REVIEW – SPECIAL ISSUE

Grading Gradients: Evaluating Evidence for Time-dependent
Memory Reorganization in Experimental Animals
Katherine G. Akers 1 and Paul W. Frankland 1–3
1

Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Canada. 2Departmentof Physiology, University of Toronto, Toronto, Canada. 3Institue of Medical Science, Universityof Toronto, Toronto, Canada.
Abstract: In humans, hippocampal damage typically produces temporally graded retrograde amnesia, with relative
sparing of remote memories compared to recent memories. This observation led to the idea that as memories age, they
are reorganized in a time-dependent manner. Here, we evaluate evidence for time-dependent memory reorganization in
animal models. We conclude that, although hippocampal lesions may not always produce temporal gradients under all
conditions, studies using alternate experimental approaches consistently support the idea that memories reorganize overtime—becoming less dependent on the hippocampus and more dependent on a cortical network. We further speculate
on the processes that drive memory reorganization such as sleep, memory reactivation, synaptic plasticity, andneurogenesis.
Keywords: memory consolidation, hippocampus, cortex

Since at least the late 19th century, it has been recognized that “the dissolution of memory is inversely
related to the recency of the event,”1 or, in other words, that new memories are more vulnerable to brain
insults than old memories. In the mid-20th century, the treatment of intractable seizures or psychosis
via surgical resection of the brain unexpectedly revealed the neuroanatomical locus of this effect. In
the most famous case,2 Henry Molaison (patient H.M.) underwent resection of a large, bilateral portionof the medial temporal lobe including the hippocampus. After surgery, he exhibited partial retrograde
amnesia, with memories formed shortly before the surgery forgotten but memories formed earlier inlife remembered.3 Over the last several decades, numerous individuals who sustained damage to the
hippocampus exhibited similar patterns of retrograde amnesia, with recent memories lost but remotememories left relatively intact.4–7
These cases of temporally graded retrograde amnesia led to the idea that the hippocampus plays atime-limited role in the storage and retrieval of memory.8–11 In particular, two major theories of systems-level memory consolidation have emerged (Fig. 1A, B). The first theory—known as standard
consolidation theory—proposes that the hippocampus is initially required for memory expression but
that, over time, memory expression becomes dependent on a cortical network.12,13 The second theory—
known as multiple trace theory—proposes that the brain regions that support memory expression
differ depending on the type of memory; semantic or context-free memories depend less on the hippocampus and more on extrahippocampal structures as they age, whereas episodic or contextually-richmemories always depend on the hippocampus.14,15 Although there are some key differences between
these two theories, both agree that memory can undergo time-dependent reorganization across brain
regions.
While clinical cases of retrograde amnesia in humans form the basis of the idea that memory reorganizes in a time-dependent manner, they involve relatively few patients and there is no control overthe extent and location of brain damage as well as the age and nature of memories that may be affected.
Experimental studies using animals, therefore, have made a significant contribution to our understanding of how memory is reorganized over time. Here, we review evidence for time-dependent memory
reorganization in experimental animals and speculate on the processes that might drive thisreorganization.

Correspondence: Paul W. Frankland, Neurosciences and Mental Health, Hospital for Sick Children, Toronto,
Canada. Email: paul.frankland@sickkids.ca
Copyright in this article, its metadata, and any supplementary data is held by its author or authors. It is published under theCreative Commons Attribution By licence. For further information go to: http://creativecommons.org/licenses/by/3.0/.

Journal of Experimental Neuroscience 2009:2 13–22

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Akers and Frankland

A)

B)

Figure 1. Two theories of time-dependent memory reorganization. A) The standard consolidation theory proposes that, over time, memories
become independent of the hippocampus. B) The multiple trace theory proposes that semantic or context-free memories become independent of the hippocampus over time, but that episodic or contextually-rich memories always depend on the hippocampus.

Temporal Gradients
after Hippocampal Damage:
Sometimes There, Sometimes Not

In one of the first studies to model temporally
graded retrograde amnesia in animals, Winocurand colleagues16 made electrolytic lesions of thedorsal hippocampus in rats at varying time points
after training in a socially-transmitted food preference task. They found that lesions made 1–2 days
after training abolished memory for the learned
food preference, but memory was spared whenlesions were made 10 days after training. This
temporal gradient of retrograde amnesia supports
the idea that memories become independent of the
hippocampus as they age. Subsequent studies
employing hippocampal lesions or disruption ofhippocampal function replicated and extended thisbasic effect to encompass not only socially-transmitted food preference,17–19 but also contextual fear
conditioning,20–27 trace fear conditioning,27 spatial
discrimination,28–32 visual discrimination,33 trace
eyeblink conditioning,34–36 object discrimination,37
inhibitory avoidance,38,39 and some variations of
the water maze.25,40–43
Not all studies, however, report evidence fora temporal gradient of retrograde amnesia.
Instead, many found that hippocampal lesions or
disruption of hippocampal function abolishedboth recent and remote memory.44–64 Although
the conditions that lead to the presence—or
absence—of a temporal gradient of retrograde
amnesia following hippocampal damage are not14

yet well defined, a number of potential factors
have been proposed.

Extent of training

An emerging theme from recent studies is that theextent of training may influence whether remotememories are spared following hippocampal
damage. That is, extensive training protocols may
produce memories that survive hippocampal damage, whereas minimal training protocols may result
in memories that are vulnerable to hippocampal
damage.
In one study, Winocur and colleagues65 reared
rats in a complex environment, or “village”, for
3 months. After hippocampal lesions, rats retained
accurate memory for the spatial layout of the environment. The authors speculated that the extensive
pre-operative experience in the spatial environment
allowed the formation of a schematic representation of the environment that did not require thehippocampus. Because the timing of the surgery
relative to training was not manipulated in thisstudy, whether memory for the spatial layout was
initially dependent on the hippocampus and later
dependent on extrahippocampal regions could not
be determined. Rather, it may be the case that
extensive experience or intense training enabled
extrahippocampal regions to encode memories
separately from the hippocampus.66
Further insight into these issues comes from astudy by Morris and colleagues,67 who trained rats
over several weeks to associate particular flavors
Journal of Experimental Neuroscience 2009:2

Grading gradientsof food to specific locations in a complex spatialenvironment. After this lengthy training period,rats were able to acquire novel flavor-place associations in just one trial, suggesting that extensive
experience with the task led to the formation of an
associative schema that allowed for the rapid
encoding of new information. After hippocampal
lesions, rats retained memory for the well-learned
flavor-place associations, indicating that theschema was stored in extrahippocampal areas. As
for the flavor-place associations acquired over a
single trial, whether they survived hippocampal
damage depended on their age. Associations thatwere 3 hours old were abolished by hippocampal
lesions, but associations that were 48 hours old
were left intact. Because this temporal gradient ofretrograde amnesia was significantly steeper thanthat typically observed after hippocampal damage(e.g. several days to a few months), this suggeststhat the creation of an extrahippocampal schemaincreases the rate at which memory becomes independent of the hippocampus. Furthermore, when
hippocampal lesions were made before training,rats failed to learn the flavor-place associations,indicating that extrahippocampal structures were
not capable of independently encoding the spatial
memories, even after extensive training.

Context-dependent versus
context-free memory

In contrast to standard consolidation theory,12,13
which predicts that all remote memories should
survive hippocampal damage, multiple trace
theory14,15 predicts that whether remote memories
survive hippocampal damage depends on whether
they are context-dependent or context-free. Remotememories that remain entangled with the context
in which they were encoded should remain permanently dependent on the hippocampus and, thus,
would not survive hippocampal damage. In contrast, remote memories that have become unraveledfrom their original context should become independent of the hippocampus and, thus, would bespared after hippocampal damage.
Consistent with multiple trace theory, studies
show that fear68–70 and food preference68 memories,
which are initially dependent on the particular context in which they were encoded, lose contextual
specificity as they age. As these memories lose
contextual specificity, they may become independentof the hippocampus. This might explain why remote
Journal of Experimental Neuroscience 2009:2

fear20–26 food preference16,17,19,71 memories typicallysurvive damage to hippocampus. In contrast, remotememories that remain tied to a particular context,
such as water maze memory,44–46,50,52–57,60 typicallydo not survive hippocampal damage.
Several studies, however, do not support thepredictions of multiple trace theory. For instance,
remote memories that are relatively context-free
do not always survive hippocampal damage.
Ungraded retrograde amnesia has been found forcontextual fear memory,48,51,59 which is expected
to lose contextual specificity over time,68–70 andobject47,49,60 and picture61 memories, which neednot be associated with a particular context at any
time point. Furthermore, attempts to reduce thespatial complexity or the need for spatial navigationin the water maze, which should conceivably allow
memory to become independent of the hippocampus, failed to reveal a temporal gradient of retrograde amnesia after hippocampal lesions.55,56
Another problem for multiple trace theory isthat remote memories that remain tied to the context in which they are encoded are sometimes
preserved after hippocampal damage. In a study
by Wang et al72 mice were trained in a 3-day context fear discrimination protocol in which one
context was always paired with shock and a second
context was never paired with shock. Different
from standard fear conditioning protocols, thiscontext fear discrimination protocol produced
precise, context-specific fear memory lasting
several weeks (Fig. 2A–C). Although extensive
hippocampal lesions made 1 day after training
abolished discrimination between contexts, discrimination was spared when lesions were made42 days after training (Fig. 2D). Thus, the hippocampus may not be permanently necessary for the
expression of precise, context-specific memory.

Extent of lesion

Another factor that may influence whether remotememories are lost after hippocampal damage is thesize of the lesion. Unlike standard consolidation
theory,12,13 which predicts that all remote memories
will survive hippocampal damage regardless oflesion size, multiple trace theory14,15 predicts that
context-dependent memories may or may notsurvive hippocampal damage depending on thesize of the lesion. Specifically, multiple trace
theory predicts that as context-dependent memories
age, they become supported by a greater number
15

A)

C)

Context Fear Discrimination
1d

A

B

A

B

A

B

A

A

B

B

42 d
A

B

A

A

B

B

Discrimination Index

Akers and Frankland

0.6Standard
Discrimination

0.4
0.2
0
−0.2
1

A

A

Standard Fear Conditioning

1d
A

B

42 d

A

B

D)

Delay (d)Discrimination Index

B)

42

1

Lesion
Sham

0.5

0
−0.5
1

42

Delay (d)Figure 2. Precise, context-specific remote memories do not require the hippocampus. A) In the context fear discrimination protocol, mice
were repeatedly exposed to context A, in which shock always occurred, and context B, in which shock never occurred. B) In the standard
fear conditioning protocol, mice were shocked during a single exposure to context A. C) In contrast to the standard fear conditioning protocol, which produced fear memories that lost context-specificity over time (i.e. reduced discrimination index), the context fear discrimination
protocol produced durable, context-specific fear memories that persisted for at least 42 days. D) Extensive lesions of the hippocampus after
training in the context fear discrimination protocol abolished recent context-specific fear memory, but spared remote context-specific fear
memory. Adapted from Wang et al.72

and wider distribution of hippocampal-corticaltraces. Because the hippocampal-cortical traces
supporting recent memory are fewer in number
and sparser in distribution compared to remotememory, partial hippocampal lesions are more
likely to disrupt recent compared to remote memory and thus result in a temporal gradient of retrograde amnesia. Extensive hippocampal lesions, on
the other hand, are likely to disrupt both recent andremote memory and thus result in ungradedretrograde amnesia. To some degree, experimental
findings support the prediction of multiple trace
theory, as many studies reporting temporal
gradients employed partial hippocampal
lesions16,20–24,30,31,34,35,38,39 and many studies reporting ungraded amnesia employed extensive hippocampal lesions.44,47,49,54,58,60,61 However, it issometimes found that remote context-dependent
memory is spared after extensive lesions,17–19,72
which is problematic for multiple trace theory.
Conversely, it is sometimes found that remotecontext-dependent memory is disrupted by partial
lesions,45,46,48,51,53,55,57,62 which is problematic for
multiple trace theory as well as standard consolidation theory.
16

Memory involving a taste
or odor component

A fourth factor that may determine the fate ofremote memory following hippocampal damageis whether it involves a significant taste or odor
component. One type of remote memory thatis consistently found to survive hippocampal
damage is socially-transmitted food preference
memory.16,17,71,73 Furthermore, it has been argued51
that when remote contextual fear memory is foundto survive hippocampal damage, it is often in studies that incorporated a prominent odor (e.g. acetic
acid, ethanol) into the training context.20–22,24 Thus,
it may be possible that memory involving taste orodor becomes completely independent of the hippocampus over time, whereas other types ofmemory tend to engage the hippocampus for as
long as they exist.

Alternate Approaches: Consistent
Evident for Time-Dependent
Memory Reorganization

Although hippocampal damage or disruption ofhippocampal function does not always result in a
Journal of Experimental Neuroscience 2009:2

Grading gradients

temporal gradient of retrograde amnesia, studies
utilizing alternate experimental approaches offer
nearly unanimous support for the idea that memories reorganize over time.
One such approach is to map region-widechanges in brain activation corresponding to theexpression of recent and remote memories. In thefirst study of this kind, performed by Bontempi
and colleagues,74 mice were trained to find food
rewards in an eight-arm radial maze and given aretention test either 5 or 25 days later. Retrieval ofmemory for the food locations 5 days after training
corresponded with increased metabolic activity inthe hippocampus. In contrast, retrieval of memory
25 days after training corresponded with increased
metabolic activity in the anterior cingulate, medial
prefrontal, and temporal cortices. This suggests
that, over time, initially-hippocampal dependent
memory becomes dependent on a widespreadcortical network. Studies examining changes in
immediate early gene (e.g. zif268, c-fos) expression
after recall of recent and remote memories also
found a time-dependent shift from primarily
hippocampal activation to primarily corticalactivation.19,30,57,75,76 Furthermore, these studies
indicate that different types of memories may
become dependent on partially dissociable cortical
networks. Recall of remote spatial discrimination,30
contextual fear,75 and water maze57 memory activated the anterior cingulate, medial prefrontal, andtemporal cortices, but recall of remote sociallytransmitted food preference memory19,76 activatedorbitofrontal and piriform cortices.
A strength of these brain-mapping studies is thatthey allow for the observation of whether the hippocampus is engaged during retrieval of remotememory, which is not possible in hippocampal
lesion studies. From the studies performed so far,it appears that whether the hippocampus isactivated by recall of remote memory depends
on the type of memory being recalled. Specifically, retrieval of remote socially-transmitted
food preference memory did not activate thehippocampus.19,76 In contrast, the hippocampus
was activated by retrieval of remote water mazememory.57,77 Notably, however, the pattern of activation across hippocampal subregions was moresparse and of lesser magnitude during retrieval of
remote compared to recent water maze memory,77
suggesting that time-dependent reorganization ofthis type of memory can occur within the hippocampus itself. For spatial discrimination30,74 andJournal of Experimental Neuroscience 2009:2

contextual fear75 memory, levels of hippocampal
activation were lower than control conditions,suggesting that for these types of memories, thehippocampus is not just passively disengaged
during recall of remote memory but is actively
inhibited by other brain regions.
Despite its strengths, there are some potential
disadvantages of the brain-mapping approach. One
is that the choice of an appropriate control condition
is difficult. For some types of tasks, such as
contextual fear conditioning, there is relative
consensus on an appropriate control group (e.g.
no-shock or immediate-shock). The situation,
however, is not as clear for tasks such as the watermaze, for which highly conservative control groups(e.g. swim or visible platform) could lead to a highfalse-negative rate, but less conservative control
groups (e.g. home cage) could produce a highfalse-positive rate. A second issue is that immediate
early gene expression is only an indirect marker
of brain activation. Although the expression ofthese genes is tightly correlated with neuronal
activity, 78 differences in endogenous activity
patterns across brain regions may limit their utility
in brain-wide studies. A third issue is that reorganization may not necessarily result in an overall
increase in activity in a given region. For example,
there was no overall increase in activation of theparietal cortex after recall of remote, compared torecent, spatial discrimination memory, but a closer
examination showed that activation shifted fromdeep to more superficial cortical layers over time.30
This example highlights the complexity of defining
reorganization and raises the question of what levelof anatomical resolution is appropriate, or evenfeasible, for this type of analysis.
Another alternate approach to studying timedependent reorganization of memory is to target
specific extrahippocampal regions that are implicated in the recall of remote memory. If certain
extrahippocampal regions gradually assume acritical role in memory, then an increase in taskrelevant neural firing or synaptic transmission
should be observable within those regions as memories age. Takehara-Nishiuchi and McNaughton79
trained rats in a trace eyeblink conditioning
protocol and recorded neural firing in the medial
prefrontal cortex. Across several weeks of toneshock pairings, neural firing became selective forthe learned associations, evidenced by increased
firing during the delay between the tone and theeyelid shock. This suggests that as trace eyeblink17

Akers and Frankland

memories age, they gradually engage the medial
prefrontal cortex. In another study, Hugues andGarcia80 trained rats in a contextual fear extinction
protocol and recorded field potentials at two different inputs to the medial prefrontal cortex. As
the extinction memory aged, there was a depotentiation of field potentials at ventral hippocampalmedial prefrontal synapses and a potentiation offield potentials at mediodorsal thalamic-medial
prefrontal synapses. This suggests that, over time,processing of the extinction memory was relinquished by hippocampal inputs and overtaken byother inputs to the medial prefrontal cortex.
Likewise, if certain extrahippocampal regions
play an increasingly critical role in memory overtime, then damage to those regions should disrupt
remote memory to a greater extent than recent
memory. Indeed, inactivation of the anterior cingulate cortex blocked expression of remote, but
not recent, memory for contextual fear,75 spatial
discrimination,30 water maze,57 and conditioned
taste aversion.81 With one exception,82 inactivationor lesions of the medial prefrontal cortex resulted
in greater disruption of remote memory than recent
memory for spatial discrimination,30 trace eyeblinkconditioning,34 and contextual and trace fear conditioning.27 Finally, inactivation of the parietal
cortex blocked the expression of remote, but notrecent, inhibitory avoidance memory.38,39 Thesestudies provide direct evidence that certain corticalareas are necessary for the recall of remote, but notrecent, memory, which provides support for theidea that memories gradually come to rely on cortical regions for storage and retrieval.
Although the selective involvement of corticalareas in the expression of remote memory may
reflect time-dependent memory reorganization, analternative interpretation is that cortical areas are
situationally recruited for the effortful retrieval ofmemories that are weak due to their age.83 As
memories tend to become weaker with time, distinguishing between these two interpretations
requires memory strength to be uncoupled frommemory age. In a study that addressed this issue,
Ding et al.81 used a taste aversion protocol in whichmice were treated with a high or low dose oflithium chloride after drinking saccharin-flavoredwater to create strong or weak taste aversion
memory, respectively. They found that inactivationof the anterior cingulate cortex disrupted retrievalof remote taste aversion memories regardless of
their strength. This is contrary to the prediction of18

the effortful retrieval hypothesis—that corticaldamage should disrupt retrieval of weak memories
regardless of their age.

Mechanisms of Time-Dependent
Memory Reorganization

It is believed that the time-dependent reorganization of memory is not passive, but rather actively
driven by memory reactivation.9,11 Successive
reactivations of memory could lead to the reinstatement of memory-relevant patterns of hippocampal
and cortical activity and the stabilization of cortical traces, thereby propelling memories to become
independent of the hippocampus.
One situation in which memory reactivation
may promote memory reorganization is during
sleep. Evidence that memory is reactivated during
sleep comes from studies showing that the sequencein which neurons fired when rats explored a spatialenvironment was replayed during subsequent slowwave sleep.84,85 Because replay of waking experience was coordinated between the hippocampus
and the cortex,86–88 this suggests a possible dialogue
between the two brain areas during slow-wave
sleep that contributes to memory reorganization.
While these studies indicate that slow-wave sleep
is important for memory reorganization, otherstudies point toward an important role for rapid
eye movement (REM) sleep. In a series of studies,
Ribeiro et al. examined the expression of zif268,
an immediate early gene involved in synaptic
plasticity and memory stabilization,89,90 during
rapid eye movement (REM) sleep. They found thatafter exploration of a novel environment91,92 or
induction of long-term potentiation (LTP) in thedentate gyrus,93 there was increased zif268 expression in hippocampal and cortical regions during
subsequent REM sleep. This increased corticalexpression of zif268 was blocked by inactivationof the hippocampus, suggesting that the hippocampus is responsible for propagating gene expression
throughout the cortex during REM sleep. Thesefindings have led to the theory that slow-wave andREM sleep play distinct roles in memory reorganization, with memory reactivation occurring
during slow-wave sleep and hippocampus-driven
stabilization of cortical memory traces during
REM sleep.94
Another situation in which memory reactivation may promote memory reorganization is during
the explicit retrieval of memories. For instance,
Journal of Experimental Neuroscience 2009:2

Grading gradientsobservations that extensive training can produce
contextually-rich memories that survive hippocampal lesions65,67,72 might reflect reorganization
driven by the repeated retrieval of task-relevant
information inherent in extensive training
protocols. Furthermore, even after memories havebecome independent of the hippocampus,
retrieval of memory may initiate additionalrounds of reorganization. Debiec and colleagues23
found that remote contextual fear memory, which
was independent of the hippocampus, briefly
returned to a hippocampal-dependent state after
rats were reminded of the training context. This
re-engagement of the hippocampus during memory retrieval may serve to further refine or toincorporate new information into existing corticalmemory traces.
Regardless of the exact situations during which
time-dependent memory reorganization occurs, itmost certainly involves plasticity both within andbetween hippocampal and cortical regions. Studies
utilizing transgenic lines of mice have implicatedseveral plasticity-related molecules in the establishment of remote memory, including α-calcium/
calmodulin kinase II,75,95,96 p21-activated kinase,97
type 1 adenylyl cyclase,98 L-type voltage-gatedcalcium channels,99 integrin β2,100 and steryl-Oacyl transferase 1.100 For example, mice that were
heterozygous for a null mutation of α-calcium/
calmodulin kinase II (αCamKII) showed normal
acquisition and retention of contextual fear andwater maze memory over short delays (1–3 days)
but pronounced forgetting at longer retention delays(10–50 days).75 Because this mutation causes a
deficit in cortical LTP, it may be the case that
αCamKII-mediated synaptic plasticity in the cortex
is essential for the establishment of remote memory.
Although some studies indicate that the maintenance of remote memory requires ongoing synaptic
plasticity for up to several months after training,101,102
others suggest a time-limited role for synaptic
plasticity.25,26,103 In particular, survival of remotememories required activation of N-methyl-Daspartate (NMDA) receptors in the hippocampus25
and medial prefrontal cortex103 only during the first
2 weeks after training but not thereafter. Likewise,
survival of remote memories required normal
αCamKII activity in the forebrain—including the
hippocampus and cortex—only during the firstweek after training.26 These studies suggest thathippocampal and cortical synaptic plasticity is
critical for the transition of memories from a
Journal of Experimental Neuroscience 2009:2

temporary, hippocampal-dependent state to a stable,cortex-dependent state.

Summary and Future Directions

A relatively conservative reading of the studies
employing inactivation or damage of the hippocampus indicates that temporal gradients of retrograde amnesia exist. Certain conditions, however,may prolong the period during which memories
depend on the hippocampus, resulting in ungradedamnesia at the time points at which memory isprobed. The inconsistency with which temporal
gradients are found suggests the interplay of anumber of influential factors (e.g. training intensity,
extent of lesion, qualitative aspects of the target
memory) that, at the present moment, are poorly
understood. Thus, more systematic examination of
how these factors determine the temporal patternof retrograde amnesia after hippocampal damage
is needed.
In contrast to studies employing hippocampal
damage, studies using alternate approaches haveprovided nearly unanimous support for the ideathat as memories age, they become less dependent
on the hippocampus and more dependent on abroad network of cortical regions. Our current
picture of how remote memories are organized,
however, is still incomplete. For example, theanalysis of six cortical regions in the Frankland
et al. brain-mapping study 75 represents only
2%–3% of total forebrain volume. Brain-wide
examinations are necessary to comprehensively
map the networks supporting remote memories andto understand how different types of remotememories may be differentially organized.
Although evidence is accumulating that memory
reactivation drives memory reorganization either
in online (e.g. memory retrieval) or offline (e.g.
sleep) situations, this evidence remains correlative.
To provide a causal link between memory reactivation and reorganization, future studies would needto determine, for example, whether blocking
memory replay during sleep prevents reorganization or whether repeated reminders of the learning
event accelerates reorganization.
Finally, some possibilities—such as the roleof neurogenesis in time-dependent memory
reorganization—are just beginning to be explored.
Tsien and colleagues104 found that transgenic micewith deficient hippocampal neurogenesis exhibited longer retention of contextual fear memory.
19

Akers and Frankland

This led them to hypothesize that the addition of
new neurons into the hippocampal network via
neurogenesis may lead to instability and eventual
erasure of the hippocampal memory trace, thereby
making room for the acquisition and temporarystorage of new memories. In line with thishypothesis, Inokuchi and colleagues105 found that
irradiation-induced reduction of hippocampal neurogenesis prolonged the hippocampal-dependencyof contextual fear memories, suggesting thathippocampal neurogenesis may expedite andenhance the efficiency of time-dependent memory
reorganization.

Disclosure

The authors report no conflicts of interest.

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