New neurons and new memories: How does adult hippocampal neurogenesis affect learning and memory?

Abstract

The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time.

Full text

The discovery of neurogenesis in the brain of adult mam-
mals overturned the long-held dogma that the adult brain
has no capacity for generating new neurons1. Although
the idea met with scepticism for a long time, it is now
generally accepted that new neurons are continuously
added in discrete regions of the brain throughout adult
life in various species, including humans2. Adult neuro-
genesis, originating from neural progenitor cells (NPCs),
has been consistently observed in two regions of the
adult brain: the subventricular zone (SVZ) of the lateral
ventricle and the subgranular zone (SGZ) of the dentate
gyrus in the hippocampus. Neurons born in the SVZ
migrate through the rostral migratory stream and
become granule neurons and periglomerular neurons of
the olfactory bulb. Neurons born in the SGZ differentiate
and integrate into the local neural network as granule
cells of the dentate gyrus.
The adult-born neurons can be identified by many
approaches, such as by incorporation of nucleotide ana-
logues (for example, bromodeoxyuridine (BrdU)), by
virus-mediated labelling and by genetically engineered
reporter genes3–5. Research in the past decade has led to a
greater understanding of the processes involved in adult
neurogenesis, including the proliferation of NPCs, the
fate determination of NPC progenies, the differentiation,
morphogenesis and maturation of adult-born neurons,
and the eventual integration of adult-born neurons into
the neural networks of both the olfactory bulb and the
hippocampus6. Furthermore, each of these processes is
subject to regulation by numerous intrinsic and extrinsic
factors7. Despite this progress, many questions regarding
the functional importance of adult neurogenesis remain
unanswered. However, the putative functions of adult-
born olfactory neurons are being revealed by many stud-
ies that are in progress8–11, and recent research has shed
light on the role of adult hippocampal neurogenesis in
hippocampus-mediated functions.
In the adult brain, the hippocampus (FIG. 1) is a cru-
cial structure for the formation of certain types of mem-
ory, such as episodic memory and spatial memory12.
Through its interactions with brain structures associ-
ated with emotion, the hippocampus is also implicated
in emotional behaviour13. Does the integration of new
neurons into the existing hippocampal circuit influence
hippocampus-related behaviours? If so, how? Correlations
between the rate of adult hippocampal neurogenesis and
the emotional status of animals have been shown in sev-
eral studies. However, there is no direct evidence that
adult neurogenesis is required for emotional regulation,
although it can mediate the efficacy of antidepressants
under certain conditions13,14. By contrast, our under-
standing of the functions of hippocampal neurogenesis
in learning and memory has advanced considerably in
the past few years. In this Review, we briefly describe
Laboratory of Genetics, The
Salk Institute for Biological
Studies, 10010 North Torrey
Pines Road, La Jolla,
California 92037, USA.
*These authors contributed
equally to this work.
Correspondence to F.H.G.
e-mail: gage@salk.edu
doi:10.1038/nrn2822
Published online
31 March 2010
New neurons and new memories: how
does adult hippocampal neurogenesis
affect learning and memory?
Wei Deng*, James B. Aimone* and Fred H. Gage
Abstract | The integration of adult-born neurons into the circuitry of the adult hippocampus
suggests an important role for adult hippocampal neurogenesis in learning and memory, but
its specific function in these processes has remained elusive. In this article, we summarize
recent progress in this area, including advances based on behavioural studies and insights
provided by computational modelling. Increasingly, evidence suggests that newborn
neurons might be involved in hippocampal functions that are particularly dependent on the
dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different
maturation stages may make distinct contributions to learning and memory. In particular,
computational studies suggest that, before newborn neurons are fully mature, they might
function as a pattern integrator by introducing a degree of similarity to the encoding of
events that occur closely in time.
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AOP, published online 31 March 2010; doi:10.1038/nrn2822
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Nature Reviews | Neuroscience
a
b
I
II
III
V
IV
VI
Dentate gyrus
CA3
EC
PP
PP
TA
Mossy fibres
Hippocampus
Mossy cells Interneurons
CA1
Schaffer collaterals
CA3
CA1
Temporoammonic
pathway
Mossy fibres Dentate gyrus
Perforant
pathway
Schaffer
collaterals
LPP
MPP
II
III
EC
Filopodia
Thin, long and highly motile
protrusions that are the
predecessors of spines in an
early stage of spine formation.
the basic processes involved in adult hippocampal
neurogenesis and consider how these processes are reg-
ulated by neural activity and how adult-born neurons
respond to environmental and behavioural stimuli. We
next examine the potential role of hippocampal neuro-
genesis in learning and memory as proposed by vari-
ous computational models and based on recent findings
from behavioural studies (see Supplementary informa-
tion S1 (table)). We discuss these observations in the
context of the functions of the hippocampus, and of the
dentate gyrus in particular.
Maturation of adult-born DGCs
Adult neurogenesis begins with the proliferation of
NPCs in the SGZ (FIG. 2). Most progeny of NPCs differ-
entiate into dentate granule cells (DGCs), whereas a
small population become glia15. The newly born DGCs
bear little resemblance to their mature counterparts and
must undergo a lengthy process of morphological
and physiological maturation16. The kinetics of DGC
maturation are species dependent17. Here, we discuss
the maturation of adult-born DGCs in mice because
most of the relevant studies have been carried out in
this species.
During the first week after birth, after committing
to the neuronal lineage, the adult-born DGCs undergo
their initial differentiation and migrate a short distance
into the inner granule cell layer of the dentate gyrus,
where they extend limited cellular processes but do not
seem to be synaptically integrated into the network.
Notably, these cells are tonically activated by ambient
GABA (γ-aminobutyric acid)16,18,19.
During the second week after birth, the adult-born
DGCs become more neuron-like: they grow polarized
processes, with dendrites extending towards the molec-
ular layer and axons (that is, mossy fibres) growing
through the hilus towards CA3 (REFS 16,20) (FIG. 2).
Nevertheless, these immature DGCs are still consider-
ably different from mature DGCs. For example, they
have a higher membrane resistance and different firing
properties18. Moreover, at this stage, the adult-born
DGCs lack glutamatergic input, which is consistent with
the absence of dendritic spines in the molecular layer (in
which the glutamatergic fibres are located) at this time16,18
(FIG. 2). However, these immature DGCs receive synaptic
GABAergic input, presumably from local interneurons,
and the resulting responses have slow rising and decay
kinetics18,19,21,22.
The GABAergic input results in neuronal depolariza-
tion owing to the presence of the Na+–K+–2Cl– cotrans-
porter, solute carrier family 12 member 2 (SLC12A2;
also known as NKCC1) on the DGC membrane18,19.
The GABA-mediated activity seems to be important for
the survival and maturation of adult-born DGCs: knock-
down of SLC12A2 by RNA interference reduced the
number of adult-born DGCs surviving the second week
after birth23, caused defects in the formation of GABA-
and glutamate-mediated synapses and reduced dendrite
arborizations19. By contrast, administration of a GABA
receptor agonist promotes dendrite growth of adult-born
DGCs19. The GABA-dependent depolarization is medi-
ated by cyclic AMP response element-binding protein
(CREB)23. The knockdown of SLC12A2 results in loss
of CREB phosphorylation (the active form of CREB) in
adult-born DGCs, and forced activation of CREB can
normalize the impaired maturation of newborn DGCs
caused by SLC12A2 knockdown23.
During the third week after birth, adult-born DGCs
start to form afferent and efferent connections with the
local neuronal network (FIG. 2). By approximately day 16,
spines begin to appear on the dendrites of adult-born
DGCs, forming synapses with the afferent axon fibres
in the perforant pathway that come from the entorhinal
cortex16,24. Initially, filopodia are frequently present on
dendrites24. The majority of the filopodia on the adult-
born DGCs target axon boutons that already synapse
with existing spines on other DGCs by forming multiple
synaptic boutons, suggesting that network integration
Figure 1 | The neural circuitry in the rodent hippocampus. a | An illustration of the
hippocampal circuitry. b | Diagram of the hippocampal neural network. The traditional
excitatory trisynaptic pathway (entorhinal cortex (EC)–dentate gyrus–CA3–CA1–EC) is
depicted by solid arrows. The axons of layer II neurons in the entorhinal cortex project to
the dentate gyrus through the perforant pathway (PP), including the lateral perforant
pathway (LPP) and medial perforant pathway (MPP). The dentate gyrus sends projections
to the pyramidal cells in CA3 through mossy fibres. CA3 pyramidal neurons relay the
information to CA1 pyramidal neurons through Schaffer collaterals. CA1 pyramidal
neurons send back-projections into deep-layer neurons of the EC. CA3 also receives
direct projections from EC layer II neurons through the PP. CA1 receives direct input from
EC layer III neurons through the temporoammonic pathway (TA). The dentate granule cells
also project to the mossy cells in the hilus and hilar interneurons, which send excitatory
and inhibitory projections, respectively, back to the granule cells.
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0 weeks ~1 week
Hilus
Glu
~3 weeks ~2 months
–
–
–
–
GABA GABA
+Glu
+
GABA
Neural progenitor cells
GCL
MOL
GABA +
Nature Reviews | Neuroscience
Existing
bouton
Existing
spine
Filopodium
from newborn
DGC
Target dendrite
of CA3
pyramidal cell
Target axonal
bouton of
EC neuron
Bouton from
newborn DGC
Thorny
excrescences
Perforant
pathway
CA3
of the adult-born DGCs is influenced by local synaptic
activity24. Similarly, the mossy fibre boutons of adult-
born DGCs initially form synapses either with the den-
dritic shaft of CA3 pyramidal neurons in a region near
existing thorny excrescences or directly with existing
thorny excrescences that already contain a bouton25,26.
This suggests that efferent synapse formation of adult-
born DGCs can also be affected by existing synapses.
Thus, the development of both afferent and efferent
synapses from newly generated DGCs seems to involve
targeting to pre-existing synaptic partners, which sug-
gests a role for circuit activity in the integration of adult-
born DGCs.
The timing of synaptic integration coincides with the
transition of GABAergic input from being excitatory to
being inhibitory and with the onset of glutamatergic
synaptic inputs18,19. The NMDA (N-methyl--aspartate)
receptor is a glutamate receptor that has been implicated
in neuronal development and plasticity27. Between 2
and 3 weeks of age, the survival of adult-born DGCs
depends on NMDA-receptor mediated cell-autonomous
activity18,19,28. The adult-born DGCs at this stage still
have characteristics — such as high membrane resist-
ance and high resting potentials18 — that could contrib-
ute to increased excitability29,30, although their action
potentials have kinetic characteristics similar to those
of mature DGCs18.
Around 4–6 weeks of age, together with the gradual
maturation of their physiology and connectivity16,18,31,
the adult-born DGCs exhibit stronger synaptic plasticity
than mature DGCs, as indicated by their lower threshold
for the induction of long-term potentiation (LTP) and
their higher LTP amplitude29. This enhanced plastic-
ity is mediated by NMDA receptor subunit NR2B29. A
transcription factor, krupple-like factor 9, seems to be
essential for the survival of adult-born DGCs during this
time32. Although the structural modification of dendritic
spines and axonal boutons continues to occur as the
adult-born DGCs become older16,24,25, the basic physi-
ological properties and synaptic plasticity at 8 weeks of
age are indistinguishable from those of mature DGCs.
As discussed below, the unique physiological character-
istics of adult-born DGCs before 6 weeks of age enable
these neurons to be discretely regulated by network
activity and possibly to make distinct contributions to
learning and memory.
Regulation of adult neurogenesis
One of the implications of a role for adult neurogen-
esis in learning and memory is that neurogenesis can
be regulated by numerous factors associated with an
animal’s behavioural and cognitive states. Indeed,
an animal’s experiences, including hippocampus-
dependent learning, environmental enrichment and
voluntary running, can affect the rate of neurogenesis.
These experiences, which are associated with enhanced
cognition, presumably do so by stimulating the hippoc-
ampal neural network.
Hippocampus-dependent learning is one of the
major regulators of hippocampal neurogenesis33. For
example, learning of hippocampus-dependent tasks
Figure 2 | Adult hippocampal neurogenesis. The proliferation of neural progenitor cells
(NPCs) with two different morphologies gives rise to adult-born dentate granule
cells (DGCs) (shown in green). The fate-committed, adult-born DGCs undergo several
stages of development, with gradual changes in morphological and physiological
characteristics. About 1 week after birth, the adult-born DGC extends its dendrite into
the granule cell layer (GCL) and molecular layer (MOL) and projects the axon into the
hilus toward CA3. The DGC receives excitatory GABA (γ-aminobutyric acid)-ergic input,
presumably from local interneurons (shown as blue cells). During the third week after
birth, the DGC receives glutamatergic input (Glu) from the perforant pathway. At this
stage, the GABA input changes from being excitatory to being inhibitory19. Both efferent
and afferent synapses of the adult-born DGCs begin to form around this time24-26.
At around 2 months of age, the basic structural and physiological properties of the
adult-born DGCs are indistinguishable from those of mature DGCs. The inset panels
illustrate the competitive nature of synapse formation24-25. Left inset: a small bouton
(shown in green) from the axon of an adult-born DGC contacts the dendritic shaft (shown
in grey) of a CA3 pyramidal neuron at a site near the thorny excrescences that contact an
existing axonal bouton (shown in yellow). During the subsequent development of the
new synapse, the bouton from the newborn DGC either replaces the existing axonal
bouton or forms a new thorny excrescence nearby, or retracts. Right inset: the filopodium
(shown in green) from an adult-born DGC dendrite extends to an axonal bouton (shown
in red) that is associated with another spine (shown in yellow), which leads to
the eventual formation of either a monosynaptic bouton targeting spines from the
adult-born DGC or a multisynaptic bouton, or leads to retraction.
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Thorny excrescences
The complex spines on the
dendrites of CA3 pyramidal
neurons in the stratum
lucidum. These spines form
multiple synapses with mossy
fibres of dentate granule cells.
Morris water maze (MWM)
A spatial learning paradigm in
which an animal must learn a
fixed location of a platform
using distal spatial cues.
Animals are released from a
variable start point in each trial
to encourage them to use a
spatial strategy to solve the
task.
BrdU birth-dating
The thymidine analogue
bromodeoxyuridine (BrdU) is
injected into adult animals and
incorporated into cells
synthesizing DNA in
preparation for division, which
are visualized using immuno-
cytochemistry. Because the
in vivo half-life of BrdU is
~2 hours, it only labels
dividing cells in a short time
window.
but not hippocampus-independent tasks increases the
number of adult-born DGCs at around 1 week of age33–36.
However, proliferation of NPCs in the SGZ immediately
after learning is not affected by learning33. Similarly,
hippocampal neurogenesis is exquisitely regulated by
spatial navigation learning in the Morris water maze
(MWM). For example, learning in the MWM promotes
the survival of DGCs that were born 7 days before the
onset of MWM training and, at the same time, induces
apoptosis in DGCs that were born 3 days before37. Of
note, at the onset of MWM training, DGCs born 1 week
earlier have begun to form GABAergic synapses with
the local network and enter the hyper-excitable stage
during MWM learning (see above), and can therefore
potentially be influenced by learning or recruited to
memories. Furthermore, the late phase of MWM train-
ing, when animals show little improvement in per-
formance, is associated with increased apoptosis in the
dentate gyrus and a decrease in the number of DGCs
that were born during the early phase of training37,38.
At the same time, such asymptotic training induces the
proliferation of NPCs in the SGZ37,38. Blocking apopto-
sis in the late phase of learning prevents the enhanced
survival of DGCs born 7 days before MWM training
and the induction of NPC proliferation, and impairs
the performance in the MWM37, suggesting that learn-
ing regulates these events interdependently. Together,
these findings suggest that learning selectively adds and
removes adult-born DGCs according to their maturity
and functional relevance.
Living in an enriched environment, which presum-
ably provides a larger number of opportunities for learn-
ing than standard laboratory housing39, can also enhance
hippocampal neurogenesis by increasing the survival of
adult-born DGCs40. Environmental enrichment for as
little as 1 week is sufficient to increase the survival of the
adult-born DGCs that are younger than 3 weeks of age
but not of older ones, suggesting that the environmental-
enrichment effect is dependent on the maturation state of
adult-born DGCs41. In addition, environmental enrich-
ment improves performance in learning and memory
tasks such as the MWM and object recognition tests40,42.
However, it is currently debated whether hippocampal
neurogenesis is necessary for these behavioural effects
of environmental enrichment42,43.
Increasing evidence suggests that physical exercise
not only improves the physical health of individuals but
also improves cognition and other brain functions44,45.
In rodents, voluntary running significantly increases
the proliferation of NPCs in the SGZ of both young
and aged animals46,47. Moreover, voluntary running
for about 3 weeks following BrdU birth-dating enhances
the survival of BrdU-labelled adult-born DGCs48,49. In
addition, voluntary running increases the amplitude of
LTP in the dentate gyrus and improves the performance
of animals in the MWM47,50, indicating that increased
neurogenesis correlates with increased network activity
and improved cognition. However, whether increased
neurogenesis is responsible for cognitive improve-
ment remains to be tested. Voluntary running also
interacts with other stimuli, such as stress and social
interactions, to regulate neurogenesis49,51. Although
physical exercise can induce angiogenesis and expression
of neurotrophic factors such as brain-derived neuro-
trophic factor in the brain45, the molecular mechanisms
responsible for exercise-induced neurogenesis remain
undetermined.
Adult hippocampal neurogenesis can also be mod-
ulated by artificial induction of network activity. For
example, induction of LTP in the dentate gyrus by
high-frequency stimulation of the perforant pathway
can increase the proliferation of NPCs in the SGZ and
enhance the survival of adult-born DGCs at 1–2 weeks
of age52,53. Electroconvulsive shock, which induces a brief
seizure in the brain and has therapeutic effects in many
emotional disorders, also increases both the prolifera-
tion of NPCs and neurogenesis in the SGZ54,55.
Finally, adult hippocampal neurogenesis and neuronal
integration can be affected by aberrant circuit activity
under pathological conditions, as observed in human
patients and animal models of neurological disorders
(reviewed in REF. 6). For example, a drug-induced sei-
zure increases NPC proliferation56, causes morphologi-
cal abnormalities in adult-born DGCs57, induces ectopic
migration of adult-born DGCs58 and accelerates the inte-
gration of adult-born DGCs59. It is currently unknown
whether the altered hippocampal neurogenesis further
exacerbates the pathological conditions.
Responsiveness of adult-born DGCs
If behavioural stimuli and network activity can modulate
the survival and integration of adult-born DGCs, how do
adult-born DGCs respond to such stimuli and activity?
This question is generally addressed by examining the
expression of immediate early genes (IEGs). IEGs, such
as FBJ osteosarcoma oncogene (Fos), activity regulated
cytoskeletal-associated protein (Arc), early growth
response 1 (Egr1; also known as Zif268), and Homer1A,
play key parts in regulating synaptic plasticity. Their
expression is tightly coupled to neuronal activity associ-
ated with learning and memory and is widely used to
study population activity of neurons in various brain
regions60. Using BrdU to birth-date adult-born DGCs, it
was found that neuronal activity (whether at physiologi-
cal or aberrant levels) does not induce IEG expression
in adult-born DGCs until they reach a certain stage of
maturation — around 3–4 weeks of age in mice17,61 and
about 2 weeks of age in rats17,52.
Neural stimuli seem to preferentially activate adult-
born DGCs. Compared with their mature counterparts,
a higher proportion of 5-month-old adult-born DGCs
expressed IEGs when rats were allowed to encounter
and explore a novel environment62. Moreover, the expe-
riences an animal undergoes when a population of adult-
born DGCs are young may influence the responsiveness
of these neurons later on. For example, MWM learning
by a mouse when a set of adult-born DGCs was at least
4–6 weeks of age led to preferential activation of these
cells during memory retrieval in the MWM when the
DGCs were 10 weeks old63. Interestingly, this time frame
coincides with the stage of enhanced synaptic plasticity
of adult-born DGCs.
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CA1
CA3DG
Associative memories formed in CA3 do not
interfere with one another
Overlapping EC inputs are encoded separately by the DG
Sparse coding
A type of neural code in which
each event is encoded by the
strong activation of a small set
of neurons.
Furthermore, it has been suggested that the experiences
of a mouse when adult-born DGCs are about 1–3 weeks
of age — a stage when newly generated DGCs are not
capable of expressing IEGs — can enhance the experi-
ence-specific responsiveness of these DGCs when they are
older41,64. In one study, mice were exposed to an enriched
environment when BrdU-labelled adult-born DGCs were
about 1–2.5 weeks of age; the mice were subsequently
exposed to different experiences and, 6 weeks after BrdU
labelling, the expression of IEGs in BrdU-labelled DGCs
was examined41. A higher proportion of BrdU-labelled
adult-born DGCs responded to re-exposure to the
enriched environment than to MWM training41.
Finally, activation of adult-born DGCs by memory
retrieval tasks seems to depend on cognitive demand64. In
one study, mice were trained in the MWM when BrdU-
labelled adult-born DGCs were 9 days old; 30 days later,
they were subjected to various paradigms in the MWM
and the expression of IEGs in BrdU-labelled DGCs was
examined64. A higher proportion of BrdU-labelled DGCs
expressed IEGs in mice that were subjected to a single
trial with the hidden platform in the original training
location (matched situation), than in mice subjected to
a single trial in the absence of the platform (mismatched
situation), suggesting that the activation of adult-born
DGCs is situation-specific64. In addition, the propor-
tion of IEG-expressing BrdU-labelled DGCs could be
further increased (by more than twofold) if mice under-
went nine trials (instead of one trial) with the platform in
the original training location, but not with the platform
moved to a new location.
Together, these findings suggest that, compared
with their mature counterparts, adult-born DGCs
may be specifically activated by an animal’s experi-
ences and thus can make unique contributions to
learning and memory.
Computational models of adult-born DGC function
As adult neurogenesis has become more widely appre-
ciated as an important form of hippocampal plasticity,
its potential to affect learning and memory has been
increasingly recognized65–67. This interest is largely due to
the position of the dentate gyrus within the hippocam-
pal circuit and its presumed role in memory formation.
The dentate gyrus, which receives direct inputs from the
entorhinal cortex and sends projections to the CA3
region (FIG. 1), is traditionally considered the information
gateway to the hippocampus. Following the seminal work
of David Marr, who suggested that the hippocampus
stores memories in associative networks68, several com-
putational studies recognized that highly separated
inputs are required to encode different memories in
the CA3 and assigned this role — a process known as
pattern separation — to the dentate gyrus (BOX 1)69–72.
Box 1 | Pattern separation
Pattern separation is a computational process that has long
been associated with the dentate gyrus (DG). Pattern
separation occurs when the output firing patterns of a
network are less similar to one another than the input
firing patterns. Similarity measures such as correlation and
cosine similarity (also known as normalized dot product)
can be used to quantify separation. If the firing patterns of
the output neurons for a set of events are more separated
from each other than the firing patterns of its input
neurons, the network can be considered a separator (see
the figure). This separation can occur either through rate
modulation of neurons within a population or by the firing
of a unique set of neurons to each input.
There are many reasons why the dentate gyrus is thought
to have such a pattern separation function. First, the
anatomy of the region seems to be ideally suited for
separation: the dentate gyrus contains five to ten times
more neurons than its principal input, the entorhinal
cortex (EC)115. In this way, the dentate gyrus is similar to
support vector machine algorithms in machine learning, by
which information is projected into higher-dimension
spaces to facilitate discrimination116. Second, it seems to have a sparse coding scheme: dentate granule cells (DGCs)
receive substantial feedforward and feedback inhibition from local interneurons117 and in vivo recordings suggest that
DGCs are rarely active during behaviour74,118. Together, these findings suggest that DGCs are finely tuned, making it
possible that even similar inputs activate distinct populations of DGCs70,72,119. Finally, individual DGC mossy fibres are
capable of depolarizing downstream CA3 pyramidal neurons120, suggesting that, despite their sparse activation, they can
drive memory encoding in the hippocampus69.
Why is pattern separation important? In the hippocampus, it has been proposed to be an essential step in information
processing to avoid interference between memories72. In associative networks, as the CA3 is thought to be, memory cues
activate a set of neurons that then, by virtue of connections within the network, activate those neurons that represent the
stored memory itself — a process known as pattern completion121. Such a scheme requires that memories be stored ‘far
apart’. If two events are encoded too similarly, the stored memories may converge into a single, inappropriate memory,
rendering future recall impossible122.
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Dendate gyrus
granule cells
Events:
Memory space Memory space Memory space
Events:
a Without neurogenesis b With neurogenesis
Time
Recent experimental evidence also supports the pattern
separation function of the dentate gyrus in information
processing73–75. However, studies of dentate gyrus pat-
tern separation have generally not taken neurogenesis
into consideration.
Following the long tradition of hippocampal model-
ling, computational approaches have been increasingly
used to identify and understand the role that adult neu-
rogenesis may have in the hippocampal network76. These
modelling studies have shown that directing learning
to adult-born DGCs can have several different effects
depending on the specific architecture of the network
model and the form of neurogenesis that is being tested.
These models have taken different forms, ranging from
‘top-down’, abstract neural network models to ‘bottom-
up’, biologically-derived models of the dentate gyrus
and hippocampus. Nevertheless, a common thread
has emerged across many of these models: neurogen-
esis allows plasticity to be mostly localized to newborn
immature DGCs, preserving the information that is rep-
resented by mature DGCs (FIG. 3).
New neurons and memory capacity: addition or
replacement? The greatest distinction in how neuro-
genesis is implemented in these different computational
models is whether new neurons replace existing neu-
rons (‘replacement models’) or whether they are added
to the network (‘addition models’). In replacement
models, old DGCs are simply removed and replaced by
new DGCs with random (or naive) synapses. In simple
feedforward architectures, replacement of neurons in
this manner accelerates learning considerably because
the random connections made by the new neurons are
flexible and can therefore participate in various network
learning paradigms (for example, neurogenesis allows
the network to avoid local minima, which are a problem
with some learning rules)7 7,78. A possible downside
indicated by these models is that this learning improve-
ment is accompanied by the forgetting of older memo-
ries through the loss of information that was encoded
by the removed neurons, although targeted cell death
could mitigate this problem79. In contrast to the abstract
networks in these replacement models, the replacement
model described by Becker80 considers neurogenesis in
a model of the full hippocampal loop (entorhinal
cortex–dentate gyrus–CA3–CA1–entorhinal cortex).
Becker’s model shows that, if the role of the dentate
gyrus is limited to encoding (with no involvement in
retrieval), the storage and subsequent recall of highly
similar items by the full hippocampal circuit are con-
siderably improved if there is substantial neuronal
replacement in the dentate gyrus, without disrupting
the retrieval of older memories80.
In contrast to the replacement models, more recent
models have considered the possibility that the granule
cell layer continues to grow through the addition of new
neurons. By not removing existing neurons and direct-
ing plasticity towards new neurons, these models have
suggested that neurogenesis allows the mature neurons
within the dentate gyrus network to remain special-
ized for the same memories for long periods of time.
Wiskott and colleagues described how limiting synaptic
plasticity to synapses made by new neurons in the net-
work can keep the network from suffering catastrophic
Figure 3 | Computational theories of neurogenesis. a | Without neurogenesis, new events (represented by different
shapes) are limited by the set of sparse ‘codes’ (combinations of active neurons) provided by mature granule cells in the
dentate gyrus. This can lead to the dentate gyrus not having the flexibility to encode new memories well80,82 or to
interference between memories formed in the hippocampus (shown as a cluster of memories in a projection of the
high-dimension hippocampal ‘memory space’)81. b | New neurons (shown in green) provide new sparse codes for encoding
new information, while older memories are preserved because they are represented by older neurons (shown in red). This
can facilitate the formation of new memories while avoiding catastrophic interference, saving older memories80–82 (shown
in the left panel as two separate clusters of memories in a projection of the high-dimension hippocampal memory space).
The three-way arrow indicates that new neurons can change how memories are encoded in the hippocampal network.
Neurons born at different times (shown in green and blue in the right panel) represent different inputs, and the sparse
codes generated at a particular time are clustered together (active neurons in a population are similar in composition to
one another), separately from sparse codes that were generated at a different time, essentially encoding time into new
memories83,84,86.
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Attractor
A stable point in a dynamic
system. Attractors are typically
found in neural networks with
strong feedback connections
and are determined by the
weights of the recurrent
connections between units
(neurons) in the network.
Depending on the initial
conditions and external inputs,
the network will evolve towards
one of these stable states.
Pattern integration
The ability of immature
dentate granule cells to provide
an association between events
owing to their indiscriminate
responses to inputs.
Pattern completion
A process by which a stored
neural representation is
reactivated by a cue that
consists of a subset of
that representation.
interference, a process by which the attractor structure of
the network breaks down81. This interference is avoided
because the attractors using old neurons are not affected
by new information that is being stored in the network
(although the old attractors are still useful for encod-
ing familiar components of new memories). Similarly,
in the full hippocampal model by Weisz and Argibay82
— which, like the Becker model, incorporates neurogen-
esis into a simulation of the entorhinal cortex–dentate
gyrus–CA3–CA1–entorhinal cortex loop but treats
neuro genesis as an additive process — after a certain
memory load was reached, new information could not be
effectively encoded if no neurogenesis took place; how-
ever, if neurogenesis was incorporated into the model
(simulated as a one-off 30% increase in dentate gyrus
size), the network could effectively store and retrieve the
new memories. Aimone and colleagues83 investigated
the long-term effects of this addition. Their model
showed that if all DGCs ‘grow’ into the network through
neurogenesis (and thus move from a high-plasticity,
immature state to a lower-plasticity, mature state), a
network ultimately results in which most DGCs perma-
nently encode their past ‘experience’83. Such an arrange-
ment could bias the dentate gyrus to preferentially
use subsets of mature DGCs during the encoding of
new information in familiar contexts. The experience-
specific modification of adult-born DGC activity
described above is consistent with this hypothesis41.
Pattern separation in models of neurogenesis. Although
most computational models that investigate the role of
neurogenesis in hippocampal function have not explic-
itly addressed the pattern separation function of the den-
tate gyrus, many of these results have implications that
are relevant to the role of neurogenesis in pattern sepa-
ration. In replacement models, the complete replace-
ment of neurons within a layer could be considered a
potent form of separation that ensures that different
memories are always represented by distinct DGC pop-
ulations without the potential for overlap. For example,
the benefits of neurogenesis on the ability for the Becker
model to store and recall similar memories could be
attributed to the substantial pattern separation between
the entorhinal cortex signals in the model. Similarly,
the results that emerge from the Wiskott and Aimone
addition models (which involve a reduction of interfer-
ence or a specialization of neurons) can be considered
‘separation effects’ in the sense that new memories
are more likely to involve new neurons that were not
available for older memories. In these cases, however,
the contribution of new neurons to pattern separation
occurs over a long timescale — probably days to weeks
— because neurogenesis ensures that the populations of
immature DGCs change continuously over several days.
What occurs over shorter timescales that are relevant
to hippocampal processing, such as minutes and hours,
during which the population of immature neurons
probably does not change substantially? One prediction
from Aimone’s model is that immature DGCs make a
distinct contribution to the separation properties of the
dentate gyrus83. Although mature DGCs are presumably
very selective in their responses (that is, tightly tuned),
allowing them to contribute to pattern separation by
making the stimulus inputs independent of one another,
the physiological properties of immature DGCs prob-
ably make them less selective (that is, broadly tuned),
allowing them to fire in response to multiple events.
We refer to this effect as pattern integration and propose
that this added similarity between the representations of
encoded memories might make a crucial contribution
to the global pattern separation function of the den-
tate gyrus. Importantly, this pattern integration effect,
which prevents new memories from becoming com-
pletely separated during encoding, is distinct from the
pattern completion that occurs during memory retrieval.
Incidentally, the full hippocampal model of Weisz and
Argibay also showed that neurogenesis decreases pattern
separation because new neurons in their model are more
likely to participate indiscriminately in the encoding
of new memories82.
The different potential effects of adult-born DGCs
on pattern separation at different timescales has led to
an additional hypothesis — namely, that adult-born
DGCs contribute to the encoding of temporal informa-
tion80,83–85. According to our model83, events (stimuli)
that occur close to each other in time will be associated
with each other owing to pattern integration by imma-
ture adult-born DGCs, but the memories of events that
occur far apart in time (and that thus will be represented
by different immature DGC populations) will be better
separated84. Modelling results showed that immature
DGCs make an important contribution in this respect
and that the pattern integration effect decreases over
several days, ensuring that memories that are formed
at different times are encoded distinctly83. From a dif-
ferent mechanistic perspective, Becker and Wojtowicz
proposed that temporal information could be encoded
by ‘waves’ of new DGCs, whereby DGCs arising from
the same NPC encode different features of the same
temporal context86.
In summary, the varied approaches to using com-
putational models to study the role of neurogenesis in
hippocampal function have suggested several potential
functions for adult-born DGCs in the dentate gyrus.
Despite differences in design and assumptions, these
models point towards similar conclusions. First, how
neurogenesis might affect learning and memory will
depend on the timescale that is being studied; the effect
of immature DGCs on the encoding of individual events
is likely to be distinct from the contribution of persistent
neurogenesis over a lifetime. Second, the specific plas-
ticity-related and physiological properties of immature
DGCs probably have an effect on the function of the
entire dentate gyrus and hippocampal circuit. As a result,
conditions that affect immature DGCs are predicted
to have a substantial effect on overall hippocampal
function.
Behavioural studies of adult-born DGC function
In the past decade, accumulating evidence has sug-
gested a correlation between the number of adult-born
DGCs and an animal’s cognitive ability (see above).
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Nature Reviews | Neuroscience
GCV GCV
NPCSP tk
NestinrtTA
NestinCreER NSE dta
TRE Bax
dta
TK Disruption of
mitosis leads to
cell death
rt-TA
Dox
+
CreER
TM
+
Apoptosis of
NPCs
stop
Death of
newborn DGCs
GFAP–tk or nestin–tk system
Nestin–rtTA/TRE–BAX system
Nestin–CreER/NSE–DTA system
P
NSE
loxP
Nevertheless, studies that directly investigated the effect
of depletion of adult-born DGCs on an animal’s cog-
nitive ability have generated inconsistent results (see
Supplementary information S1 (table)), making it diffi-
cult to formulate basic principles regarding the function
of adult neurogenesis in learning and memory. In this
section, we describe the experimental observations, dis-
cuss possible causes for the inconsistencies and propose
potential strategies to resolve them.
A common strategy for studying the function of
adult neurogenesis is to examine the consequences
of neurogenesis ablation on cognitive performance.
Several methods have been developed to suppress the
production of new neurons in the adult brain (BOX 2).
Most of the studies evaluated cognitive performance
by using common behavioural paradigms designed to
examine the role of the hippocampus in learning and
memory (see Supplementary information S1 (table)).
These studies have revealed that neurogenesis is required
for some but not other hippocampus-dependent tasks,
and is not required for tasks that do not involve the hip-
pocampus87–89. For example, the ablation of adult neuro-
genesis in rats by methylazoxymethanol acetate (MAM)
treatment results in deficits in hippocampus-dependent
trace conditioning tasks but not in hippocampus-inde-
pendent delay conditioning t asks89,90. Among several other
hippocampus-dependent tasks, MAM treatment pre-
vents the improvement of long-term recognition memory
by environmental enrichment, but it does not alter
contextual fear conditioning or spatial navigation learn-
ing in the MWM42,90. Similar task-dependent involve-
ment of hippocampal neurogenesis has been observed
in other studies in both rats and mice87,88,91–94. Therefore,
the involvement of adult neurogenesis in learning and
memory seems to depend on the demands in each task,
similar to the task-specific responsiveness of adult-born
DGCs discussed above64.
Even among studies that used the same task to inves-
tigate the cognitive effects of hippocampal neurogen-
esis, the data can be inconsistent (see Supplementary
information S1 (table)). The reference memory version
of the MWM is one of the most frequently used tests for
the functional assessment of neurogenesis. Surprisingly,
an apparent deficit in spatial-navigation learning, as
measured by the latency or the distance travelled to reach
the hidden platform, was only detected in two mouse
studies using genetic ablation of neurogenesis87,93, but not
in studies using other knockdown methods to prevent
neurogenesis88,90,94–96. However, many studies showed
impairments in the long-term but not the short-term
retention of spatial memory as a consequence of reduced
adult neurogenesis92,94,96,97. Similarly, inconsistent data
have been obtained regarding the role of adult neuro-
genesis in contextual fear conditioning, which is another
commonly used hippocampus-dependent learning and
memory task. Deficits in this task have been repeatedly
observed in rodents in which neurogenesis was almost
completely eliminated by irradiation88,98,99 and in two
lines of transgenic mice with genetic ablation of neuro-
genesis88,97. However, such defects were not detected in
several other rodent studies in which neurogenesis was
suppressed using different methods87,90,92,93.
Some of these results support the hypotheses that
have arisen from computational studies. For example,
the observations of impaired long-term spatial mem-
ory retention in some studies are consistent with the
Box 2 | Methodologies for ablating neurogenesis
The early approaches for ablating neurogenesis such as anti-mitotic drug treatments
(for example, methylazoxymethanol acetate and temozolomide) and irradiation89,95
were traditionally used in cancer therapy. These methods take advantage of the fact
that the proliferative neural progenitor cells (NPCs) are more sensitive than
differentiated neurons to these insults, which disrupt cell cycle progression. Although
these methods are effective in reducing neurogenesis, they have considerable side
effects in animals, such as general health deterioration and inflammation123,124.
More precise, cell type-specific targeting of neurogenesis could be achieved through
the development of numerous transgenic mouse models by expressing suicide genes
driven by NPC-specific promoters (NPCSPs), such as nestin and glial fibrillary acidic
protein (GFAP) promoters (see the figure). In an example of such a method, expression of
thymidine kinase (tk) from herpes simplex virus in NPCs facilitates the incorporation of
the nucleotide analogue ganciclovir (GCV) into DNA during replication, which disrupts
DNA replication and leads to cell death (top panel)88,125. In the nestin–rtTA/TRE–BAX
(nestin– reverse tetracycline-controlled transactivator/tetracycline response
element–BAX) mice (middle panel), the expression of the pro-apoptotic protein BAX is
induced by doxycycline (Dox), which activates the apoptosis pathway in NPCs87. In the
nestin–CreER/NSE–DTA (nestin–CRE recombinase-modified oestrogen receptor/
neuron-specific enolase 2–diphtheria toxin fragment A) mice (bottom panel),
nestin–CreER targets the expression of a tamoxifen (TM)-inducible form of Cre in NPCs
and a CRE-inducible DTA is engineered into the locus of the Nse gene97. TM-induced
CRE activity leads to the recombination of loxP sites (red triangles) and removal of the
stop cassette upstream of the dta gene, thus allowing the expression of dta from the
NSE promoter. This strategy allows tamoxifen-dependent ablation of NPC progeny that
are committed to a neuronal lineage.
Our increasing understanding of the molecular mechanisms of adult neurogenesis
allows the development of new techniques for blocking neurogenesis. WNT signalling
is important for neuronal fate determination at the early stages of neurogenesis. A
lentivirus-mediated overexpression of a dominant-negative WNT protein that blocks
WNT signalling suppresses the production of adult-born dentate granule cells (DGCs)
in the subgranular zone94. TLX is an orphan nuclear receptor that is of key importance
for the proliferation of NPCs. Induced deletion of Tlx in the adult mouse brain by
cytomegalovirus CreER also suppresses adult neurogenesis93. Polycomb 3 homologue
(PC3; also known as CBX8) is a factor that promotes terminal differentiation in the
CNS. Ectopic expression of PC3 in NPCs results in a smaller NPC population, which is
accompanied by accelerated differentiation and impaired morphogenesis of
adult-born DGCs126.
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Trace conditioning
A form of classical conditioning
in which the conditioned
stimulus occurs before the
unconditioned stimulus with a
stimulus-free period (the ‘trace
interval’ or ‘conditioning
interval’) between the two.
Delay conditioning
A form of classical conditioning
in which the onset of the
conditioned stimulus precedes
the onset of the unconditioned
stimulus, with an overlap
between the presentation of
the conditioned stimulus
and the presentation of the
unconditioned stimulus.
Recognition memory
The ability to correctly
remember something that has
been previously encountered.
It is a subcategory of
declarative memory.
Contextual fear conditioning
A form of conditioning in which
animals associate the
conditioning context
(the ‘neutral’ conditioned
stimulus) with an aversive
stimulus — for example, a foot
shock.
prediction from computational studies that the addition
of newborn neurons helps to maintain the stability of old
memories during the encoding of new information80–82.
Similarly, the involvement of neurogenesis in tasks such
as trace conditioning and contextual fear conditioning
support the hypothesis that newborn neurons are
involved in associating events that occur within a short
time span83,84,86. However, these roles for neurogenesis are
not corroborated by other studies (see Supplementary
information S1 (table)).
Possible factors underlying contradictory findings.
Many factors in the details of experimental design
might have contributed to these discrepancies, including
the species and strains of animals tested, the efficiency
and side effects of ablation methods, the specific param-
eters in the design of behavioural paradigms and the
parameters for evaluation of the behavioural phenotype
(see Supplementary information S1 (table)). For exam-
ple, recent studies revealed that contextual learning
was defective in irradiated rats and in some but not
other strains of mice17,88. Even in the same mouse strain,
contextual fear conditioning deficits were detected if
mice were treated with a high dose but not a low dose
of irradiation, with the high dose of irradiation causing
a greater reduction of neurogenesis100. Blocking neuro-
genesis (the rate of which declines exponentially with
ageing101,102) at different ages can result in substantially
different behavioural phenotypes103,104.
The designs of behavioural paradigms are another
source of discrepancies in the aforementioned studies.
For example, prolonged pre-training procedures may
mask defective performance in behavioural tasks90,93. In
addition, different studies use different parameters to
evaluate behavioural phenotypes, which are not equally
sensitive for revealing learning and memory deficits.
For example, a recent study105 showed that ablation of
neuro genesis by temozolomide treatment in mice did
not alter path length or latency to find the hidden plat-
form during the learning phase of the MWM task; how-
ever, it did affect the ability of the animals to efficiently
adopt a precise, place-specific strategy to localize the
hidden platform, a function that is presumably depend-
ent on the hippocampus. It is therefore likely that the
most commonly used parameters in the MWM, such as
path length and latency to find the platform, may not be
sensitive enough to reveal the subtle defects in learning
caused by loss of adult neurogenesis.
In addition to the differences in the experimental
details discussed above, there are two issues that are
worth particular consideration when comparing data
from different studies. First, a lack of adult-born DGCs at
different maturation stages may lead to different behav-
ioural phenotypes. As discussed in previous sections,
newly generated DGCs that are less than 1 week old
have not yet made connections with the local network
and would probably not be involved in learning and
memory. Indeed, rats that had received a 6-day MAM
treatment were not impaired in eye blink trace condi-
tioning when tested 2 days after treatment, in contrast
to rats that had undergone a 14-day treatment scheme89.
Furthermore, adult-born DGCs aged between 1 and 6
weeks may make distinct contributions to learning and
memory owing to their enhanced excitability and plastic-
ity, which could also account for the memory impairment
in rats treated with MAM for 14 days89. Using pharmaco-
genetic approaches to reduce the number of adult-born
DGCs at particular maturation stages in mice, a recent
study detected deficits in long-term spatial memory and
extinction of spatial preference and contextually evoked
fear by specifically ablating adult-born DGCs of approxi-
mately 1–4 weeks of age — that is, before they were
fully mature92. The transient nature of this transgenic
model also allowed the authors to show that the pheno-
type was restored after replenishment of the affected
DGC population, further corroborating the notion that
the behavioural deficits were caused by reduced adult
neurogenesis92. Finally, the survival of adult-born DGCs
was compromised around 4–6 weeks after their birth in
mice lacking kruppel-like factor 9. These mice were
impaired in contextual discriminative learning, implying
a role for adult-born DGCs at 4–6 weeks of age in pat-
tern separation32. Together, these observations suggest
that adult-born DGCs at the immature stage may make
a distinct contribution to learning and memory.
Another major reason for data discrepancy in the
field is that the behavioural paradigms used in most
studies do not directly assess the function of the dentate
gyrus, despite the fact that adult-born neurons differen-
tiate and integrate into the neural network exclusively
as DGCs. Instead, the majority of studies of adult neu-
rogenesis investigate the role of adult-born DGCs in
hippocampus-dependent functions. It is possible that
learning and memory in some common hippocampus-
dependent behavioural tasks do not rely on the dentate
gyrus, as direct inputs from the entorhinal cortex to CA3
and CA1 might underlie the tasks (FIG. 1). Recent studies
suggest that the monosynaptic pathway (entorhinal
cortex–CA1–entorhinal cortex) is sufficient for MWM
learning under certain conditions106. In fact, this mono-
synaptic pathway is necessary for forming precise spatial
representations, as suggested by physiological studies in
rats107. Additionally, the absence of NMDA receptor-
mediated plasticity in the dentate gyrus does not affect
the performance of mice in the MWM task or in the con-
textual fear conditioning task75. Therefore, examining
the role of hippocampal neurogenesis using such tasks
may result in inconsistent observations.
Previous studies suggest that pattern separation
might be a role of the dentate gyrus in both animals
and humans73,75,108. Does adult neurogenesis have a role
in pattern separation, and if so, how? Computational
modelling suggests that immature adult-born DGCs
might function as pattern integrators by responding
indiscriminately to events that occur closely in time83. A
lack of neurogenesis may allow each event to be encoded
more distinctly, which could be beneficial when a large
amount of information needs to be learned in a short
time. Indeed, mice in which neurogenesis was sup-
pressed by two independent approaches performed
better than controls in a spatial working memory task
in an eight-arm radial maze with high interference (for
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Spatial discrimination
The ability to discriminate
separate locations in space.
Conjunctive encoding
A form of information encoding
in which a neuron requires the
concurrent activity of multiple
input neurons. In the
hippocampus, dentate granule
cells can associate spatial
information from the medial
entorhinal cortex with
non-spatial information from
the lateral entorhinal cortex to
form a multi-dimensional
representation of an event.
example, the sample arms and/or goal arm being used
repeatedly and interchangeably) and long delays between
the sample trial and the test trial109. In this case, it is pos-
sible that a lack of pattern integration mediated by adult-
born DGCs may have allowed each learning trial to
be encoded more distinctly, resulting in less intra-trial
or inter-trial interferences and eventually the observed
performance improvement.
The role of adult-born DGCs in pattern separation
has recently been examined directly in behavioural tasks
for spatial pattern discrimination. Chronic ablation of
neurogenesis by either irradiation or lentivirus-mediated
overexpression of dominant-negative Wn t in mice
impaired performance in two spatial discrimination tasks
when two stimuli were presented with limited spatial sep-
aration but not when two stimuli were widely separated
in space91. Although the function of the dentate gyrus in
these two specific tasks awaits validation, this finding
provides the first evidence for a possible involvement of
adult-born DGCs in pattern separation. How does this
observation relate to the pattern integration function
of adult-born DGCs? One possible explanation is that
the integrative ability of adult-born DGCs facilitates the
association of the target stimuli with other elements in
the context and leads to better pattern separation and
eventually better spatial discrimination ability.
In summary, despite all of these inconsistent results,
accumulating evidence suggests that adult-born DGCs
do make contributions to learning and memory, consist-
ent with computational theories that newborn neurons
in the networks are likely to be selected for encoding
new information. To resolve the controversies discussed
above, future studies need to take into consideration
both the design of behavioural paradigms (for example,
by directly targeting the function of the dentate gyrus
and carefully selecting the experimental timeline) and
characteristics of the experimental animals (for example,
the species and age).
Conclusions and future directions
Neurogenesis in the hippocampus represents a form of
cellular plasticity in the adult brain that had not been
previously recognized. Activity-dependent regulation
of neurogenesis and experience-dependent participa-
tion of adult-born DGCs in information processing
both imply a relationship between adult neuro genesis
and learning and memory. Despite mixed results,
behavioural evaluation of rodents with reduced adult
neurogenesis has consistently suggested an involve-
ment of adult-born DGCs in learning and memory.
Nevertheless, the precise function of adult-born DGCs
in cognitive processes remains elusive. Although many
hypotheses have been proposed by computational mod-
elling, most of them have not been explicitly tested in
experimental studies.
Emerging data have already suggested that hippo-
campal neurogenesis is involved in pattern separation91,
which can be modulated by pattern integration83. The
observation that adult-born DGCs between 2 and 6 weeks
of age are hyper-excitable18,29,30 might mean that these
DGCs are particularly suited to mediating pattern
integration. It will be intriguing to investigate whether
these adult-born DGCs have a distinct influence on pat-
tern separation and integration in a maturation stage-
dependent manner. Furthermore, the long-lasting
nature of these properties (that is, hyper-excitability
and enhanced plasticity) and the constant turnover of
immature DGCs suggest that adult-born DGCs could
have a role in temporal association and separation
during learning and memory. Experimental evidence
is needed to support this hypothesis. Moreover, adult-
born DGCs at 4–6 weeks of age show enhanced plastic-
ity29, which makes them more suited to encoding new
information, as predicted by computational studies (see
above). These hypotheses are consistent with the finding
that adult-born DGCs are preferentially activated upon
memory retrieval once they reach a certain stage of
maturation62,63. Further studies are needed to clarify the
functional importance of this preferential activation and
recruitment and whether it is dependent on the matura-
tion stage of adult-born DGCs.
An important consideration when interpreting both
IEG expression and behavioural studies is that it remains
unclear whether adult neurogenesis is involved in the
encoding, the consolidation or the recall of memory.
Combining optogenetic techniques110 with retrovirus-
mediated labelling of adult-born DGCs28 could provide
a system to examine the physiology of adult-born DGCs
in awake, behaving animals. Furthermore, some com-
putational models suggest that addition of new neurons
to the network increases memory capacity in the hip-
pocampus80–82. Intriguingly, a recent study in mice
suggested that adult neurogenesis facilitated memory
reorganization that led to a gradual reduction of the
hippocampus-dependence of memories and the perma-
nent storage of these memories in extra-hippocampal
regions111. Finally, both computational and experimental
studies are needed to investigate whether (and if so,
how) adult-born DGCs are involved in other dentate
gyrus-mediated functions, such as conjunctive encoding112.
In summary, future studies using a combination of
molecular, genetic, behavioural and physiological
approaches will be helpful in testing these hypotheses
and elucidating the involvement of adult-born DGCs
in cognition.
Hippocampal neurogenesis in humans is affected
by various neurological disorders, including depres-
sion, epilepsy, cerebral ischaemia, Alzheimer’s disease
and Parkinson’s disease, many of which are associated
with cognitive decline6. Recently, several non-invasive
imaging techniques have been developed for monitoring
neurogenesis in human subjects113,114. Although their
robustness and reproducibility await further testing,
these techniques might allow the function of neuro-
genesis to be investigated in humans under various
physiological or pathological conditions. Combined with
sophisticated cognitive tasks and psychiatric examina-
tions in humans, such studies have the potential to reveal
functional mechanisms of adult neurogenesis that can-
not be addressed in animal models, and will hopefully
lead to improvement in therapies for these neurological
disorders.
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Acknowledgments
We thank M. L. Gage for editorial comments. This work is
funded by the James S. McDonnell Foundation, the Lookout
Fund, the Kavli Institute for Brain and Mind, the NSF
Temporal Dynamics of Learning Center, the US National
Institutes of Health (NS-050217) and National Institute on
Aging (AG-020938).
Competing interests statement
The authors declare competing financial interests: see web
version for details.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/gene
Arc | Egr1 | Fos | Homer1A
UniProtKB: http://www.uniprot.org
CREB | SLC12A2
FURTHER INFORMATION
Fred H. Gage’s homepage: http://www.salk.edu/faculty/
gage.html
SUPPLEMENTARY INFORMATION
See online article: S1 (table)
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