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Hippocampal neurogenesis andforgetting
Paul W. Frankland1,2,3,4, Stefan Köhler5,6, and Sheena A. Josselyn1,2,3,4
1

Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
Department of Psychology, University of Toronto, Toronto, Ontario M5S 3GM, Canada
3
Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
4Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada
5
Brain and Mind Institute and Department of Psychology, University of Western Ontario, London, Ontario N6A 5B7, Canada
6
Rotman Research Institute, Baycrest Centre, Toronto, Ontario, M6A 2E1, Canada
2

The hippocampus is thought to automatically encode all
experience, yet the vast majority of our experiences are
not remembered later. Although psychological theories
have postulated the existence of decay processes fordeclarative memory, the corresponding neurobiologicalmechanisms are unknown. Here we develop the hypothesis that ongoing hippocampal neurogenesis represents
a decay process that continually clears memories fromthe hippocampus. As newborn granule cells integrate
into established hippocampal circuits, they form new
input and output connections over the course of several
weeks. Because successful memory retrieval relies on
reinvoking patterns of activity that occurred at the timeof encoding (pattern completion), neurogenesis-induced
remodeling of hippocampal circuits incrementally
reduces the likelihood that a given retrieval cue will
reinvoke a previously stored pattern.
Introduction
In the 1960s Altman published pioneering studies showingthat neurogenesis persists in the subgranular zone of the
hippocampus beyond development and into adulthood[1–3]. Although this field largely lay dormant for the better
part of the next three decades, interest was rekindled in
the 1990s when new immunohistochemical methods weredeveloped that made it possible to definitively label newborn granule cells [4]. This prompted an explosion ofstudies asking whether and how new neurons contributeto hippocampal memory formation. These studies havetaken advantage of increasingly sophisticated methods
for ablating [5–7] or, more recently, disrupting the activity[8,9] of new neurons, with the general premise of thesestudies being that new neurons are in some way ‘good’ forhippocampal memory. Accordingly, there is now an extensive (but sometimes messy) body of literature examining
the impact of both increasing and decreasing adult neurogenesis on the formation of new hippocampal memories[10]. By contrast, here we consider the impact of ongoingneurogenesis on existing memories and propose a novelrole for neurogenesis in forgetting.
Corresponding authors: Frankland, P.W. (paul.frankland@sickkids.ca);Köhler, S. (stefank@uwo.ca); Josselyn, S.A. (sheena.josselyn@sickkids.ca).
0166-2236/$ – see front matterß 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tins.2013.05.002

New neurons and new memories
It is surprising that, almost without exception, previous
studies have used essentially the same experimental design
to examine the role of new neurons in memory. Neurogenesis levels are usually manipulated in adult rodents, andthen, days or weeks later, the ability to form new hippocampus-dependent memories is evaluated. The typical result
from these studies is that reducing neurogenesis impairs
subsequent hippocampal memory formation. Conversely,
increasing neurogenesis facilitates hippocampal memory
formation in some cases. These anterograde effects were
initially observed using a trace eyeblink conditioning paradigm [11], and subsequently shown across a range of otherhippocampus-dependent tasks, including various forms ofcontextual and spatial learning [10]. Memory impairments
are not universally observed following reduction of adultneurogenesis, however. Whether memory impairment isobserved may depend on animal age at the time of neurogenesis reduction [12], the number of neurons targeted [13],the maturational stage of the targeted neurons at the time oflearning [8,14], and the type of behavioral task used toassess learning and memory [15]. The finding that reducing
neurogenesis does not always produce memory impairment
may not be entirely unexpected because memory formation
can probably be supported by developmentally generated
granule cells alone [5].
How does neurogenesis regulate the ability to form new
hippocampal memories? One idea is that neurogenesis
enhances the process of pattern separation [16]. To encode
distinct episodic memories, the brain must distinguishbetween different places in which these events occur[17,18]. Theoretical models originally proposed that thisprocess of disambiguation of different places (pattern separation) is mediated by the entorhinal cortex–dentate
gyrus (DG)–CA3 hippocampal circuit [19,20]. Within thiscircuit, the DG transforms similar overlapping patterns ofactivity from the entorhinal cortex into distinct population
codes in the CA3. This model is supported by data fromrodent in vivo recording studies [21–23]. In contrast to theDG (in which changes in context are signaled by changes in
the firing rate of the same populations of neurons, i.e., arate code), the CA3 region uses a population code (in which
the same context shifts change the identity of the populations of CA3 cells that fire [22]). That the CA3 signals
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Opinioncontext shifts by engaging different populations of neurons
is supported by data from cellular imaging studies using
activity-dependent genes to identify neurons activated by
the same versus different contexts [24].
Interestingly, recent studies suggest that adult hippocampal neurogenesis enhances memory formation bymodulating the efficiency of pattern separation. Using
the activity-dependent gene mapping approach, Niibori
and colleagues showed that reducing adult neurogenesis(via either chemical or genetic approaches) degraded theability of the CA3 to separate patterns via population
coding (there was a large overlap in the population of
CA3 neurons that were active in similar contexts) [25].
The finding that a reduction in adult neurogenesis impairs
the ability of the CA3 to separate patterns at the circuit
level is mirrored by results at the behavioral level thatshowed that reducing adult neurogenesis produces deficits in visual, context, and spatial discrimination [25–30].
Conversely, increasing adult neurogenesis by promoting
the survival of newborn cells facilitates spatial and contextual discrimination, perhaps by enhancing patternseparation [28]. Similarly, silencing the output of developmentally generated DG neurons only (thereby shifting
the balance of the DG towards a more immature state) also
facilitated spatial and contextual discrimination [9]. Together these studies suggest that neurogenesis positively
modulates the ability of the hippocampus to form distinct
memories of different episodes by facilitating patternseparation [16].
New neurons and old memories
This focus on the anterograde effects of manipulating adultneurogenesis on memory has come at the expense of an
examination of potential retrograde effects: how does theintegration of new neurons into existing hippocampal circuits impact information already stored in those circuits?
The integration of newborn neurons into the hippocampus
follows a stereotypical course [31]. Division of progenitor
cells in the subgranular zone gives rise to new cells that
migrate into the innermost part of the granule cell layer.
The vast majority of these cells differentiate into neurons,
extending apical dendrites into the molecular layer of the
hippocampus and mossy fiber axons toward the CA3 region. Input and output synapses begin to form on adultgenerated neurons at 2.5 weeks, and synaptic integrationof these neurons into hippocampal circuits continues overthe next several weeks [8,32–35]. During this integration
process, new neurons compete with existing granule cells
for inputs and outputs, establishing new synaptic connections that either coexist with, or even replace, establishedsynaptic connections in both the DG and CA3 (Figure 1)[36–38]. Although the time-course of integration of newneurons is largely invariable, the proliferation and survival rates of new neurons may be regulated by several
factors, including stress, exercise, environmental enrichment, drugs of abuse, and age [31,39].
In addition to this direct structural remodeling,
the integration of new neurons into the hippocampus
may indirectly modify the strength of established synaptic
connections. Immature neurons are more excitable thantheir mature counterparts [32,33,40]. Therefore, newly2

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generated granule cells fire more action potentials to agiven stimulus than mature granule cells do. Accordingly,
the addition of new neurons to an established DG–CA3
circuit might lead to an overall increase in circuit excitation. Networks strive to maintain homeostasis by altering
network and cellular properties to counteract perturbations. Therefore, the addition of new highly excitable cells
to this circuit would likely engage these circuit-wide compensatory changes to regulate network stability [41].
These mechanisms may include a decrease in the intrinsic
excitability of existing DG and/or CA3 neurons (e.g., bydecreasing sodium currents and/or upregulating fast-inactivating and calcium-activated potassium currents [42–45]) or neuron-wide synaptic scaling (e.g., loss or endocytosis of post-synaptic GluA2 AMPA receptors [46,47])
which may eventually lead to silencing of some synapses[48]. Therefore, in addition to generating new synaptic
connections, the addition of new neurons may alter thestrength of existing hippocampal connections.
How does this continuously evolving hippocampal landscape impact previously stored information? Computational models predict that the addition of new neurons
degrades existing memories. These models have typicallyused a simple, three-layer architecture (an input [entorhinal cortex], middle [DG] and output [CA3] layer), withneurogenesis modeled by either replacing mature neurons
or adding new neurons to the middle DG layer [48–52].
Mature dentate neurons constitute a critical component of
the memory trace in these models, so replacement of theseessential neurons leads to memory degradation. Resultsfrom experimental studies, however, indicate that neurons
that are committed to a memory trace may actually have asurvival advantage [53], suggesting that these mature
memory-committed neurons are not likely to be replaced.
However, these computational models still predict memory
loss when new neurons are simply added to the existing
circuit, rather than replacing existing neurons [48–50].
Therefore, these neurocomputational data predict that
adult neurogenesis increases forgetting.
New neurons and forgetting
Successful memory retrieval requires intact encoding, consolidation, and retrieval. Some instances of memory failure
are simply due to ineffective encoding (such as not attending to where one puts one’s glasses; a type of memory
failure common during multitasking). However, as Tulving
emphasized, forgetting is ‘the inability to recall something
now that could be recalled on an earlier occasion’ [54]. Moreprecisely, forgetting may be defined as the inability toaccess information that was (i) successfully encoded and(ii) could previously be retrieved by the same retrieval cuethat now leads to retrieval failure [55]. Within this definition, forgetting can be due to either a failure of memory
consolidation or problems that arise as a consequence of
the act of retrieving itself (i.e., retrieval-induced forgetting[56]). Notably, even a failure of memory consolidation
would ultimately be manifest as unsuccessful memory
retrieval.
In the brain, successful memory retrieval is thought toreflect reactivation of the patterns of neural activity present at the time of memory encoding (a process known as

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(A)

(D)

m.l.
p.p.

s.l.

DG / molecular layer
Structural

CA3

DG

Homeostac

hilus

(B)

CA3 / stratum lucidum
Homeostac

StructuralP(retrieval success)

(C)

Time

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Figure 1. The integration of new neurons into the dentate gyrus induces forgetting of previously acquired (old) memories. (A) New dentate granule cells (DGCs, green)
integrate into an established DG circuit in which existing DGCs (red) receive perforant path (p.p.) inputs from the entorhinal cortex and send a mossy fiber axon towardpyramidal cells in the CA3 (gray). (B) New DGCs form input and output connections, starting at 2.5 weeks of age. (C) Neurogenesis-induced remodeling of hippocampal
circuits accumulates over time. (D) The integration of new DGCs produces both direct structural (pink insets) and indirect homeostatic (blue insets) changes in hippocampal
circuits. New neurons compete with existing granule cells for inputs and outputs, establishing new synaptic connections that either coexist with or even replace establishedsynaptic connections in both the DG molecular layer (m.l.) and CA3 stratum lucidum (s.l.). Because these new DGCs are more excitable than their mature counterparts, theaddition of new neurons to an established DG–CA3 circuit might lead to an overall increase in circuit excitation. These changes are counteracted, for instance, by decreasing
the intrinsic excitability of existing DG/CA3 neurons (top) or neuron-wide synaptic scaling (e.g., loss/endocytosis of post-synaptic GluA2 AMPA receptors) (middle), which
may eventually lead to silencing of some synapses. In this way, the integration of new neurons into an existing hippocampal circuit produces ongoing changes tohippocampal circuitry, resulting in a decrease in the likelihood of successful pattern completion (memory retrieval succcess) over time (bottom).

pattern completion) [57–60]. Neurally, therefore, forgetting may be defined as the failure of a retrievalcue to reinvoke the pattern of neural activity present atencoding. Accordingly, we propose that the incremental
integration of new neurons into existing hippocampal
circuits promotes forgetting by reducing the ability of aonce-effective retrieval cue to reinvoke the same pattern ofactivity present during memory encoding. Thus, adultneurogenesis would promote a failure of pattern completion and therefore unsuccessful memory retrieval.
Types of forgetting
Although forgetting has received scant attention inneurobiological studies of memory (for some notable
exceptions, see [61–64]), within the traditions of experimental psychology, forgetting has received significantly
more consideration.

The most common form of forgetting studied in thepsychological laboratory (although probably not the mostcommon form of forgetting in daily life) is a type of retrieval-induced forgetting known as cue overload [65]. As statedabove, successful memory retrieval rests on the availability of an effective retrieval cue. The most effective retrieval
cue is one that is uniquely associated with a memory
episode or trace. However, some cues acquire associations
with multiple memories. The greater the number of associations a cue acquires (i.e., the more overloaded a cue
becomes), the less efficient it becomes at retrieving thedesired memory [66]. From this perspective, some forgetting occurs because of interference present at the timeof retrieval. Similar items tend to be associated with thesame cue, so it is predominantly information that is similaror related in content that induces interference at the timeof retrieval. Cue overload may increase with time (because
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there are more opportunities for a cue to acquire new
associations). However, because this type of forgetting istied to the retrieval process itself, it does not occur in theabsence of any retrieval attempt.
Ongoing neural activity that takes place outside of
retrieval represents an alternative source of interference
that might contribute to forgetting. In particular, Wixted
has proposed that the process of forming new memories,
and associated changes in synaptic weights, may create
retroactive interference by degrading previously encoded
information [65,67]. That is, new learning changes the
hippocampal circuitry such that a retrieval cue would beless likely to reproduce the pattern of neural activity
required for successful memory retrieval. Consistent withthis hypothesis, induction of long-term potentiation (LTP)in the hippocampus, which would change synaptic weights,
weakens both previously established LTP [63] and hippocampal memory [68]. In contrast to retrieval-induced formsof forgetting such as cue overload, this type of forgetting is
indifferent to memory content: forgetting occurs regardlessof the similarity between the previously encoded and current experience (as long as both experiences engage asimilar neural circuit). Thus, this forgetting reflects a formof nonspecific retroactive interference[65], with the formation of new memories (and the corresponding changes insynaptic strength) weakening any existing memory that (i)engages the same or overlapping hippocampal circuits and(ii) has not yet been fully consolidated.
Neurogenesis and nonspecific retroactive interference
We propose that ongoing neurogenesis represents an additional distinct form of forgetting that also depends onnonspecific retroactive interference. Similar to the modification of existing synaptic connections produced by theformation of new memories, the integration of new neurons
into hippocampal circuits adds new and modifies existing
synaptic connections. The consequence of this structuralinterference is that the circuitry of the hippocampus iscontinuously evolving, and so the likelihood that a retrieval cue will be able to reinvoke the same pattern of activity
within this circuitry declines as a function of time. From
this perspective, neurogenesis may be viewed as an unrelenting decay process that impacts all hippocampus-dependent memories, regardless of content.
Accordingly, neurogenesis-induced forgetting sharessome, but not all, features of the learning-induced forgetting process described by Wixted [65]. Importantly, boththe neurogenesis-induced forgetting we describe and thelearning-induced forgetting described by Wixted are notdriven by any retrieval process and therefore proceed evenin the absence of retrieval attempt, making both processes
distinct from cue-overload-induced forgetting. Furthermore, unlike cue overload, both forms of forgetting areagnostic to memory content (i.e., the degree of similarity
between encoded and current experience is irrelevant).
Where neurogenesis- and learning-induced forgetting differ is in their respective time-courses. Synaptic strengthening following learning (i.e., cellular consolidation in the
hippocampus) begins within minutes and these changes
stabilize within hours [69]. Therefore, the form of synaptic
over-writing induced by new learning should degrade only
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labile (not fully consolidated) memories within this relatively brief time window. By contrast, remodeling of hippocampal circuits via the integration of new neurons is a
prolonged process. In the DG, several thousand new granule cells are generated daily. Each new cell projects amossy fiber that reaches the CA3 region within approximately 2 weeks, contacting 11–15 pyramidal cells [70].
Therefore, the likelihood of retrieval failure due to neurogenesis-induced remodeling increases as circuit changes
accumulate. In this way, forgetting slowly emerges overtime (most likely over days and weeks) and impacts memories beyond the initial phase of cellular consolidation.
At present, there are no direct tests of the proposed roleof neurogenesis in forgetting, with perhaps one exception.
High-frequency stimulation of perforant path induces LTPof perforant path–DG synapses. Although this form of LTP
is maintained in vivo over several days, it weakens overtime and returns to baseline after approximately 2 weeks.
Remarkably, reduction of neurogenesis during this period
sustains this form of LTP [71], suggesting that decreasing
neurogenesis reduces forgetting of LTP. These findings are
consistent with the idea that neurogenesis-induced remodeling of hippocampal circuits is incompatible with stable
information storage.
Forgetting versus consolidation
Although much of what we experience is ultimately forgotten, memories for some events persist. In the face ofcontinuous neurogenesis-dependent decay, how mightsome memories survive? In our proposal, the fate of any
memory depends on the outcome of a competition between
two opposing processes: memory trace consolidation (i.e.,the cellular and systems processes that promote stabilization of traces within hippocampal and extra-hippocampal
circuits [72–76]) and memory trace decay (i.e., ongoingneurogenesis and other related decay mechanisms [64]that weaken traces).
Consolidation and neurogenesis are regulated in multiple ways, and so the balance between these two opposing
processes is highly dynamic. For instance, memory consolidation is thought to be driven by trace reactivation that
occurs during retrieval or off-line replay (e.g., during
sleep) [77]. The reactivation of a trace is thought to leadto a proliferation of traces within the hippocampus and/or
stabilization of traces within the cortex [78,79]). In thisway, more frequently reactivated traces are strengthened.
Levels of neurogenesis are also highly regulated. For
example, a large number of factors have been identified
that robustly downregulate neurogenesis, including
stress, drugs of abuse, and diet. Conversely, other factors
promote proliferation and/or survival of new hippocampal
granule cells, including exercise, environmental enrichment, and serotonin-specific reuptake inhibitors (SSRIs)[31,39]. We predict that memories survive if consolidation
processes outstrip neurogenesis-induced decay. Sucha reactivation-based account of consolidation can bethought of as a sort of ‘use it or lose it’ (or, more accurately,
reactivate it or lose it) Darwinism for memory traces, with
only the most frequently reactivated memories prevailingand less frequently reactivated memories eventually
being over-written and forgotten. Interestingly, during

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Box 1. Forgetting during infancy
Typically, our earliest memories are from when we were 4 or 5 yearsof age. Sigmund Freud was one the first to pay attention to thisphenomenon of infantile or childhood amnesia, noting that his adultpatients rarely recalled any memories from their earliest childhood
years. Since the time of Freud, infantile amnesia has been studied
using more empirical approaches and across cultures. A near
universal pattern emerges: adults typically have no memories fromthe first three years of life, and inconsistent memory for events
between the ages of 3 and 7 [83]. Psychological theories of infantileamnesia emphasize the co-emergence of language or sense of selfidentity with the ability to form persistent memories for episodes.
However, experimental animals also exhibit pronounced forgetting
during infancy, so the phenomenon cannot be accounted for using
purely human concepts. Within the framework proposed here (andexpanded upon elsewhere [80]), the high levels of neurogenesis
during infancy are incompatible with stable memory storage, withall hippocampal memories destined to fade as they succumb toneurogenesis-induced decay. Interestingly, not all animals studied
exhibit infantile forgetting. For instance, in precocial species such as
guinea pigs, the vast majority of granule cells are generated prerather than postnatally. Therefore, during infancy, levels of neurogenesis-induced remodeling in the hippocampus are much lower
than in rats or mice. Corresponding to this more mature hippocampus, 5-day-old infant guinea pigs are able to acquire and retain
spatial discrimination memories as well as adult guinea pigs can[84], and therefore do not display infantile amnesia.

infancy, episodic memories typically do not survive, aphenomenon known as infantile or childhood amnesia.
It has been proposed that the high rates of neurogenesis
during this developmental stage are incompatible withstable memory storage (Box 1) [80].
Summary and predictions
Previous studies have examined the impact of manipulating levels of hippocampal neurogenesis on future memory
formation. By contrast, here we focused on how the integration of newborn neurons into hippocampal circuits
Retrograde impact(Old memories)

impacts existing memories, and therefore provided a
new perspective on how ongoing neurogenesis impacts
hippocampal memory function. We propose that ongoingneurogenesis produces an unrelenting form of retroactive
interference that is indifferent to memory content. Thishypothesis, founded mainly on anatomical and neurocomputational evidence, provides the basis for several behavioral predictions (Figure 2):
 In adult animals, increasing hippocampal neurogenesis
should weaken existing hippocampal memories. Morespecifically, we predict that if neurogenesis is transiently increased after learning, the probability of successful
retrieval will be reduced when animals are exposed to apreviously effective retrieval cue. Forgetting might beeven more pronounced when the retrieval cue is partial
or impoverished (i.e., pattern completion should be
impaired).
 Conversely, decreasing hippocampal neurogenesis may
have a protective effect on existing hippocampal
memories. More specifically, the probability of successful retrieval will be increased when animals are exposed
to a previously effective retrieval cue. This beneficial
effect may be more pronounced when the retrieval cue ispartial or impoverished (i.e., pattern completion should
be facilitated).
In this review, we focused on the retrograde effects ofchanging levels of neurogenesis. However, our model also
makes predictions in the anterograde direction.
 When learning of new information conflicts with stored
information, acquisition is slowed. Therefore, to theextent that we predict that increasing neurogenesis in
adult animals weakens existing memories, it should
also reduce this form of proactive interference. In otherwords, learning new information that conflicts withstored information may be facilitated in adult animals if

Experimental
manipulaon ofneurogenesis

Anterograde impact(New memory formaon)

Reduced paern compleon(More forgeng)

Reduced proacve interference(Facilitated acquision of conﬂicng
informaon)

Increased paern compleon(Less forgeng)

Increased proacve interference(Inhibited acquision of conﬂicng
informaon)
TRENDS in Neurosciences

Figure 2. Model predictions. Our model predicts that experimental manipulation of neurogenesis impacts both old memories (retrograde effects) and new memory
formation (anterograde effects). By remodeling hippocampal circuits, increasing neurogenesis is predicted to reduce the probability of successful retrieval of oldmemories (i.e., reduce the likelihood of successful pattern completion). At the same time, insofar as increasing neurogenesis induces forgetting of existing memories,
acquisition of new information that conflicts with previously stored information will be facilitated in adult animals if neurogenesis is transiently increased after original
learning (i.e., proactive interference will be reduced). Conversely, decreasing neurogenesis is predicted to increase the probability of successful retrieval of oldmemories (i.e., increase the likelihood of successful pattern completion). At the same time, insofar as decreasing neurogenesis protects existing memories, acquisitionof new information that conflicts with previously stored information will be impeded in adult animals if neurogenesis is transiently reduced after original learning (i.e.,
proactive interference will be increased).

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Opinionneurogenesis is transiently increased after original
learning.
 Conversely, to the extent that we predict that decreasing
neurogenesis in adult animals protects existing memories, it should also increase this form of proactive
interference. In other words, learning new informationthat conflicts with stored information should be impededin adult animals if neurogenesis is transiently decreased
after original learning. From this perspective, although
the retrograde effects are agnostic to memory content(similarity), the consequences of these retrograde effects
on new learning are sensitive to content (i.e., conflict).
There has long been an appreciation that memory decay
or clearance may be critical for normal healthy memory
function [81,82]. This idea is motivated by the recognition
that there are probably costs associated with remembering. These costs may include the energy expenditure required to maintain information storage over large spans oftime, the consumption of finite storage space, and potential
reductions in the efficiency or reliability of retrieval thatmight emerge with the proliferation of memory traces.
Here we identify neurogenesis as a key regulator of memory decay in the hippocampus. Because forgetting or clearing of some types of information is beneficial, we argue thatneurogenesis is indeed ‘good’ for memory, even with respect to the fate of previously stored information.
Acknowledgments
This project was supported by Canadian Institutes of Health Research(CIHR) grants to P.W.F. (MOP-86762), S.K. (MOP-93644), and S.A.J.
(MOP-74650) and by a ‘Chase an Idea in Paediatric Neuroscience’ grantfrom The Centre for Brain and Behaviour at the Hospital for Sick
Children. We thank Leonardo Restivo for artwork.

References
1 Altman, J. (1962) Are new neurons formed in the brains of adultmammals? Science 135, 1127–1128
2 Altman, J. (1963) Autoradiographic investigation of cell proliferation in
the brains of rats and cats. Anat. Rec. 145, 573–591
3 Altman, J. and Das, G.D. (1965) Autoradiographic and histologicalevidence of postnatal hippocampal neurogenesis in rats. J. Comp.
Neurol. 124, 319–335
4 Cameron, H.A. et al. (1993) Differentiation of newly born neurons andglia in the dentate gyrus of the adult rat. Neuroscience 56, 337–344
5 Arruda-Carvalho, M. et al. (2011) Posttraining ablation of adultgenerated neurons degrades previously acquired memories. J.
Neurosci. 31, 15113–15127
6 Deng, W. et al. (2009) Adult-born hippocampal dentate granule cells
undergoing maturation modulate learning and memory in the brain.
J. Neurosci. 29, 13532–13542
7 Yu, T.S. et al. (2008) Traumatic brain injury-induced hippocampal
neurogenesis requires activation of early nestin-expressing
progenitors. J. Neurosci. 28, 12901–12912
8 Gu, Y. et al. (2012) Optical controlling reveals time-dependent roles for
adult-born dentate granule cells. Nat. Neurosci. 15, 1700–1706
9 Nakashiba, T. et al. (2012) Young dentate granule cells mediate patternseparation, whereas old granule cells facilitate pattern completion. Cell
149, 188–201
10 Deng, W. et al. (2010) New neurons and new memories: how does adulthippocampal neurogenesis affect learning and memory? Nat. Rev.
Neurosci. 11, 339–350
11 Shors, T.J. et al. (2001) Neurogenesis in the adult is involved in theformation of trace memories. Nature 410, 372–376
12 Martinez-Canabal, A. et al. (2013) Age-dependent effects ofhippocampal neurogenesis suppression on spatial learning.
Hippocampus 23, 66–74
6

Trends in Neurosciences xxx xxxx, Vol. xxx, No. x

13 Ko, H.G. et al. (2009) Effect of ablated hippocampal neurogenesis on theformation and extinction of contextual fear memory. Mol. Brain 2, 1
14 Drew, M.R. et al. (2010) Arrest of adult hippocampal neurogenesis inmice impairs single- but not multiple-trial contextual fear
conditioning. Behav. Neurosci. 124, 446–454
15 Shors, T.J. et al. (2002) Neurogenesis may relate to some but not all
types of hippocampal-dependent learning. Hippocampus 12, 578–584
16 Sahay, A. et al. (2011) Pattern separation: a common function for new
neurons in hippocampus and olfactory bulb. Neuron 70, 582–588
17 Eichenbaum, H. (2004) Hippocampus: cognitive processes andneural representations that underlie declarative memory. Neuron
44, 109–120
18 Yassa, M.A. and Stark, C.E. (2011) Pattern separation in the
hippocampus. Trends Neurosci. 34, 515–525
19 Marr, D. (1971) Simple memory: a theory for archicortex. Philos. Trans.
R. Soc. Lond. B: Biol. Sci. 262, 23–81
20 Treves, A. and Rolls, E.T. (1994) Computational analysis of the role ofthe hippocampus in memory. Hippocampus 4, 374–391
21 Leutgeb, J.K. et al. (2007) Pattern separation in the dentate gyrus andCA3 of the hippocampus. Science 315, 961–966
22 Leutgeb, S. et al. (2004) Distinct ensemble codes in hippocampal areas
CA3 and CA1. Science 305, 1295–1298
23 McHugh, T.J. et al. (2007) Dentate gyrus NMDA receptors mediate
rapid pattern separation in the hippocampal network. Science 317,
94–99
24 Vazdarjanova, A. and Guzowski, J.F. (2004) Differences inhippocampal neuronal population responses to modifications of anenvironmental context: evidence for distinct, yet complementary,functions of CA3 and CA1 ensembles. J. Neurosci. 24, 6489–6496
25 Niibori, Y. et al. (2012) Suppression of adult neurogenesis impairs
population coding of similar contexts in hippocampal CA3 region. Nat.
Commun. 3, 1253
26 Clelland, C.D. et al. (2009) A functional role for adult hippocampal
neurogenesis in spatial pattern separation. Science 325, 210–213
27 Kheirbek, M.A. et al. (2012) NR2B-dependent plasticity of adult-born
granule cells is necessary for context discrimination. J. Neurosci. 32,
8696–8702
28 Sahay, A. et al. (2011) Increasing adult hippocampal neurogenesis issufficient to improve pattern separation. Nature 472, 466–470
29 Tronel, S. et al. (2012) Adult-born neurons are necessary for extended
contextual discrimination. Hippocampus 22, 292–298
30 Winocur, G. et al. (2012) Adult hippocampal neurogenesis and memory
interference. Behav. Brain Res. 227, 464–469
31 Zhao, C. et al. (2008) Mechanisms and functional implications of adultneurogenesis. Cell 132, 645–660
32 Ge, S. et al. (2007) A critical period for enhanced synaptic plasticity innewly generated neurons of the adult brain. Neuron 54, 559–566
33 Mongiat, L.A. et al. (2009) Reliable activation of immature neurons in
the adult hippocampus. PLoS ONE 4, e5320
34 Laplagne, D.A. et al. (2006) Functional convergence of neurons
generated in the developing and adult hippocampus. PLoS Biol. 4, e409
35 Marin-Burgin, A. et al. (2012) Unique processing during a period ofhigh excitation/inhibition balance in adult-born neurons. Science 335,
1238–1242
36 Toni, N. et al. (2008) Neurons born in the adult dentate gyrus form
functional synapses with target cells. Nat. Neurosci. 11, 901–907
37 Toni, N. et al. (2007) Synapse formation on neurons born in the adulthippocampus. Nat. Neurosci. 10, 727–734
38 Yasuda, M. et al. (2011) Multiple forms of activity-dependentcompetition refine hippocampal circuits in vivo. Neuron 70, 1128–1142
39 Ming, G.L. and Song, H. (2005) Adult neurogenesis in the mammalian
central nervous system. Annu. Rev. Neurosci. 28, 223–250
40 Schmidt-Hieber, C. et al. (2004) Enhanced synaptic plasticity in newly
generated granule cells of the adult hippocampus. Nature 429, 184–187
41 Karmarkar, U.R. and Buonomano, D.V. (2006) Different forms of
homeostatic plasticity are engaged with distinct temporal profiles.
Eur. J. Neurosci. 23, 1575–1584
42 Wilhelm, J.C. et al. (2009) Compensatory changes in cellular
excitability, not synaptic scaling, contribute to homeostatic
recovery of embryonic network activity. Proc. Natl. Acad. Sci.
U.S.A. 106, 6760–6765
43 Desai, N.S. et al. (1999) Plasticity in the intrinsic excitability of corticalpyramidal neurons. Nat. Neurosci. 2, 515–520

TINS-992; No. of Pages 7

Opinion
44 Golowasch, J. et al. (1999) Activity-dependent regulation of potassium
currents in an identified neuron of the stomatogastric ganglion of the
crab Cancer borealis. J. Neurosci. 19, RC33
45 Brickley, S.G. et al. (2001) Adaptive regulation of neuronal excitability
by a voltage-independent potassium conductance. Nature 409, 88–92
46 Turrigiano, G.G. (2008) The self-tuning neuron: synaptic scaling of
excitatory synapses. Cell 135, 422–435
47 Frohlich, F. et al. (2008) Pathological effect of homeostatic synaptic
scaling on network dynamics in diseases of the cortex. J. Neurosci. 28,
1709–1720
48 Meltzer, L.A. et al. (2005) A role for circuit homeostasis in adultneurogenesis. Trends Neurosci. 28, 653–660
49 Deisseroth, K. et al. (2004) Excitation-neurogenesis coupling in adultneural stem/progenitor cells. Neuron 42, 535–552
50 Weisz, V.I. and Argibay, P.F. (2012) Neurogenesis interferes with theretrieval of remote memories: forgetting in neurocomputational terms.
Cognition 125, 13–25
51 Chambers, R.A. et al. (2004) Simulated apoptosis/neurogenesis
regulates learning and memory capabilities of adaptive neuralnetworks. Neuropsychopharmacology 29, 747–758
52 Wiskott, L. et al. (2006) A functional hypothesis for adult hippocampal
neurogenesis: avoidance of catastrophic interference in the dentate
gyrus. Hippocampus 16, 329–343
53 Leuner, B. et al. (2004) Learning enhances the survival of new neurons
beyond the time when the hippocampus is required for memory. J.
Neurosci. 24, 7477–7481
54 Tulving, E. (1974) Cue-dependent forgetting. Am. Sci. 62, 74–82
55 Wixted, J.T. (2007) Forgetting: it’s not just the opposite ofremembering. In Science of Memory: Concepts (Roediger, H.L. et al.,eds), pp. 329–338, Oxford University Press
56 Anderson, M.C. et al. (1994) Remembering can cause forgetting:retrieval dynamics in long-term memory. J. Exp. Psychol. Learn.
Mem. Cogn. 20, 1063–1087
57 Liu, X. et al. (2012) Optogenetic stimulation of a hippocampal engram
activates fear memory recall. Nature 484, 381–385
58 Reijmers, L.G. et al. (2007) Localization of a stable neural correlate of
associative memory. Science 317, 1230–1233
59 Richards, B.A. and Frankland, P.W. (2013) The conjunctive trace.
Hippocampus 23, 207–212
60 Danker, J.F. and Anderson, J.R. (2010) The ghosts of brain states past:
remembering reactivates the brain regions engaged during encoding.
Psychol. Bull. 136, 87–102
61 Redondo, R.L. and Morris, R.G. (2011) Making memories last: thesynaptic tagging and capture hypothesis. Nat. Rev. Neurosci. 12, 17–30
62 Shuai, Y. et al. (2010) Forgetting is regulated through Rac activity in
Drosophila. Cell 140, 579–589
63 Villarreal, D.M. et al. (2002) NMDA receptor antagonists sustain LTP
and spatial memory: active processes mediate LTP decay. Nat.
Neurosci. 5, 48–52

Trends in Neurosciences xxx xxxx, Vol. xxx, No. x

64 Hardt, O. et al. (2013) Decay happens: the role of active forgetting inmemory. Trends Cogn. Sci. 17, 111–120
65 Wixted, J.T. (2004) The psychology and neuroscience of forgetting.
Annu. Rev. Psychol. 55, 235–269
66 Watkins, O.C. and Watkins, M.J. (1975) Buildup of proactive
inhibition as a cue overload. J. Exp. Psychol. Hum. Learn. Mem. 1,
442–452
67 Mednick, S.C. et al. (2011) An opportunistic theory of cellular andsystems consolidation. Trends Neurosci. 34, 504–514
68 Brun, V.H. et al. (2001) Retrograde amnesia for spatial memory
induced by NMDA receptor-mediated long-term potentiation. J.
Neurosci. 21, 356–362
69 Mayford, M. et al. (2012) Synapses and memory storage. Cold Spring
Harb. Perspect. Biol. 4, 1–18
70 Acsady, L. et al. (1998) GABAergic cells are the major postsynaptic
targets of mossy fibers in the rat hippocampus. J. Neurosci. 18,
3386–3403
71 Kitamura, T. et al. (2009) Adult neurogenesis modulates the
hippocampus-dependent period of associative fear memory. Cell 139,
814–827
72 Wang, S.H. and Morris, R.G. (2010) Hippocampal-neocorticalinteractions in memory formation, consolidation, and reconsolidation.
Annu. Rev. Psychol. 61, 49–79 C41–C44
73 Frankland, P.W. and Bontempi, B. (2005) The organization of recent
and remote memories. Nat. Rev. Neurosci. 6, 119–130
74 Squire, L.R. and Alvarez, P. (1995) Retrograde amnesia and memory
consolidation: a neurobiological perspective. Curr. Opin. Neurobiol. 5,
169–177
75 Nadel, L. and Moscovitch, M. (1997) Memory consolidation,
retrograde amnesia and the hippocampal complex. Curr. Opin.
Neurobiol. 7, 217–227
76 Dudai, Y. (2004) The neurobiology of consolidations, or, how stable isthe engram? Annu. Rev. Psychol. 55, 51–86
77 Diekelmann, S. and Born, J. (2010) The memory function of sleep. Nat.
Rev. Neurosci. 11, 114–126
78 Winocur, G. and Moscovitch, M. (2011) Memory transformation andsystems consolidation. J. Int. Neuropsychol. Soc. 17, 766–780
79 Squire, L.R. and Bayley, P.J. (2007) The neuroscience of remotememory. Curr. Opin. Neurobiol. 17, 185–196
80 Josselyn, S.A. and Frankland, P.W. (2012) Infantile amnesia: aneurogenic hypothesis. Learn. Mem. 19, 423–433
81 Ribot, T. (1882) Diseases of Memory. Appleton
82 James, W. (1898) The Principle of Psychology (Vol. 1), Holt
83 Rubin, D.C. and Schulkind, M.D. (1997) Distribution of important andword-cued autobiographical memories in 20-, 35-, and 70-year-old
adults. Psychol. Aging 12, 524–535
84 Campbell, B.A. et al. (1974) Species differences in ontogeny of memory:indirect support for neural maturation as a determinant of forgetting.
J. Comp. Physiol. Psychol. 87, 193–202

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