Debates in Neuroscience
DOI 10.1007/s11559-007-9004-8

Grading the gradient: Evidence for time-dependent
memory reorganization in experimental animals
Paul W. Frankland & Cátia M. Teixeira & Szu-Han Wang

Received: 18 November 2006 / Accepted: 18 January 2007
# Springer Science + Business Media, LLC 2007

Abstract In humans, damage limited to the hippocampus
produces temporally graded retrograde amnesia, withrelative sparing of remote compared to recent memory.
This observation forms the cornerstone of the idea that as
memories mature they are reorganized in a time-dependent
manner. In this paper, we evaluate evidence for similar timedependent reorganization in experimental animals. In the
majority of behavioral paradigms examined, these studies
provide evidence that memories are gradually reorganizedover time, with the hippocampus and cortex playing
preferential (although not necessarily mutually exclusive)roles in the expression of recent and remote memory,
respectively. This pattern is not observed in all tasks,
however. For example, in the water maze hippocampal
activity is always necessary for memory expression. Identifying situations when the hippocampus is, and is not,required for remote memory expression will help us tounderstand hippocampal contributions to memory, and, more

P. W. Frankland (*) : C. M. Teixeira : S.-H. Wang
Program in Neurosciences and Mental Health,The Hospital for Sick Children, Toronto, Canada, M5G 1X8
e-mail: paul.frankland@sickkids.ca
P. W. Frankland : S.-H. Wang
Department of Physiology, University of Toronto,
Toronto, Canada
P. W. Frankland : S.-H. Wang
Institute of Medical Science, University of Toronto,
Toronto, Canada
C. M. Teixeira
Graduate Program in Areas of Basic and Applied Biology(GABBA), Universidade do Porto, Porto, Portugal

generally, whether changes in memory organization lead toqualitative changes in the nature of memory.
Keywords memory consolidation . cortex . hippocampus .
remote memory . retrograde amnesia
In the late part of the 19th century, the French psychologist,
Theodule Ribot, described how memory loss after brain insult
was often related to the age of the memory: the effect on more
recent memories was typically greater than that on older (ormore remote) memories [1]. The dissociation has become
known as Ribot’s law (or Ribot’s gradient), and subsequentneuropsychological studies went on to establish a more
precise relationship between the locus of brain damage andthe gradient. Penfield, Scoville, and Milner [2, 3] characterized memory loss in patients with damage to the medial
temporal lobe (MTL, including the hippocampus, and theentorhinal, perirhinal, and parahippocampal cortices) andprovided the first evidence that MTL damage preferentiallyaffects recent, but not remote, memories. Later studies ofpatients with more circumscribed lesions established thatdamage to the hippocampus, in particular, is responsible forthis typical graded amnesia [4–7].
This observation forms the basis of the idea thatmemories are reorganized in a time-dependent manner.
Within this general framework, the relative contributions ofdifferent brain regions may vary as a function of memory
age. Accordingly, some regions may play important roles inthe expression of newly formed (or recent) memory, but
their contributions may fade over time. Conversely, otherregions may play preferential roles in the expression ofolder (or remote) memories. Here we shall criticallyevaluate the evidence for memory reorganization inexperimental animal studies. First, we shall consider theDebates in Neuroscienceevidence that the hippocampus (including CA fields,
dentate gyrus, and subiculum) plays a time-limited role in
the expression of memory. Second, we shall consider newer
evidence for a preferential role of the prefrontal cortex in
the expression of remote memory.

12, 15–34]). The differential effects of hippocampal damage
on recent vs. remote memory essentially recapitulate effects
seen in patients, and are consistent with a more global andgradual process of memory reorganization.
Evidence for hippocampal gradientsfrom convergent approaches

Hippocampal gradients
Hippocampal lesions and graded retrograde amnesia
Two studies in the early 1990s were the first to model
temporally graded retrograde amnesia in rodents. In thefirst, Winocur and colleagues [8] made electrolytic lesionsof the dorsal hippocampus at different times after training inthe socially transmitted food preference task [9]. Whereas
lesions made 1–2 days after training abolished memory forthe learned preference, similar lesions made 10 days
posttraining were ineffective [8]. In the second study, Kim
and Fanselow [10] examined the impact of electrolytic
lesions of the dorsal hippocampus on contextual fear
memory. Similar to the Winocur study, they found that
there was substantial retrograde amnesia when the lesions
were carried out 1 or 7 days after training, but hippocampal
lesions were ineffective at longer training-surgery delays.
The graded nature of these effects supported the idea thatthe hippocampus is playing a nonessential role in theexpression of some forms of remote memory, and theseresults nicely paralleled observations in human amnesics(albeit on a much shorter timescale).
These initial observations have subsequently been
extended in a number of important ways. First, gradedamnesia after hippocampal damage has been shown in a
number of different tasks, including trace eyeblink conditioning, visual discrimination, inhibitory avoidance, as wellas in a subset of spatial tasks. Second, graded amnesia has
been observed in a range of species, ranging from mice tomonkeys. Third, graded amnesia has been observed after
both partial and complete hippocampal lesions (using avariety of lesion techniques). For example, both partial(dorsal hippocampus [8]) and more extensive [11–13]
hippocampal lesions produce graded effects on memory inthe socially transmitted food preference task. Fourth,
graded amnesia has been observed using both within- andbetween-subject designs. Although one advantage of within
subject design is that it more closely mimics the clinicalcases, equating the learning experience at two or more time
points before surgery is sometimes challenging [14]. Thisdrawback is addressed in studies using between-subject
designs (such as in the Winocur [8] and Kim and Fanselow[10] examples above). To date, there are 25 or so publishedstudies showing that damage to the hippocampus preferentially affects recent but not remote memory (Table 1; [8, 10–

One of the strengths of the above data set is that graded
effects were observed in such a diversity of tasks, including
tasks that differ greatly in terms of their stimulus properties,
performance demands, and motivation. However, a potential
weakness of this data set is the reliance on a single techniqueto establish the gradient. Lesions, like any technique, have anumber of advantages and inherent limitations. In particular,
the fact that memories can survive hippocampal damage atremote time points does not necessarily imply that the
hippocampus would not have been engaged in an intact
animal. In this regard, therefore, demonstrations of graded
effects using alternate approaches are especially valuable,
and have strengthened the idea that circuits supporting
memory are reorganized in a time-dependent manner. Twomain classes of approaches have been applied.
First, mouse-genetic approaches. Tsien and colleagues
generated mice in which the NR1 subunit of the Nmethyl-D-aspartate (NMDA) receptor in CA1 region of the
hippocampus could be deleted in an inducible manner [28].
Mice with normal NMDA function were trained in two
hippocampus-dependent learning tasks: the Morris water
maze and contextual fear conditioning. Only suppressing
NMDA receptor function in the week immediately after
training, rather than at later time points, blocked theestablishment of remote memories. Like the lesion studies,
these experiments emphasize the importance of maintaining
the integrity of the hippocampal trace in the days after
training and indicate that recent memories are preferentiallysensitive to a disruption of hippocampal function. Perhaps
what is most striking is that two dramatically different typesof hippocampal manipulations—nonreversible anatomicallesions and reversible molecular lesions—both produce
very similar graded effects on memory.
Second, brain mapping approaches. The (14C)2-deoxyglucose approach can be used to monitor changes inmetabolic activity across brain regions [35]. Taking
advantage of this technique, Bontempi and colleagues[36] were the first to comprehensively map time-dependentchanges in memory organization in mice, and in particularshow that recall of recent, but not remote, spatial
discrimination memory was associated with activation of
the dorsal hippocampus. Subsequent studies have used theexpression of immediate early genes (such as c-fos andzif268) as markers of neuronal activity to examine the roleof the hippocampus in recent and remote memory [13, 24,

Debates in Neuroscience
Table 1 Hippocampal (and/or extrahippocampal) graded amnesia
Behavioral
paradigm

SpeciesBraintargetExtent ofdamageMethodOutcome

References

Sociallyacquiredfood
preference

Rat

Dorsalhippocampus
Dorsal andventralhippocampus
Hippocampus
and subiculum
Hippocampus

PartialElectrolytic

Winocur, [8]Extensive

Neurotoxic

Extensive

Electrolytic

Extensive

Electrolytic

Extensive

Aspiration

Deficit at 2 days,
no deficit at 10 days
Deficit at 1 and 2 days,
no deficit at 5
and 10 days
Deficit at 1 day,no deficit at 30 days
Deficit at 1 day,no deficit at 21 days
Deficit up to 4 weeks

PartialNeurotoxic

Objectdiscrimination

MonkeyContextual fear
conditioning

Rat

Hippocampal
formation(hippocampus,
subiculum,
entorhinal andparahippocampal
cortices)
Dorsalhippocampus

Mouse

CA1 field of
hippocampus

PartialMutation: inducible
CA1- specificknockout of
NMDA receptors

Contextual
and cued fear
conditioning

Mouse

Hippocampus andother forebrain
regions

Extensive

Mutation:
inducible
forebrain-specificdisruption of
αCaMKII function

Spatialtwo-choicediscrimination

Mouse

Entorhinal
cortexDorsalhippocampus

Extensive

Neurotoxic

Deficit at 1 and 28 days,
no deficit at 100 days
Deficit at 1, 7, and 14 days,
no deficit at 28 days
Deficit at 1 day,no deficit at 50 days
Deficit up to 14 days
No deficit at 45 days
Memory probed at 30 days,
deficit when mutation activefrom day 1 to 14
posttraining, no deficit
when active fromday 22 to 29
Memory probed at 30 days,
deficit when mutation
active from day 1 to 7
posttraining, no deficit
when active fromday 8 to 28
Deficit up to 4 weeks

PartialElectric stimulation

Deficit up to 4.5 weeks

Spatialmultiplechoicediscrimination

Mouse

Dorsalhippocampus
Entorhinal
cortexDorsalhippocampus
Perirhinal
cortexTemporoammonic
path (projection)
CA1 field of
hippocampus

PartialInactivation

Extensive

Electrolytic

Deficit at 1 day,no deficit at 30 days
Deficit up to 4 weeks

PartialElectrolytic

Deficit up to 32 days

Extensive

Aspiration

Complete

Electrolytic

Deficit at 2 days,
no deficit at 28 days
Deficit up to 21 days

PartialMutation:
inducible CA1specific knockoutof NMDA

Memory probed at 30 days,
deficit when mutation
active from day 1 to 14
posttraining, no deficit

Electrolytic

Watermaze spatial
learning

Rat

Rat

Mouse

Winocur
et al., [12]Clark et al., [11]Ross and
Eichenbaum, [13]Zola-Morgan
and Squire, [34]Maren et al., [23]Kim andFanselow, [10]Anagnostaras
et al., [15]Ward et al., [32]Debiec et al., [18]Shimizu
et al., [28]Wang et al., [31]Cho et al., [16]LaurentDemir andJaffard, [22]Maviel et al., [24]Cho andKesner, [17]Ramos, [26]Glenn et al., [19]Remondes andSchuman, [27]Shimizu
et al., [28]

Debates in Neuroscience
Table 1 (continued)
Behavioral
paradigm

SpeciesBraintargetExtent ofdamageMethodreceptors

Traceeyeblink
conditioning

RabbitMouse
Rat

Inhibitory
avoidance

Visualdiscrimination

Rat

Rat

Medialentorhinal
cortex,pre- andparasubiculum
Hippocampus
Dorsalhippocampus
Dorsalhippocampus
Dorsalhippocampus

Fornix or
perirhinal
cortex or
both

PartialExtensive

Mutation:
inducible
disruptionof αCaMKII
function
Aspiration

PartialAspiration

PartialAspiration

PartialInactivation

Extensive

Inactivation
or NMDAantagonist
Electrolytic

37]. Similar to the initial study by Bontempi and colleagues,
these studies showed that the hippocampus was preferentially
activated after expression of recent, but not remote, five-arm
maze [24], contextual fear [37] and socially transmitted foodpreference [13] memories. Therefore, together with themouse-genetic and lesion-based approaches, these brain
mapping studies support the idea that the circuits supportingthese memories evolve over time, with the hippocampus
playing a time-limited role in memory expression. The brain
mapping studies go perhaps one step further to show that not
only might the hippocampus be not necessary, but it might
not even be engaged, during the expression of remotememory (at least in the tasks studied here). In humanimaging studies, the situation is less clear-cut. For semantic
memories, there is evidence for reduced hippocampal
contribution as a function of time. However, for episodic
memories, retrieval may engage the hippocampus at bothrecent and remote time points (especially when the material
being recalled is detailed in nature; for detailed discussion ofthese issues see [38, 39]).

Examples of ungraded amnesia
Extrahippocampal damage
One set of situations where graded amnesia is typically notobserved is when significant damage occurs beyond the

Outcome

References

when active fromday 22 to 29
Deficit when mutation
active 0–21 days,
no deficit whenmutation active
22–42 days
Deficit at 1 day,no defict at 30 days
Deficit at 1 day,no deficit at 28 days
Deficit up to 14 days,
no deficit at 28 days
Deficit at 1 day,no deficit beyond
Deficit at 1 day,no deficit beyond

Kim
et al [21]Takehara
et al., [30]Takehara
et al., [29]Quillfeldt
et al., [25]Izquierdo
et al., [20]Deficit up to 3 weeks

Wiig et al., [33]Yasuda andMayford, [75]hippocampus (see Table 2; [40–54]). For example, perirhinal or combined perirhinal/postrhinal lesions have
ungraded effects on water maze, object discrimination[45], and contextual fear [54] memories, respectively. Theseobservations parallel similar observations in human patientswhere the length of the gradient is related to the extent ofdamage. When damage is limited to the CA1 region of the
hippocampus in humans retrograde amnesia may span only
1–2 years. However, when damage is more extensive (alsoincluding the perirhinal, entorhinal, and parahippocampal
cortices) amnesia may cover decades. Damage beyond the
MTL is typically associated with ungraded retrograde
amnesia, perhaps because sites of permanent storage areaffected [55–58]. These studies suggest that cortices
adjacent to the hippocampus play more extended roles in
the consolidation process.
Water maze studies
There are other important exceptions that cannot be
accounted for in terms of extrahippocampal damage. By
far the most common (and widely recognized) instance
where hippocampal lesions produce ungraded retrograde
amnesia is in studies using the water maze (Table 2). In thewater maze, rodents are trained to navigate to a submerged
escape platform using an array of extra maze cues. Studies
have consistently shown that hippocampal lesions disrupt
the expression of spatial memories regardless of the intervalDebates in Neuroscience
Table 2 Hippocampal (and/or extrahippocampal) ungraded amnesia
Behavioral paradigm

SpeciesBrain target

Water maze
spatial learning

Rat

Dorsal hippocampus
Partialor subiculum
Dorsal and ventral
Extensive
hippocampus and partof subiculum
Dorsal hippocampus
PartialSpatial task incross maze
Spatial task incomplex maze
Objectrecognition
Objectdiscrimination

Visual (scene)
discrimination
Contextual
fear conditioning

Extent of damage Method
Neurotoxic
Neurotoxic

Subchronic
neuronal
Inactivation

Perirhinal cortex

Extensive

Dorsal and ventral
hippocampus
Dorsal or dorsal andventral hippocampus
Dorsal or dorsal andventral hippocampus
Hippocampus

Extensive
Partial or
extensive
Partial or
extensive
Extensive

Dorsal hippocampus

Partial

Mouse

Dorsal hippocampus

PartialRat

Hippocampus

Extensive

Rat

Hippocampus

Extensive

Rat

Extensive

Dorsal and ventral
hippocampus
Monkey Rhinal (entorhinal +perirhinal) cortex
Rat
Dorsal and ventral
hippocampus
Monkey Fornix

Extensive

Rat

Extensive

Perirhinal andpostrhinal cortices

Extensive
Extensive

between training and surgery. This is the case even after
extensive pretraining in the water maze [42], partial lesionsof hippocampus [43, 44], when extended delays between
training and surgery are used [43], when water mazes with
reduced spatial complexity are used [43] or when reminders
to aid retrieval are used [44]. Similarly, reversibly inactivating the dorsal hippocampus disrupts the expression of bothrecent and remote water maze memory in rats [41] and mice[49]. Consistent with these lesion and inactivation studies,brain mapping approaches indicate that the hippocampus
may be activated during the expression of both recent andremote water maze memory [49] (but see [59]). It isparticularly important to note here that the absence of ahippocampal gradient does not simply imply that circuits
supporting water maze memories are not reorganized over

Outcome

References

Flat RA up
to 14 weeks
Flat RA up to
14 weeks

Bolhuiset al., [40]Mumby
et al., [45]Flat RA up to
16 days but
memory not probed
at longer delay
Electrolytic
Flat RA up to
2 weeks
Neurotoxic
Flat RA up to
14 weeks
Neurotoxic
Flat RA up to
6 weeks
Thermocoagulation Flat RA up to
9 or 14 weeks
Thermocoagulation Flat RA up to
114 days
Inactivation
Flat RA up
to 30 days
Inactivation
Flat RA up
to 30 days
Neurotoxic
Flat RA up
to 9 months
Neurotoxic
Flat RA up
to 14 weeks
Neurotoxic
Flat RA up
to 5 weeks
Aspiration
Flat RA up
to 16 weeks
Neurotoxic
Flat RA up
to 14 weeks
Transection
Flat RA up
to 6 months
Neurotoxic
Flat RA up
to 100 days

Riedelet al., [47]Mumby andGlenn, [46]Sutherland
et al., [48]Martinet al., [44]Clark
et al., [43]Clark
et al., [42]Broadbent
et al, [41]Teixeira
et al, [49]Winocur
et al., [50]Winocur
et al., [65]Gaskinet al., [52]Thornton, [53]Sutherland
et al., [48]Gaffan, [51]Burwell
et al, [54]time. Indeed, inactivation of the anterior cingulate cortex(ACC) disrupts the expression of remote, but spares recent,water maze memory [49]. These results indicate that theanterior cingulate cortex is recruited into circuits supportingwater maze memories over time and are consistent with theidea that water maze memories undergo reorganization.
To understand why the water maze studies are a consistentexception, two accounts have been proposed. First, thehippocampus may be important for the expression of spatial
memories that require animals to navigate through space, as
in the water maze. In such tasks, hippocampal activity may
be required to continuously integrate both idiothetic (selfmotion cues) and allothetic (e.g., distal visual cues)
information to successfully navigate to the escape platform(for discussion, see [43, 44]). This performance account isDebates in Neuroscience

consistent with the standard view of consolidation [60, 61],that is, memories are initially encoded in hippocampalcortical networks, but gradual strengthening of connections
between cortical regions allows memories to eventually
become independent of the hippocampus at remote time
points. Accordingly, removal of the hippocampus does notabolish the spatial memory, but interferes with the expressionof this memory, in part, by affecting the animal’s ability tointegrate idiothetic and allothetic information.
The second account has its roots in multiple trace theory[62, 63]. In this model, it is argued that hippocampaldependent and hippocampal-independent memories arefundamentally different. The expression of detailed, context-dependent memories always depends on the hippocampus, regardless of their age. In contrast, memories may
persist in the absence of the hippocampus, but thesehippocampal-independent memories are necessarily lessdetailed, context-free, and more gist-like [62, 64, 65].
Accordingly, the water maze is a special case because a
precise, detailed spatial representation of the environment isessential for normal performance. Lack of access to such a
precise spatial representation in hippocampal-damaged
animals therefore results in impaired performance.
Designing experiments that distinguish between thesetwo possibilities has proven to be quite tricky. One strategy
has been to develop spatial tasks that place reduced
navigational demands on animals. However, even tasks
with minimal navigational demands (such as the oasis mazeand annular maze) are associated with flat gradients [43].
Only when navigation is eliminated—for example, in tasks
where animals must use spatial information to discriminate
between arms in a maze [16, 17, 24, 26]—is performancespared at remote time points after hippocampal disruption.
This dissociation suggests that the hippocampal activity
contributes to navigational performance.
A second strategy has been to provide extensive
preoperative experience [65]. This is motivated by thefinding that remote spatial memory is spared after large
medial temporal lobe damage in a number of patients (T.T.
[66], E.P. [67], and K.C. [64]). To mimic this situation, in
one study rats were reared in a “rodent village” for 3 months[65]. At the completion of the 3 months, rats were trainedon a specific spatial problem within the village environment
before receiving lesions of the hippocampus. Remarkably,
hippocampal-damaged rats performed as well as controls
when tested postoperatively in the trained task. However,some perturbations of the spatial environment (e.g., village
rotation, room change), but not others (e.g., substitution of
distal cues) produced deficits in hippocampal-damaged rats[65]. These findings parallel those in some of the patients
described above. For example, T.T. was previously a
London taxi driver. After bilateral hippocampal damage
he showed relatively intact performance navigating mainroutes through London, but navigation was impaired in
non-main routes. This suggests the interesting possibility
that hippocampal-dependent and hippocampal-independent
representations of the spatial environment may differ inimportant ways, and is consistent with multiple trace
theory, which predicts that hippocampus-dependent memories are richer in detail compared to hippocampusindependent memories. In the rodent village study [65],whether the spared spatial memory is less precise, or just
weaker, is less clear. Furthermore, the lesions wereincomplete and so it is not clear whether this less robust
representation of the village is supported by extrahippocampal structures, or by residual ventral hippocampal
tissue. To resolve this issue it will be important to examine
whether complete hippocampal lesions produce equivalenteffects in the village task and extend these sorts of analyses
to nonspatial tasks.

Cortical gradients
The hippocampus is only one of several potential windows
on what is likely a more global process of memory reorganization. By focusing on cortical contributions to thedevelopment and expression of remote memory, recent
mouse-genetic and brain-mapping approaches have further
strengthened the idea that circuits supporting different types ofmemory are reorganized over time (Table 3; [24, 29, 37, 49]).
First, mouse-genetic studies. During consolidation, thestrengthening of cortico-cortical connections is thought to be
crucial for cortical memories to gain independence from the
hippocampus [68]. Therefore, disrupting cortical plasticity
should hinder the establishment of remote hippocampalindependent memories, and result in premature forgetting at
extended retention delays. This prediction was tested using
mice that are heterozygous for a null mutation of αcalcium/calmodulin kinase II [69]. These mice have global
deficits in cortical plasticity, but normal hippocampal
plasticity [70–73]. Accordingly, they have normal memory
at short retention delays (1–3 days), but pronounced
forgetting at longer delays (10–50 days). Similar findings
in mice that overexpress a dominant-negative mutant form of
p21-activated kinase [74] also suggest that normal corticalplasticity is essential for the development of remote(hippocampal-independent) memories.
One of the limitations of the first generation of knockout
and transgenic approaches is that gene function is alteredthroughout development. More recent studies have used
mice where the expression of a dominant active form of αCaMKII can be regulated in a temporally specific manner[31, 75]. For example, Tsien and colleagues [31] trained
these mice in contextual fear conditioning and tested them amonth later. They found that forebrain overexpression of theDebates in Neuroscience
Table 3 Cortical graded amnesia
Behavioral paradigm

SpeciesBrain target

MethodOutcome

References

Water maze spatial
learning

Mouse

Anterior cingulate
cortexInactivation

Teixeira
et al, [49]

Mouse

Forebrain

Spatial multiple choicediscrimination

Mouse

Prefrontal, anterior
cingulate cortex

Mutation: Disruption of
p21-activated kinase
activity
Inactivation

Contextual fear
conditioning

Mouse

Anterior cingulate
cortexDeficit at 30 days,
no deficit
at 1 day
Deficit at 21 days,
no deficit
at 1 day
Deficit at 30 days,
no deficit
at 1 day
Deficit at 18 and 36 days,
no deficit at 1 and 3 days
Deficit at 36 days,
no deficit at 1 day
Deficit at 28 days,not 1 dayInactivation
αCaMKII+/− mutation

Trace eyeblinkconditioning

Rat

Medial prefrontal cortex

mutant α-CaMKII in the week immediately after training,
but not thereafter, blocked the formation of remote memory.
Similarly, pharmacological inhibition of NMDA receptor
function in the prefrontal cortex in the week immediately
after training, but not thereafter, blocks the formation of
remote trace eyeblink conditioning memory [76]. Thesestudies not only identify a window during which hippocampal–cortical interactions are critical for the successful
development of remote memories, but also begin to provide
hints into molecular mechanisms underlying reorganization.
They suggest that reactivation of networks of neurons
supporting a memory induces a round of NMDA/αCaMKII-dependent synaptic modifications. These modifications may incrementally alter the network, and many
iterations of this process may eventually lead to wholesalechanges in circuits supporting memory [68, 77, 78].
Second, brain mapping studies. Bontempi and colleagues[36] were the first to systematically compare activation
patterns after expression of recent and remote memory
throughout the brain. In the spatial discrimination task, theyfound that activation patterns depended on the age of thememory: Whereas the recall of recent spatial memories was
associated with activation of the hippocampus and entorhinal cortex, the recall of remote spatial memories was
predominantly associated with activation of cortical regions
including the prefrontal, frontal, anterior cingulate, retrosplenial, and temporal cortices. This study provided the firstbrain-wide perspective on memory reorganization, andsuggested that remote memories may be supported by
distributed cortical circuits.
This time-dependent shift toward greater levels ofcortical activation has now been observed in a number ofother tasks using immediate early gene expression as an

Aspiration

Hayashi
et al, [74]
Mavielet al, [24]Frankland
et al, [37]Frankland
et al, [37]Takehara
et al., [29]index of neuronal activation [13, 24, 37, 49]. For example,
expression of a remote socially transmitted food preference
is associated with activation of the orbitofrontal cortex[13], expression of a remote five-arm maze memory is
associated with activation of the anterior cingulate, prelimbic, and infralimbic cortices [24], and expression of aremote water maze memory is associated with activation of
the anterior cingulate cortex [49]. Similarly, expression of
remote contextual fear memory was associated withactivation of a number of prefrontal cortical regions,
including the prelimbic, infralimbic, and anterior cingulate
cortices [37]. Most importantly, this activation was absent
in α-CaMKII+/- mice with deficits at this remote time point.
This suggests that activity in these regions is playing a keyrole in the expression of remote memory [37].
The above experiments examined gene expression
induced by memory expression (i.e., online memory
reactivation). In a related series of studies, Ribeiro andcolleagues [79, 80] have examined the induction of zif268
during offline states (i.e., various stages of sleep) after
behavioral exploration and long-term potentiation (LTP)
induction. For example, after rats had explored a novel
environment, upregulation of Zif268 was observed in the
hippocampus and various cortical regions such as thepiriform and frontal cortices during subsequent sleep [79].
Similarly, LTP induction in the dentate gyrus in awake,
behaving rats led to upregulation of Zif268 in various
cortical regions such as the entorhinal, auditory, somatosensory and frontal cortices during subsequent sleep [80].
Importantly, tetracaine-induced inactivation of the hippocampus before the onset of rapid eye movement (REM)
sleep blocked the upregulation of Zif268 in these corticalregions. This indicates that gene expression in the cortex

Debates in Neurosciencemight be under the control of the hippocampus and,
therefore, cortical remodeling depends on hippocampal
activity at least in the first several hours after training[80].
Although these brain-mapping studies provide evidence
that different cortical regions play increasingly importantroles in the expression of memory as a function of time, onedifficulty in these studies is the choice of an appropriate
control group. For some types of tasks (e.g., fear conditioning), there is relative consensus as to what an
appropriate control is (e.g., no-shock group, immediateshock group). However, in tasks such as the water maze thesituation is much less clear, and controls that are overly
conservative will lead to a high false-negative rate (e.g.,swimming or visible platform controls). In contrast, lessconservative controls (e.g., home cage) are likely to
produce a high false-positive rate. A second issue is that
immediate early genes such as c-fos and zif268 are only
indirect markers of activation. Whereas the expression ofthese genes is tightly correlated with levels of neuronal
activity [81], differences in endogenous expression patterns
across brain regions may limit their utility in brain-wide
mapping studies. A third issue is that reorganization may
not necessarily result in an overall increase in activity in agiven region. For example, there is no overall increase ingene expression in the parietal cortex after recall of remote,compared to recent, spatial discrimination memory. However, closer examination showed that activation shiftedfrom the deep cortical layers to more superficial layers overtime [24]. These observations highlight the complexities ofdefining reorganization and raise the issue of what level ofanatomical resolution is appropriate (or even feasible) for
this type of analysis [82]. Keeping these caveats in mind,
there is nonetheless convergent evidence from lesion andinactivation studies that prefrontal cortical regions preferentially contribute to the expression of remote memories.
A number of studies have now shown that disrupting
prefrontal cortical function preferentially affects remotecompared to recent memories (Table 3). In the first suchstudy, Takehara and colleagues [29] showed that lesions of
the prefrontal cortex (including the anterior cingulate cortex
and prelimbic cortex) preferentially affected month-old
trace eyeblink conditioning memories. (In this case, recent
trace eyeblink memories were also affected, albeit to alesser degree). Similarly, pharmacological inactivation
studies have highlighted the role of the anterior cingulate
cortex in the expression of remote contextual fear [37],spatial discrimination [24] and water maze [49] memories.
Together these studies establish a causal role for theseregions in the expression of remote memory, and areconsistent with the idea that memories are reorganized ina time-dependent manner. However, to date there are
relatively few studies, and many issues remain. For example,

are these effects localized to a specific prefrontal corticalregion (e.g., the anterior cingulate cortex) or do different
regions support different types of remote memory? Are theseregions storing remote memories, or merely coordinating
their retrieval? Perhaps most central is the issue as to whether
activation of prefrontal regions during remote memory recall
depends on the age (or remoteness) of the memory or more
effortful recall. Because older or more remote memories may
be weaker, it is possible that increased activation of
prefrontal regions reflects greater effort required to access apartially degraded memory trace [83].

Summary and future directions
Graded retrograde amnesia after hippocampal damage inpatients forms the cornerstone of the idea that memories forcertain types of information are reorganized in a timedependent manner. However, these neuropsychologicalstudies inevitably involve relatively few patients, and thereis necessarily a lack of control over what is learned andwhen (because of the retrospective nature of these analyses), and over the size and extent of the lesion (combined
with, in many cases, limited anatomical information). The
superior level of control available in experimental animalstudies (e.g., control of what is learned and when, extent oflesion, temporally and spatially specific overexpression ofmutant genes), therefore, offers a huge opportunity to better
define and understand how memories are reorganized overtime. This brief review has highlighted what these studies
have told us, but the fact that many issues remainunresolved suggests that this opportunity has not yet been
fully exploited.
When hippocampal gradients occur
What we know A relatively conservative reading of theabove experiments indicates that hippocampal gradients
exist. At least in the majority of conditions and paradigms,
these studies show that the hippocampus is preferentially
activated during the expression of recent memory, andmemory consolidation is preferentially affected by hippocampal manipulations in the days immediately after training(but not thereafter). These effects have been demonstratedusing a range of different tasks, and importantly, a wide
variety of approaches—including neuroanatomical lesions,brain-mapping and mouse-genetic manipulations. Insofar asthese studies show that the circuits supporting the expression of recent and remote memory differ, they are generally
consistent with the broad notion of reorganization. Thisconclusion that hippocampal gradients exist is not necessarily even a controversial one: Both standard models of
consolidation [60, 61], as well as alternative accounts [62,Debates in Neuroscience63], posit reorganization as a central process and both canreadily account for hippocampal gradients.
What we do not know Whereas these studies successfully
recapitulate the observations in human patients, it is lessclear whether they provide any additional insights into themechanisms underlying reorganization. Two issues inparticular stand out. First, when hippocampal gradients areobserved, the length of the gradient may vary dramatically
across studies. For example, estimates of temporal gradientsin studies of contextual conditioning vary between 28 and100 days in rats [10, 15, 23]. This variability indicates thatthe relationship between a number of factors (e.g., intensityof learning, type of learning, type of lesion) and gradient
length is poorly understood, and more systematic examination of how these factors impact on gradient length areneeded.
Second, what is the role of memory reactivation inreorganization? The general idea is that memory reactivationis the driving force behind reorganization [68]. Within thisframework, reactivations in either online situations (e.g.,during explicit recall) or offline situations (e.g., during sleep)
provide an opportunity for modifying a memory trace, andmany iterations of this process will eventually lead todramatic changes in the way memories are organized at thesystems level. Consistent with the idea that reactivation plays
a key role are recording studies showing that patterns ofbrain activity associated with earlier activity are selectively
replayed during sleep [84]. However, establishing a causal
relationship between reactivation and reorganization has
been more difficult. To establish this, one would need toshow that selectively blocking replay prevents timedependent changes in the organization of memory.
Alternatively, increasing replay (e.g., by using explicit
reminders) might accelerate reorganization.
When hippocampal gradients do not occur
What we know There are several examples of ungradedamnesia after hippocampal damage (and it is likely thatthese flat gradients are underrepresented in publishedliterature). In some instances, flat gradients are associatedwith extrahippocampal damage (e.g., perirhinal cortex).
However, there are a significant number of examples thatcannot be accounted for in terms of extrahippocampal
damage. The most common (and widely recognized)
instance is in the water maze where lesion, inactivation,and brain-mapping studies suggest that the hippocampus isalways necessary for the expression of spatial memory. It isalso important to recognize that the absence of hippocampal
gradients in the water maze does not imply that water mazememories do not undergo reorganization because thefinding that the anterior cingulate cortex (ACC) plays apreferential role in the expression of remote water mazememory suggests that circuits supporting water mazememories evolve over time [49].
What we do not know The key question here is not whether
hippocampal damage is sometimes associated with flat
gradients—in the case of the water maze there is widespread agreement that this is the case. Rather, it is whether
flat gradients can tell us anything about hippocampal
contributions to memory expression, and, more generally,
the relationship between memory reorganization and memory quality. The finding that hippocampal manipulations
tend to have greater impact in spatial tasks with greaternavigational demands suggests that hippocampal activity
contributes to navigational aspects of performance. However, the rodent village paradigm also raises the possibility
that hippocampal-dependent and hippocampal-independent
spatial memories differ qualitatively [65]. In these sorts ofparadigm it will be important to establish explicit predictions about what a less precise or gist-like memory mightlook like, and extend these sorts of studies to examine
nonspatial memories.
Cortical gradients
What we know We described accumulating evidence thatdifferent cortical regions play increasingly important rolesin the expression of memory as a function of time. Again,
this conclusion is based on experiments using a variety oftasks, and importantly, a wide variety of approaches. These
initial results are generally consistent with the broad notionof reorganization, and, more specifically, a role for the
prefrontal cortex in the expression of remote memory.
What we do not know It is perhaps surprising that localized
inactivation of prefrontal cortical regions would have suchprofound effects on the expression of remote memory,
given that it is widely thought that remote memories aresupported by a much broader, distributed network. Thissuggests that some regions within this network (such as theACC) may be more critical for function than others. Twogoals are therefore important: first, to comprehensively
identify regions supporting remote memory; second, tounderstand how the architecture of this network impacts on
its function. Regarding the former, our current picture of
how remote memories are organized is still very muchincomplete. For example, the analysis of six corticalregions in the Frankland et al. study [37] represents only
2–3% of total forebrain volume, and brain-wide analyses
are necessary to comprehensively map networks supporting
remote contextual fear and other memories. Regarding thelatter, the analysis of other complex systems may provide
some clues [85, 86]. Any network—whether an airline

Debates in Neuroscienceroute map, a protein interaction network, or the anatomical
connectivity of the cortex—can be described as a collectionof nodes (in this case, brain regions) connected by links (inthis case, afferent and efferent projections). An emerging
theme is that many real-world networks, from metabolicand protein interaction networks to the World Wide Web[86, 87], have a “scale-free” structure [85]. The defining
feature of such networks is that whereas the vast majority ofnodes have few links, a small number of nodes are highly
connected, and the distribution of linkages in such a scalefree network is then best described by a power law. In
general, scale-free networks are robust, as the majority of
localized perturbations will, more often than not, affect lessconnected nodes. However, the functional integrity of the
network is vulnerable to targeted lesions of highly
connected “hubs”. The inactivation experiments raise thepossibility that the ACC (and other prefrontal regions)occupy hub-like positions in networks supporting remotememory [88].

Acknowledgements This work was supported by grants from the
Canadian Institutes of Health Research and the EJLB Foundation.
CMT received support from the Graduate Program in Areas of Basicand Applied Biology (GABBA) and the Portuguese Foundation for
Science and Technology (FCT). We thank Robert Clark, Sheena
Josselyn and Karim Nader for discussions of these ideas.

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