing (%)

Baseline response (%)

Spatial300

Wild typeα-CaMKII+/–Time in TQ (%)

Baseline response (%)

200

120
110

110

25

100

100
90

90

–10

0

10

20

Time after TBS (min)

30

40

50

0

–10

0

10

20

30

Time after TBS (min)

40

1

3

17

Delay (days)

Figure 2 | Deficient cortical plasticity and memory consolidation in α-CaMKII+/– mice. a | Physiology experiments indicate that aheterozygous null mutation for α-CaMKII has dissociable effects on hippocampal and cortical plasticity. Both early and late long-term
potentiation (LTP) is normal in the CA1 region of the hippocampus in brain slices from wild-type and α-CaMKII+/– mice. By contrast, LTP
is impaired in the visual and temporal cortices in slices from α-CaMKII+/– mice. In these experiments, LTP was induced using theta-burst
stimulation (TBS) protocols113. b | When trained in two forms of hippocampal-dependent learning (spatial learning in the water maze andcontextual fear conditioning), α-CaMKII+/– mice show premature memory loss. At longer delays, α-CaMKII+/– mice spend less time
searching the training quadrant (TQ) during the spatial probe test, and show decreased freezing in the training context, respectively.
This indicates that normal α-CaMKII-dependent plasticity in the cortex might be crucial for the development of remote memories113.

ZIF268ZIF268 is a transcription factor
that regulates the expression ofmany genes that have diverse
cellular functions. Expression of
ZIF268 correlates with neuronalfiring and is, therefore,
commonly used as a marker ofneuronal activity.
MORRIS WATER MAZE

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

α-calcium/calmodulindependent protein kinase II(α-CaMKII) is a signalling
enzyme activated by Ca2+ influx
through the NMDA (N-methylD-aspartate) receptor. It is
expressed in excitatory forebrainneurons and has a crucial role inneuronal plasticity.

thereafter, abolish contextual fear memories in rats42,
and indicates that proper maintenance of the hippocampal trace is essential for establishing remotememories in the cortex. The results also indicatethat reactivation might initiate several rounds ofNMDAR/α-CaMKII-dependent synaptic modification. This might re-stabilize reactivated traces in the
hippocampus and remodel reactivated traces in
the cortex109,110.
Alternative approaches have focused on the role ofcortical plasticity. During consolidation, the strengthening of cortico-cortical connections is thought to be
crucial in allowing cortical memories to gain independence from the hippocampus. Therefore, disrupting
cortical plasticity should hinder the formation of
remote hippocampus-independent memories, andresult in premature memory loss at extended retention
delays. This prediction is supported by studies of two
strains of mice with abnormal cortical function. Micethat are heterozygous for a null mutation of α-CaMKII(α-CaMKII+/– mice) have global deficits in corticalplasticity, but normal hippocampal plasticity112 (FIG. 2).
Accordingly, they show normal learning and memory
at short retention delays (1–3 days) — time points
at which memory would normally depend on the

1 2 4 | FEBRUARY 2005 | VOLUME 6

hippocampus. However, their memory is impaired atlonger delays (10–50 days) when it would normally
have become dependent on the cortex113,114. These data
indicate that deficits in cortical plasticity might preventthe formation of hippocampus-independent memories
in α-CaMKII+/– mice.
A similar pattern of memory loss was observed inmice that overexpress a dominant-negative mutant
form of p21-activated kinase (PAK). PAK regulates
spinogenesis in neuronal cultures115, and altered spine
structure and synaptic function are observed in micethat overexpress dominant-negative PAK116. Theseabnormalities were shown to be limited to the cortex,
where neurons had fewer dendritic spines and anincreased proportion of larger synapses. These alterations in synaptic architecture were associated withabnormal bidirectional plasticity (enhanced LTP and
decreased long-term depression). When tested in thewater maze, dominant-negative Pak-transgenic micelearned normally and had normal memory when tested
1 day later. However, their memory was impaired 21days after training, which is consistent with abnormal
cortical function. More rapid memory loss wasobserved when these mice were tested using contextual
fear conditioning116.

www.nature.com/reviews/neuro

REVIEWSa8-arm radial maze

Recent memory

Remote memory

Same context
Same baited arms

Same context
Same baited arms

5 days
1st

9th
Retention interval
Daily sessions

By testing memory at recent and remote time points,
researchers have been able to characterize how the circuits that support memories are gradually reorganizedover time, to identify sites of permanent storage in thecortex, and to provide evidence for reorganization at
both regional and sub-regional levels.

25 days

Different context
Different baited armsb

Intravenous(14C)2-DG
injection

Retention
testing
35 minBrain removal
and sectioning

Film exposure
7 daysProcess film

1 minAutoradiographic
cassette
Densitometricanalysis of
autoradiographscRecentRemote2 mm

Remote new context

aCC
FC

Frontallevel

Relative
metabolicactivity

5
4
3
2
1

dHPC

Hippocampal
level

CA3

pCC
PC

CA1
DG

Figure 3 | Time-dependent reorganisation of brain circuitry that underlies spatial
discrimination memories. a | Behavioural protocol. Mice were first trained to forage for food in
an 8-arm radial maze. Training took place over 9 consecutive days, and the same 3 arms werebaited on each day. Retention of this spatial discrimination memory was then tested either 5 days(recent memory) or 25 days (remote memory) later. An additional group of mice was tested at
the remote time-point with the maze located in a different context. b | (14C)2-DEOXYGLUCOSE((14C)2-DG) procedure. Testing-induced changes in neuronal activity were visualized using the(14C)2-deoxyglucose autoradiographic method148, a technique that is similar to position emission
tomography (PET) scan imaging in humans. c | Colour-coded autoradiographs of coronal sections
following recent memory test (left), remote memory test (centre) or remote memory test in thealternate context (right). The lower section of each panel shows a magnified view of the dorsal
hippocampus (CA1, CA3 and dentate gyrus, DG). Increasing the retention interval resulted indecreased metabolic activity in the dorsal hippocampus (dHPC) and increased activity in several
cortical areas including the frontal (FC) and anterior cingulate (aCC) cortices. These data indicate thatthe hippocampus has a transient role in memory storage, and that, over time, distributed corticalareas become capable of mediating recall of remote memories independently. By contrast, testing
mice in the different context at the remote time-point re-engages the hippocampus, indicating that
this brain region is required to encode new information. PC, parietal cortex; pCC, posterior cingulate
cortex. Adapted, with permission, from REF. 118  (1999) Macmillan Magazines Ltd.

Memory reorganization

Reactivation is thought to result in gradual remodellingof hippocampal–cortical memory networks and, consequently, changes in memory organization. Recent studies
have used imaging approaches to track changes in networks over periods of weeks in healthy animals44,114,117,118.

NATURE REVIEWS | NEUROSCIENCE

Reorganization at the regional level. In the replay studies
described above, there was typically only a 1-hour delay
between neural activity recordings during behavioural
tests and subsequent reactivation in either sleep or rest
states. The longest delay used was 96 hours93. As system
consolidation in animals takes place over weeks, it would
be useful to track reactivation over a much longer time
period. However, the probability that a specific trace isreactivated is thought to decline exponentially with
time14, which makes signal detection of offline reactivation a problem at longer delays. An alternative approachis to investigate memory reactivation during online
states, such as after memory retrieval. This approach
offers experimental control over the timing of the reactivation. Using this strategy, Bontempi and colleagues
tracked changes in the organization of spatial discrimination memory in mice (FIG. 3). This group used either(14C)2-deoxyglucose uptake to map changes in brain
metabolic activity at the regional level118, or expressionof activity-regulated genes such as c-fos and Zif268 tovisualize changes in neuronal activity at the cellularlevel44. The recall of recent spatial memories was associated with activation of the hippocampus and entorhinal
cortex. By contrast, the recall of remote spatial memories was predominantly associated with activation ofcortical regions such as the prefrontal, frontal, anterior
cingulate, retrosplenial and temporal cortices.
This same dissociation was observed in studies ofcontextual fear conditioning in mice. The expression ofactivity-dependent genes (Zif268 and c-fos) was elevatedin the hippocampus after the recall of recent contextual
fear memories, whereas these genes were upregulated in
multiple cortical regions, such as the anterior cingulate,prefrontal and temporal cortices, following recall of
remote memories114. These imaging studies indicate thatspatial and contextual memories are represented in
distributed cortical networks. Activation of some corticalregions was observed following recall of recent memories114, indicating that these cortical regions are importantin the initial stages of consolidation. However, withincortical regions, recall of remote spatial and contextual
memories was associated with activation of more expansive neuronal networks44,114. These expanded networks
could reflect the integration of the current memory withpre-existing memories in the cortex — a process thatmight underlie the generation of semantic knowledge14.
Finally, the hippocampus was not activated after recall of
spatial or contextual remote memories, which indicatesthat cortical memories are independent of the hippocampus at these extended delays13. In fact, there isevidence that the hippocampus is inhibited (relative tocontrols) in these studies, which indicates that hippocampal activity might be actively suppressed during therecall of remote memories.

VOLUME 6 | FEBRUARY 2005 | 1 2 5

REVIEWS
and modulation of axonal and dendritic growth)119.
Growth-associated protein 43 (GAP43), a marker ofsynaptogenesis120, is induced in the cortex following recallof both spatial and contextual fear memories44,114, whichis consistent with the idea that cortical consolidation
involves rewiring. Furthermore, in α-CaMKII+/– mice,
which have deficient cortical plasticity and deficits inremote contextual fear memory, time-dependentchanges in cortical organization are not observed114. This
indicates that normal cortical levels of α-CaMKII might
be necessary for establishing hippocampus-independent
contextual memories in the cortex.

aI

II–III

Parietal layers

IV

V

VI

From other cortical areas

To othercortical areas

To thalamus

To brainstemand spinal cordb

From thalamuscI

RecentRemoteII–IIIII–III

IV
IV

V

V

VI

VI

10

RecentRemote2030

40c-Fos counts per layer (%)

Figure 4 | Laminar reorganization in the parietal cortex. a | Schematic diagram of the parietal
cortex showing local arborisation of dendrites and axons within layers, as well as more distantprojections to and from the thalamus and other cortical areas. b | Mice were trained in a spatial
discrimination procedure44, and their memory tested either 1 day (recent memory) or 30 days
(remote memory) later. Expression of the activity-dependent gene, c-fos, was used as a marker ofneuronal activation. Immunoreactivity of c-Fos was pronounced in deep cortical layers (V–VI)
following the recent memory test, and in more superficial layers (II–III and IV) following the remotememory test. c | Quantitative levels of c-Fos protein in the different cortical layers. Note the shift in
activation from deep cortical layers V–VI to superficial layers II–III and IV as memories
progressively mature. Remote memory storage in layers II–III is likely to involve slow changes inthe strengthening of cortico-cortical connections by Hebbian mechanisms (coincident activationfrom cortico-cortical and thalamo-cortical inputs). Panel a adapted, with permission, from REF. 121
 Springer-Verlag, Heidelberg. Panels b and c adapted, with permission, from REF. 44 
American Association for the Advancement of Science.

The imaging studies provide evidence for timedependent reorganization of the cortical circuits that
support spatial and contextual memories. Such remodelling might be mediated by either weight plasticity (that is,
rapid modification of existing connections between
neurons) or wiring plasticity (that is, slower structuralchanges leading to the addition/elimination of synapses

1 2 6 | FEBRUARY 2005 | VOLUME 6

Reorganization at the sub-regional level. Reorganization
might also occur at the sub-regional level across different cortical layers. In this case, only cellular imaging
approaches would be sufficiently sensitive to detect
shifting patterns of activation within regions. Somecortical regions showed similar levels of activation afterrecall of recent or remote spatial discrimination memories44. However, in the parietal cortex, the pattern ofneuronal activation shifted from the deep cortical layers
V–VI to more superficial layers (II–III and IV) over time
(FIG. 4). This is important from a functional point of view,
because layers II and III are the origin and termination ofmost cortico-cortical connections121. Therefore, thislaminar reorganization is consistent with the idea thatnew cortico-cortical connections are established overtime. Such connections might support the coordinatedactivation of several cortical networks organized in ‘CELL
ASSEMBLIES’. This concept was originally proposed by
Hebb122 and has recently been supported in a study thatshowed coordinated replay of waking patterns of neuralactivity in three cortical regions (motor, somatosensory
and parietal cortices)92.
Reorganization at the sub-regional level could also
explain why it has been difficult to find evidence forincreased cortical activation in studies of human remotememory. Sub-regional changes in organization might
not result in greater levels of activation at the regional
level. Therefore, the lack of sub-regional spatial resolution of functional imaging techniques might makethese techniques insensitive to more localized changes inorganization123.
Targeted disruption of system consolidation. Post-training,hippocampal lesions preferentially disrupt recent, but
not remote, memories. Is it possible to affect system consolidation by targeting extra-hippocampal regions? For
example, this might be achieved by creating a lesion thatblocks dialogue between the hippocampus and cortex
shortly after training. A lesion of this type would allow
hippocampal memories to form normally, but prevent
their subsequent consolidation in cortical networks. Thisprediction is supported by a recent study 65, in which it
was shown that a lesion of the temporoammonic (TA)projection from layer III of the entorhinal cortex to the
hippocampal CA1 region allows the hippocampus tofunction normally but disrupts cortical–hippocampal
interactions. Rats with TA lesions showed normal spatial
learning in the Morris water maze, and normal memorywww.nature.com/reviews/neuro

REVIEWSab Remote memory

Recent memory
Cortical modules

Prefrontal cortex

Prefrontal cortex

Cortical modules

regions in mice44,114,118. In principle, the distributed
nature of remote memories should make them resistant
to disruption by focal cortical lesions125, as a sufficientportion of the network survives and can support the
memory14,122. However, pharmacological and anatomicallesion studies indicate that the prefrontal cortex might bean essential node in this network44,52,114.
The prefrontal cortex and remote memory

Hippocampus

Hippocampus

Figure 5 | Prefrontal cortex and remote memory. Results from imaging and inactivation
studies using animal models indicate that the prefrontal cortex might have dual roles during
remote memory recall. Initially, memories are encoded in hippocampal–cortical networks, as
previously proposed13,14,26. At this early time point, the hippocampus is crucial in integrating
information from distributed cortical modules, each representing individual components of amemory (a). However, as the memory matures connections between the different corticalmodules are strengthened, allowing the memory to function independently of the hippocampus.
At this later time point, the integrative role is assumed by the prefrontal cortex (b), via reciprocal
connections with the sensory, motor and limbic cortices. Consistent with this model, lesions or
pharmacological inactivation of the prefrontal cortex disrupt recall of remote, but not recent,memories. Conversely, lesions or pharmacological inactivation of the hippocampus produces the
opposite pattern of results, that is, they impair recent, but not remote, memory. This model also
proposes that the prefrontal cortex regulates hippocampal activity during memory recall. The
hippocampus is normally active when processing the external environment. However, whenincoming information matches a previously stored remote, cortical memory, the prefrontal cortex
activity inhibits hippocampal activity by either direct149 or indirect22,150 connections to prevent
encoding of redundant information. In the absence of a match condition, there is no inhibition andthe hippocampus will be engaged as usual.

(14C)2-DEOXYGLUCOSE

A functional brain imaging
technique that is commonlyused in rodents to estimate thelevel of neuronal activity in
specific brain regions. The
glucose analogue, (14C)2deoxyglucose, is administered tothe animals and is subsequently
taken up and trapped by active
neurons.
CELL ASSEMBLIES

Large collections of neurons thatshow coordinated firing activity.
Activation of any part of thisnetwork can reconstitute activity
in the entire cell assembly. Thesecell assemblies are thought toform the basic neuronal code ofrepresentation.

when tested one day later, which is consistent with sparedhippocampal function. However, when the animals were
tested after a 28 day delay, spatial memory was impaired.
This indicates that cortical–hippocampal interactions are
required for the formation of remote spatial memory.
This requirement for ongoing cortical input through theTA pathway was time-limited since similar lesions 1 day(but not 21 days) after the completion of training blocked
the formation of remote spatial memories.
An alternative strategy to disrupt remote, but notrecent, memories is to target the cortical regions that aresupposed to store remote memories. Several experiments have provided evidence that manipulations of thecortex preferentially affect remote, but not recent, memories44,52,59,60,114. In these studies, the prefrontal cortex(including the prelimbic and anterior cingulate cortices)
has emerged as a particular hotspot for these effects44,52,114.
In humans, the prefrontal cortex is thought to beimportant in strategic retrieval of stored information124.
In animals, anatomical lesions and pharmacologicalinactivation of the prelimbic cortex and anterior cingulate cortex preferentially disrupt remote trace eye-blinkconditioning and spatial discrimination memories,
respectively 44,52. Similarly, pharmacological inactivationof the anterior cingulate cortex preferentially blocks recallof remote contextual fear memories114. Brain imaging
approaches indicate that remote contextual and spatial
memories are encoded in a broad network of cortical

NATURE REVIEWS | NEUROSCIENCE

These imaging and inactivation studies have provided amore detailed picture of how memories are organized at
different points in their life. Although the imaging data
show that remote spatial and contextual memories
might be supported by a broad cortical network, theinactivation experiments indicate that some parts of thisnetwork might be more important than others44,52,114,118.
These studies have identified different regions of the prefrontal cortex as playing a crucial role during remotememory recall. The prefrontal cortex consists of several
highly interconnected regions, including the anterior
cingulate, prelimbic and infralimbic cortices. These
regions are reciprocally connected to sensory, motor andlimbic cortices126, and are therefore ideally situated tointegrate and synthesize information from a large number of different sources121. This potential for integration
indicates that the ability of the prefrontal cortex toprocess remote memories might mirror that of the
hippocampus to process recent memories (FIG. 5).
Initially, the hippocampus is thought to integrate information from distributed, but relatively independent,
cortical modules that represent the various features of anexperience, and then to rapidly fuse these various features into a coherent memory trace70,127. Consistent with
this, recall of recent memories is associated with activation of the hippocampus, and lesioning or inactivating
the hippocampus preferentially disrupts the recall ofrecent memories. As memories mature, this integrative
function might be transferred to the prefrontal cortex(and possibly other association cortices) through thestrengthening of cortico-cortical connections. This
process would allow cortical networks to function independently of the hippocampus, because the prefrontal
cortex could integrate information from multiple cortical regions128. Consistent with this, inactivation or lesionsof the prelimbic or anterior cingulate cortices blockrecall of remote memory44,52,114, even in the presence ofan intact hippocampus. Whether or not the prefrontal
cortex is involved in storage or retrieval (for example,
effortful recall129) of remote memories remains to be
determined.
The prefrontal cortex might have another importantfunction during memory recall (FIG. 5). Imaging studies
in animals show that hippocampal activity is actively
inhibited when remote spatial and contextual memories
are successfully recalled44,114,118. From a functional pointof view, this makes sense as it prevents the hippocampus
from re-encoding existing memories, and it also indicates that the cortex might be more than just a passive,
permanent repository for memory. Although the sourceof this inhibition is not known, the prefrontal cortex
exerts top-down inhibitory control over posterior cortical

VOLUME 6 | FEBRUARY 2005 | 1 2 7

REVIEWS
regions during sensory processing130 and voluntary
recall131 and might, therefore, exert similar influences
over hippocampal function during the recall of remotememories. Whether inhibition occurs might depend onwhether incoming information corresponds to a previously stored cortical memory. If retrieval is successful,hippocampal function will be rapidly inhibited. If there
is a mismatch (for example, if the information has beenforgotten), then there will be no inhibition and the
hippocampus will be re-engaged. This idea is consistent
with the existence of match and mismatch comparator
neurons in the cortex, especially in the prefrontal
cortex132. These predictions are partially supported in
α-CaMKII+/– mice, which forget at extended retention
delays. In remote memory tests, the hippocampus isre-engaged, which indicates that, in the absence of a‘match’ condition in the cortex, the hippocampus comesback online in these mutant mice114.
Future directions

In the past, neuropsychological studies of both humans
and animals have established that damage to the MTL(including the hippocampus) produces temporallygraded retrograde amnesia for at least some forms ofmemory. These gradients imply that memories aregradually reorganized as they mature, and recent studies
are starting to shed new light on how this reorganization
progresses. These studies have used imaging and genetic
techniques, as well as pharmacological and anatomicallesion approaches, to identify the network of corticalregions that supports remote memory, and the molecular events that are important for their consolidation.
In the future, studies will focus on aspects of consolidation models that have been neglected and those that arecontroversial. We will briefly highlight three such areas.
First, although memories are rapidly encoded in
hippocampal networks70,127, it takes rather more time forthem to be embedded in cortical networks and become
independent of the hippocampus. This has led to the ideathat the hippocampus is a fast learner and the cortex is aslow one14,133. Connectionist models propose that thishelps to avoid catastrophic interference and protects
existing cortical memories from being erased by newly
formed ones. However, it is not clear which neurobiological differences between the cortex and hippocampus
would account for this apparent division of labour. It is
possible that different forms of plasticity predominate in
the hippocampus and cortex, which could account for thedifferential learning rates119,134. In the hippocampus, rapid
encoding might involve changing the weighting between
already connected neurons (for example, by an LTP-likemechanism). In contrast, there are vast numbers of

1.
2.

3.

4.

Squire, L. R. & Kandel, E. R. Memory: From Mind to
Molecules (W. H. Freedman & Co., New York, 1999).
Lechner, H. A., Squire, L. R. & Byrne, J. H. 100 years ofconsolidation — remembering Müller and Pilzecker. Learn.
Mem. 6, 77–87 (1999).
Müller, G. E. & Pilzecker, A. Experimentelle Bieträge zur
Lehre vom Gedächtnis. Z. Psychol. Ergänzungsband 1,
1–300 (1900).
Dudai, Y. The neurobiology of consolidations, or, how stable
is the engram? Annu. Rev. Psychol. 55, 51–86 (2004).

1 2 8 | FEBRUARY 2005 | VOLUME 6

5.
6.
7.

8.

neurons in the cortex, yet only a small fraction of all
possible connections among these neurons exist. The
dominant form of cortical plasticity might involvethe formation of new connections between previously
unconnected neurons119. This form of wiring plasticity
is important in experience-dependent remodelling inprimary sensory cortices 135. An intriguing possibility isthat similar mechanisms might underlie the gradual consolidation of memories in associative cortical networks.
Second, Marr proposed that the hippocampus rapidly
stores the day’s events before this information is transferred to the neocortex. This hypothesis was motivated, inpart, by consideration of the finite storage capability of
the hippocampus136. Although the involvement of the
hippocampus almost definitely exceeds 24 hours (and ispermanent in some models 26,62), a necessary componentof most contemporary consolidation models is that
redundant memories must be routinely cleared from the
hippocampus. In connectionist models, the rate of clearance regulates how rapidly memories are consolidated in
the cortex (with high decay rates being associated withshorter gradients14). However, little is known about how
memories are erased. At the molecular and cellular levels,
several candidate mechanisms have been identified. For
example, in the absence of any behavioural manipulation,
inhibiting protein phosphatase 1 (PP1)137 or NMDARs138
after learning reduces memory loss, which might indicatethat basal PP1 and/or NMDAR-dependent processes
gradually expunge memories. Another interesting possibility is that adult neurogenesis contributes to the clearance of hippocampal traces139. Newly formed neurons in
the dentate gyrus rapidly make synaptic connections
with neurons in CA3. The incremental addition of newneurons to this memory network might lead to trace
instability and, eventually, erasure. In support of thismodel, retention of fear memories is facilitated in micewith reduced levels of adult neurogenesis139. Interestingly, adult neurogenesis occurs at a much slower
rate in the cortex, consistent with proposed slower rates
of decay 14.
As in humans studies, a central issue in animal
experiments of system consolidation is whether therecalled memory is qualitatively the same or different atrecent and remote time points. It is possible that performance in recent and remote memory tests might bebased on different types of knowledge, with remotememories becoming more semantic in nature32. Using
tests that effectively tax episodic components of memory at remote time points may or may not reveal a role
for the hippocampus. Resolution of this debate depends
on finding ways to distinguish episodic versus semantic
components of memories in animal models140,141.

Ledoux, J. E. Synaptic Self (Viking, New York,
2001).
Ribot, T. Diseases of Memory (Appleton-Century-Crofts,
New York, 1882).
Scoville, W. B. & Milner, B. Loss of recent memory after
bilateral hippocampal lesions. J. Neurochem. 20, 11–21(1957).
Penfield, W. & Milner, B. Memory deficit produced bybilateral lesions in the hippocampal zone. AMA Arch. Neurol.
Psychiatry 79, 475–497 (1958).

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).
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).
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).

www.nature.com/reviews/neuro

REVIEWS
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).
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 thestandard view of system consolidation.
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 andmemory. Psychol. Rev. 102, 419–457 (1995).
This landmark paper provides a thorough overview ofconnectionist models of learning and memory,
focusing especially on the role of hippocampal–
cortical interactions during the formation andconsolidation of memories. The complementary
concepts of the hippocampus as a fast learner andthe cortex as a slow learner are developed.
15. Corkin, S. What’s new with the amnesic patient H.M.?
Nature Rev. Neurosci. 3, 153–160 (2002).
16. Scoville, W. B. The limbic lobe in man. J. Neurosurg. 11,
64–66 (1954).
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).
18. Squire, L. R., Stark, C. E. & Clark, R. E. The Medial Temporal
Lobe. Annu. Rev. Neurosci. 27, 279–306 (2004).
19. Gaffan, D. Recognition impaired and association intact in thememory of monkeys after transection of the fornix. J. Comp.
Physiol. Psychol. 86, 1100–1109 (1974).
20. Hirsh, R. The hippocampus and contextual retrieval of
information from memory: a theory. Behav. Biol. 12,
421–444 (1974).
21. Nadel, L. & O’Keefe, J. in Essays on the Nervous System(eds Bellairs, R. & Gray, E. G.) 367–390 (Clarendon, Oxford,
1974).
22. Squire, L. R. Memory and the hippocampus: a synthesis
from findings with rats, monkeys, and humans. Psychol.
Rev. 99, 195–231 (1992).
23. O’Kane, G., Kensinger, E. A. & Corkin, S. Evidence forsemantic learning in profound amnesia: an investigation
with patient H.M. Hippocampus 14, 417–425 (2004).
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).
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 ofsystem consolidation and provides original
arguments to account for observations of flat
retrograde amnesia gradients.
27. Bayley, P. J., Hopkins, R. O. & Squire, L. R. Successful
recollection of remote autobiographical memories byamnesic patients with medial temporal lobe lesions. Neuron
38, 135–144 (2003).
28. Manns, J. R., Hopkins, R. O. & Squire, L. R. Semantic
memory and the human hippocampus. Neuron 38,
127–133 (2003).
29. Rosenbaum, R. S., McKinnon, M. C., Levine, B. &Moscovitch, M. Visual imagery deficits, impaired strategic
retrieval, or memory loss: disentangling the nature of anamnesic person’s autobiographical memory deficit.
Neuropsychologia 42, 1619–1635 (2004).
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).
31. Teng, E. & Squire, L. R. Memory for places learned long
ago is intact after hippocampal damage. Nature 400,
675–677 (1999).
32. Rosenbaum, R. S. et al. Remote spatial memory in anamnesic person with extensive bilateral hippocampal
lesions. Nature Neurosci. 3, 1044–1048 (2000).
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).
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).

NATURE REVIEWS | NEUROSCIENCE

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).
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).
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).
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).
39. Debiec, J., LeDoux, J. E. & Nader, K. Cellular and systems
reconsolidation in the hippocampus. Neuron 36, 527–538(2002).
40. Gaffan, D. Additive effects of forgetting and fornix
transfection in the temporal gradient of retrograde amnesia.
Neuropsychologia 31, 1055–1066 (1993).
41. Glenn, M. J., Nesbitt, C. & Mumby, D. G. Perirhinal cortex
lesions produce variable patterns of retrograde amnesia inrats. Behav. Brain Res. 141, 183–193 (2003).
42. Kim, J. J. & Fanselow, M. S. Modality-specific retrograde
amnesia of fear. Science 256, 675–677 (1992).
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).
44. Maviel, T., Durkin, T. P., Menzaghi, F. & Bontempi, B. Sites of
neocortical reorganization critical for remote spatial memory.
Science 305, 96–99 (2004).
45. Mumby, D. G. & Glenn, M. J. Anterograde and retrograde
memory for object discriminations and places in rats withperirhinal cortex lesions. Behav. Brain Res. 114, 119–134(2000).
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).
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).
48. Riedel, G. et al. Reversible neural inactivation reveals
hippocampal participation in several memory processes.
Nature Neurosci. 2, 898–905 (1999).
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.
50. Sutherland, R. J. et al. Retrograde amnesia after
hippocampal damage: recent vs. remote memories in twotasks. Hippocampus 11, 27–42 (2001).
51. Takehara, K., Kawahara, S., Takatsuki, K. & Kirino, Y. Timelimited role of the hippocampus in the memory for trace
eyeblink conditioning in mice. Brain Res. 951, 183–190 (2002).
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, thisstudy is the first to identify an important role for the
prefrontal cortex in processing remote memory.
53. Thornton, J. A., Rothblat, L. A. & Murray, E. A. Rhinal cortex
removal produces amnesia for preoperatively learned
discrimination problems but fails to disrupt postoperativeacquisition and retention in rhesus monkeys. J. Neurosci.
17, 8536–8549 (1997).
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).
55. Wiig, K. A., Cooper, L. N. & Bear, M. F. Temporally gradedretrograde amnesia following separate and combined
lesions of the perirhinal cortex and fornix in the rat. Learn.
Mem. 3, 313–325 (1996).
56. Winocur, G. Anterograde and retrograde amnesia in rats
with dorsal hippocampal or dorsomedial thalamic lesions.
Behav. Brain Res. 38, 145–154 (1990).
57. Winocur, G., McDonald, R. M. & Moscovitch, M.
Anterograde and retrograde amnesia in rats with large
hippocampal lesions. Hippocampus 11, 18–26 (2001).

58. Zola-Morgan, S. M. & Squire, L. R. The primate
hippocampal formation: evidence for a time-limited role inmemory storage. Science 250, 288–290 (1990).
Using circumscribed lesions of the hippocampal
formation, this is the first study to provide evidence forgraded retrograde amnesia in non-human primates.
59. Quillfeldt, J. A. et al. Different brain areas are involved inmemory expression at different times from training.
Neurobiol. Learn. Mem. 66, 97–101 (1996).
60. Izquierdo, I. et al. Sequential role of hippocampus andamygdala, entorhinal cortex and parietal cortex in formation
and retrieval of memory for inhibitory avoidance in rats.
Eur. J. Neurosci. 9, 786–793 (1997).
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 (watermaze) memories, which indicates that the expressionof 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).
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).
65. Remondes, M. & Schuman, E. M. Role for a cortical input tohippocampal 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 toform normally, but prevents them from becoming
consolidated in cortical networks.
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).
67. Gaskin, S., Tremblay, A. & Mumby, D. G. Retrograde andanterograde object recognition in rats with hippocampal
lesions. Hippocampus 13, 962–969 (2003).
68. Fanselow, M. S. Contextual fear, gestalt memories, and the
hippocampus. Behav. Brain Res. 110, 73–81 (2000).
69. Galef, B. G. Jr. Food selection: problems in understanding
how we choose foods to eat. Neurosci. Biobehav. Rev. 20,
67–73 (1996).
70. Eichenbaum, H. Hippocampus; cognitive processes andneural representations that underlie declarative memory.
Neuron 44, 109–120 (2004).
71. Anagnostaras, S. G., Gale, G. D. & Fanselow, M. S. The
hippocampus and Pavlovian fear conditioning: reply to Bastet al. Hippocampus 12, 561–565 (2002).
72. Winocur, G., Moscovitch, M., Fogel, S., Rosenbaum, R. S. &Sekeres, M. Preserved spatial memory following
hippocampal lesions: effects of extensive experience in acomplex 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).
74. Marr, D. A theory for cerebral neocortex. Proc. R. Soc.
Lond. B 176, 161–234 (1970).
75. Marr, D. Simple memory: a theory for archicortex. Philos.
Trans. R. Soc. Lond. B 262, 23–81 (1971).
76. Cipolotti, L. et al. Long-term retrograde amnesia... thecrucial role of the hippocampus. Neuropsychologia 39,
151–172 (2001).
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).
78. Gilboa, A., Winocur, G., Grady, C. L., Hevenor, S. J. &Moscovitch, M. Remembering our past: functional
neuroanatomy of recollection of recent and very remotepersonal events. Cereb. Cortex 14, 1214–1225 (2004).
79. Ryan, L. et al. Hippocampal complex and retrieval of recent
and very remote autobiographical memories: evidence fromfunctional magnetic resonance imaging in neurologicallyintact people. Hippocampus 11, 707–714 (2001).
80. Maguire, E. A. & Frith, C. D. Lateral asymmetry in the
hippocampal response to the remoteness of autobiographicalmemories. J. Neurosci. 23, 5302–5307 (2003).
81. Mednick, S. C. et al. The restorative effect of naps on
perceptual deterioration. Nature Neurosci. 5, 677–681(2002).

VOLUME 6 | FEBRUARY 2005 | 1 2 9

REVIEWS
82. Walker, M. P., Brakefield, T., Morgan, A., Hobson, J. A. &Stickgold, R. Practice with sleep makes perfect: sleepdependent motor skill learning. Neuron 35, 205–211 (2002).
83. Stickgold, R., James, L. & Hobson, J. A. Visual
discrimination learning requires sleep after training. Nature
Neurosci. 3, 1237–1238 (2000).
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).
85. Fenn, K. M., Nusbaum, H. C. & Margoliash, D.
Consolidation during sleep of perceptual learning of spoken
language. Nature 425, 614–616 (2003).
86. Wagner, U., Gais, S., Haider, H., Verleger, R. & Born, J.
Sleep inspires insight. Nature 427, 352–355 (2004).
87. Walker, M. P. & Stickgold, R. Sleep-dependent learning andmemory consolidation. Neuron 44, 121–133 (2004).
88. Vertes, R. P. Memory consolidation in sleep; dream or reality.
Neuron 44, 135–148 (2004).
89. Maquet, P. et al. Experience-dependent changes in cerebral
activation during human REM sleep. Nature Neurosci. 3,
831–836 (2000).
90. Huber, R., Ghilardi, M. F., Massimini, M. & Tononi, G. Local
sleep and learning. Nature 430, 78–81 (2004).
91. Peigneux, P. et al. Are spatial memories strengthened in thehuman hippocampus during slow wave sleep? Neuron 44,
535–545 (2004).
92. Hoffman, K. L. & McNaughton, B. L. Coordinatedreactivation of distributed memory traces in primate
neocortex. Science 297, 2070–2073 (2002).
This study provides the first evidence thatcoordinated replay occurs in multiple cortical regions
and supports the idea that offline reactivation of
distributed cortical traces is crucial for corticalconsolidation.
93. Ribeiro, S. et al. Long-lasting novelty-induced neuronalreverberation during slow-wave sleep in multiple forebrain
areas. PLoS Biol 2, E24 (2004).
94. Siapas, A. G. & Wilson, M. A. Coordinated interactions
between hippocampal ripples and cortical spindles duringslow-wave sleep. Neuron 21, 1123–1128 (1998).
95. Lee, A. K. & Wilson, M. A. Memory of sequential experiencein the hippocampus during slow wave sleep. Neuron 36,
1183–1194 (2002).
96. Louie, K. & Wilson, M. A. Temporally structured replay of
awake hippocampal ensemble activity during rapid eye
movement sleep. Neuron 29, 145–156 (2001).
97. Wilson, M. A. & McNaughton, B. L. Reactivation ofhippocampal ensemble memories during sleep. Science
265, 676–679 (1994).
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).
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).
100. Dave, A. S. & Margoliash, D. Song replay during sleep andcomputational rules for sensorimotor vocal learning. Science
290, 812–816 (2000).
101. Wilson, M. A. Hippocampal memory formation, plasticity,and the role of sleep. Neurobiol. Learn. Mem. 78, 565–569(2002).
102. Sutherland, G. R. & McNaughton, B. Memory tracereactivation in hippocampal and neocortical neuronalensembles. Curr. Opin. Neurobiol. 10, 180–186 (2000).
103. Qin, Y. L., McNaughton, B. L., Skaggs, W. E. & Barnes,
C. A. Memory reprocessing in corticocortical andhippocampocortical neuronal ensembles. Philos. Trans.
R. Soc. Lond. B 352, 1525–1533 (1997).
104. Cirelli, C., Gutierrez, C. M. & Tononi, G. Extensive anddivergent effects of sleep and wakefulness on brain gene
expression. Neuron 41, 35–43 (2004).
105. Jones, M. W. et al. A requirement for the immediate earlygene Zif268 in the expression of late LTP and long-term
memories. Nature Neurosci. 4, 289–296 (2001).
106. Lee, J. L., Everitt, B. J. & Thomas, K. L. Independent cellular
processes for hippocampal memory consolidation andreconsolidation. Science 304, 839–843 (2004).
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).
108. Ribeiro, S. et al. Induction of hippocampal long-term
potentiation during waking leads to increased
extrahippocampal zif-268 expression during ensuing rapideye-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.

1 3 0 | FEBRUARY 2005 | VOLUME 6109. Wittenberg, G. M. & Tsien, J. Z. An emerging molecular andcellular framework for memory processing by the
hippocampus. Trends Neurosci. 25, 501–505 (2002).
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).
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).
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).
113. Frankland, P. W., O’Brien, C., Ohno, M., Kirkwood, A. &Silva, A. J. α-CaMKII-dependent plasticity in the cortex isrequired for permanent memory. Nature 411, 309–313(2001).
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 toestablish a crucial role for the anterior cingulate
cortex in processing remote contextual fear
memories.
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).
116. Hayashi, M. L. et al. Altered cortical synaptic morphology
and impaired memory consolidation in forebrain-specificdominant-negative PAK transgenic mice. Neuron 42,
773–787 (2004).
Together with reference 113, this study shows thatmice with abnormal cortical plasticity are unable toform enduring, hippocampus-independent
memories.
117. Hall, J., Thomas, K. L. & Everitt, B. J. Cellular imaging ofzif268 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).
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, theresults of this paper show that the hippocampus has atransitory role in memory storage. In addition, thisstudy was the first to identify possible sites ofpermanent storage in the cortex.
119. Chklovskii, D. B., Mel, B. W. & Svoboda, K. Cortical rewiringand information storage. Nature 431, 782–788 (2004).
This excellent review contrasts mechanisms
underlying weight and wiring plasticity, and proposesthat the latter may play a crucial role in corticalmemory consolidation.
120. Benowitz, L. I. & Routtenberg, A. GAP-43: an intrinsic
determinant of neuronal development and plasticity. Trends
Neurosci. 20, 84–91 (1997).
121. Miller, R. Neural assemblies and laminar interactions in the
cerebral cortex. Biol. Cybern. 75, 253–261 (1996).
122. Hebb, D. O. The Organization of Behavior (Wiley, New York,
1949).
123. Haist, F., Bowden Gore, J. & Mao, H. Consolidation ofhuman memory over decades revealed by functional
magnetic resonance imaging. Nature Neurosci. 4,1139–1145 (2001).
124. Ridderinkhof, K. R., Ullsperger, M., Crone, E. A. &Nieuwenhuis, S. The role of the medial frontal cortex incognitive control. Science 306, 443–447 (2004).
125. Lashley, K. S. In search of the engram. Symp. Soc. Exp.
Biol. 4, 454–482 (1950).
126. Uylings, H. B., Groenewegen, H. J. & Kolb, B. Do rats havea prefrontal cortex? Behav. Brain Res. 146, 3–17 (2003).
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).
128. Miyashita, Y. Cognitive memory: cellular and network
machineries and their top-down control. Science 306,
435–440 (2004).
129. Ungerleider, L. G. Functional brain imaging studies ofcortical mechanisms for memory. Science 270, 769–775(1995).
130. Miller, E. K. & Cohen, J. D. An integrative theory of
prefrontal cortex function. Annu. Rev. Neurosci. 24,
167–202 (2001).

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).
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).
133. O’Reilly, R. C. & Rudy, J. W. Computational principles oflearning in the neocortex and hippocampus. Hippocampus
10, 389–397 (2000).
134. Lisman, J. & Morris, R. G. Memory: why is the cortex a slow
learner? Nature 411, 248–249 (2001).
135. Trachtenberg, J. T. et al. Long-term in vivo imaging ofexperience-dependent synaptic plasticity in adult cortex.
Nature 420, 788–794 (2002).
136. Willshaw, D. J. & Buckingham, J. T. An assessment ofMarr’s theory of the hippocampus as a temporary memory
store. Philos. Trans. R. Soc. Lond. B 329, 205–215 (1990).
137. Genoux, D. et al. Protein phosphatase 1 is a molecularconstraint on learning and memory. Nature 418, 970–975(2002).
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).
139. Feng, R. et al. Deficient neurogenesis in forebrain-specificpresenilin-1 knockout mice is associated with reduced
clearance of hippocampal memory traces. Neuron 32,
911–926 (2001).
140. Fortin, N. J., Wright, S. P. & Eichenbaum, H. Recollectionlike memory retrieval in rats is dependent on the
hippocampus. Nature 431, 188–191 (2004).
141. Day, M., Langston, R. & Morris, R. G. Glutamate-receptormediated encoding and retrieval of paired-associatelearning. Nature 424, 205–209 (2003).
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 andPKA. Learn. Mem. 5, 365–374 (1998).
143. Kida, S. et al. CREB required for the stability of new andreactivated fear memories. Nature Neurosci. 5, 348–355(2002).
144. Shadmehr, R. & Holcomb, H. H. Neural correlates of motor
memory consolidation. Science 277, 821–825 (1997).
145. McBride, S. M. et al. Mushroom body ablation impairs
short-term memory and long-term memory of courtshipconditioning in Drosophila melanogaster. Neuron 24,
967–977 (1999).
146. Menzel, R. Searching for the memory trace in a mini-brain,
the honeybee. Learn. Mem. 8, 53–62 (2001).
147. Gale, G. D. et al. Role of the basolateral amygdala in thestorage of fear memories across the adult lifetime of rats.
J. Neurosci. 24, 3810–3815 (2004).
148. Sokoloff, L. et al. The [14C]deoxyglucose method for themeasurement of local cerebral glucose utilization: theory,
procedure, and normal values in the conscious andanesthetized albino rat. J. Neurochem. 28, 897–916 (1977).
149. Laroche, S., Davis, S. & Jay, T. M. Plasticity at hippocampal
to prefrontal cortex synapses: dual roles in working memoryand consolidation. Hippocampus 10, 438–446 (2000).
150. Dutar, P., Bassant, M. H., Senut, M. C. & Lamour, Y. The
septohippocampal pathway: structure and function of acentral cholinergic system. Physiol. Rev. 75, 393–427 (1995).

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.).

Competing interests statement
The authors declare no competing financial interests.

Online links
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene
α-CaMKII | c-fos | Zif268
FURTHER INFORMATION
Encyclopedia of Life Sciences: http://www.els.net/
Learning and memory
Frankland’s homepage:
http://individual.utoronto.ca/franklandlab/
Bontempi’s homepage: http://www.neurocog.ubordeaux1.fr/bontempi.htm
Access to this interactive links box is free online.

www.nature.com/reviews/neuro