RESEARCH ARTICLES
Hippocampal Neurogenesis Regulates
Forgetting During Adulthoodand Infancy
Katherine G. Akers,1* Alonso Martinez-Canabal,1,2* Leonardo Restivo,1* Adelaide P. Yiu,1Antonietta De Cristofaro,1 Hwa-Lin (Liz) Hsiang,1,2 Anne L. Wheeler,1,2 Axel Guskjolen,1,3
Yosuke Niibori,1 Hirotaka Shoji,4 Koji Ohira,4 Blake A. Richards,1 Tsuyoshi Miyakawa,4Sheena A. Josselyn,1,2,3,5† Paul W. Frankland1,2,3,5†
Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous
addition remodels hippocampal circuits, computational models predict that neurogenesis leads todegradation or forgetting of established memories. Consistent with this, increasing neurogenesis
after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast,
during infancy, when hippocampal neurogenesis levels are high and freshly generated memories
tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation
mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells
are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis,
infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis
after memory formation induced infantile amnesia in these species.
n both artificial systems and brain networks
there is a trade-off between plasticity—the
ability to incorporate new information—andstability—ensuring that the process of incorporating new information does not degrade information already stored in that network (1). In the
hippocampus, new neurons continue to be generated in the subgranular zone of the dentate gyrus(DG) beyond development and into adulthood(2, 3). These new neurons synaptically integrate
into hippocampal circuits (4–9) and provide potential substrates for new learning. Promoting the
production of new neurons in adult mice facilitates the formation of new hippocampal memories (10, 11). However, the continuous integrationof new neurons may affect memories already stored
in these circuits (12). As new neurons integrate into
the hippocampus, they compete with existing cells
for inputs and outputs, establishing new synaptic
connections that may coexist with, or even replace,older synaptic connections (5, 6, 13). As such remodeling necessarily alters the configuration of
DG-CA3 circuits and likely rescales synaptic
weights of preexisting connections, computationalmodels predict that high levels of hippocampal
neurogenesis will lead to forgetting of information
already stored in those circuits (14–16).

I

1
Program in Neurosciences and Mental Health, The Hospital for
Sick Children, Toronto, M5G 1X8, Canada. 2Institute of Medical
Science, University of Toronto, Toronto, M5S 1A8, Canada.
3
Department of Physiology, University of Toronto, Toronto,
M5S 1A8, Canada. 4Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health
University, Toyoake, Aichi, 470-1192, Japan. 5Department of
Psychology, University of Toronto, Toronto, M5S 3GM, Canada.

*These authors contributed equally to this work.
†Corresponding author. E-mail: paul.frankland@sickkids.ca(P.W.F.), sheena.josselyn@sickkids.ca (S.A.J.)

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Although hippocampal neurogenesis persists
throughout life, rates decline dramatically with age(17, 18). Therefore, this predicted remodelinginduced forgetting should be most pronounced during infancy, when hippocampal neurogenesis ishigh. Consistent with this, infantile forgetting [orinfantile amnesia (19)] is observed across a wide
range of species (20), including humans (21). Neurobiological accounts of infantile amnesia previously emphasized that continued brain maturation
might interfere with consolidation and/or storage of
infant memories, rendering them inaccessible atlater time points (22). Here, we test whether postnatal hippocampal neurogenesis, in particular, modulates ontogenetic changes in memory persistence.
Inverse Relationship Between Levels of Postnatal
Neurogenesis and Memory Persistence
We first characterized levels of hippocampal
neurogenesis in infant and adult mice using a
retrovirus expressing green fluorescent protein(GFP) to label neural progenitors and their progeny (11) and immunohistochemistry. Fourweeks after retroviral microinjections in infant(postnatal day 17; P17) and adult (P60) mice, we
observed a pronounced age-dependent reduction in neurogenesis (i.e., reduction in the number of GFP+ DG granule cells and their terminal
processes in the CA3 region) (Fig. 1, A and C).
From infancy to adulthood, there was also a decrease in the number of proliferating (Ki67+) cells(Fig. 1D and fig. S1) and immature (doublecortin+[DCX+]) neurons (Fig. 1, B and E). Postnatally
generated DG granule cells project a mossy fiberthat reaches the CA3 region after ~2 weeks,contacting 11 to 15 pyramidal cells (5, 7, 23). We
observed a reduction in the number of immature(DCX+) large mossy fiber terminals (LMTs) in

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the CA3 region of adult mice (Fig. 1, B and F),
consistent with a predicted reduction in synaptic
rearrangements in the CA3 with age (fig. S2).
Next, we evaluated how age-dependent changes
in neurogenesis influence the ability to form enduring hippocampus-dependent memories using
the contextual fear conditioning paradigm (24).
Infant and adult mice were placed in a novel context and presented with a series of foot shocks.
One to 28 days later, separate groups of mice
were returned to the context, and memory retention was evaluated by measuring freezing behavior (Fig. 1G). Mice trained as adults froze
robustly regardless of retention delay. By contrast, mice trained as infants only exhibited highlevels of freezing when tested 1 day after training.
If infant mice were tested at longer retention delays, less freezing was observed (Fig. 1H) (25).
Infant mice trained similarly but not shocked
showed little freezing when tested 1 day after
training (fig. S3), indicating that the freezing observed in shocked infant mice reflects conditioned fear. There were no age-related differencesin reaction to the foot shock (Fig. 1I), indicatingthat forgetting in infant mice was not due to diminished nociception. This pattern of accelerated
forgetting in infant mice was replicated using an
incidental context learning paradigm (fig. S4).
Increasing Neurogenesis Promotes
Forgetting in Adult MiceTo determine if levels of neurogenesis and memory persistence are causally related, we tested
whether increasing hippocampal neurogenesis
after learning promotes forgetting in adult mice
(Fig. 1J) (26). We initially used voluntary running, a naturalistic intervention that robustly
increases neurogenesis (27) (Fig. 2A). Relative
to sedentary controls, running increased the number of proliferating (Ki67+) cells (Fig. 2B) andimmature (DCX+) neurons in the DG (Fig. 2C),
as well as DCX+ LMTs in the CA3 of adult mice
(Fig. 2D). These increases were evident within
7 days of commencing running, sustained forthe duration of exercise, and not associated withincreased death of developmentally generated
granule cells (fig. S5). We next injected retrovirus
expressing GFP into the DG of adult mice. Fourweeks later, we observed many GFP+ neurons in
the innermost layers of the DG and GFP+ LMTs inthe stratum lucidum of the CA3. Counterstaining
with a marker of mature presynaptic terminals,
zinc transporter-3 (ZnT3) (28), revealed many new(GFP+/ZnT3+) LMTs in close apposition to preexisting (GFP–/ZnT3+) LMTs (Fig. 2E), suggestingthat new contacts coexist with established connections (5). Running increased the ratio of new-toestablished LMTs, indicating that running increases
remodeling of DG-CA3 circuits (fig. S6).
To determine whether running-induced increases in hippocampal remodeling induce forgetting of an established hippocampus-dependent
memory, we trained adult mice in contextual fear
conditioning. After training, mice were givenwww.sciencemag.org

RESEARCH ARTICLESFig. 1. Age-dependent levels of hippocampal neurogenesis
and memory stability are inversely related in mice. (A) GFP
labeling of granule cells in the DG and CA3 1 month after
retroviral infection shows that infant (P17) mice had higher
levels of neurogenesis than adult (P60) mice. (Left) Low magnification of DG and CA3 regions. Scale bar, 200 mm. (Right)
High magnification of CA3 region showing GFP+ mossy fibers
and LMTs. Scale bar, 50 mm. (B) Top row: Infants had more DCX+
cells in the DG and CA3 than adults. Scale bar, 100 mm. Bottom
row: High magnification of DG and CA3. Scale bar, 50 mm. (Cto F) Infants showed more (C) GFP+ neurons (t6 = 8.57, P <0.001), (D) proliferating (Ki67+) cells (t7 = 4.53, P < 0.01),
and (E) immature (DCX+) neurons in the DG (t6 = 18.65, P < 0.001),
as well as more (F) DCX+ LMTs in the CA3 (t6 = 15.03, P <0.001) than adults (n = 4 to 5 per group). (G) Separate groups
of infant and adult mice were trained in contextual fear conditioning and tested 1, 7, 14, or 28 days later (n = 8 to 9 pergroup). (H) Context fear memory persisted for at least 28 daysin adult mice, whereas infants showed intact memory shortly
after training but forgetting after longer delays (age × day,
F3,62 = 13.07, P < 0.001; post-hoc t tests, 1 day, P < 0.05; 7 days,
P < 0.001; 14 days, P < 0.001; 28 days, P < 0.001). (I) Infants
and adults showed equivalent shock reactivity during training(P17 n = 9, P60 n = 8; arbitrary units, P > 0.05). (J) Inverse relationship between neurogenesis and memory persistence predicts
that increasing neurogenesis in adults will induce forgetting,whereas decreasing neurogenesis in infants will mitigate
forgetting. In all panels, cells/LMTs are expressed as numberof cells/LMTs per 1000 mm2. *P < 0.05. For all figures, error
bars represent standard error of the mean (SEM). DAPI,
4′,6-diamidino-2-phenylindole.

Fig. 2. Voluntary running increases neurogenesis and promotes
forgetting in adult mice. (A) Adult (P60) mice given access to a running
wheel for 28 days showed more immature (DCX+) neurons in the DG and LMTs in
the CA3 than sedentary mice. Scale bar, 50 mm. (B to D) Adult mice were given
access to a running wheel for 0, 3, 7, 14, or 28 days. Running increased thenumber of (B) proliferating (Ki67+) cells (n = 8 per group; running × day, F4,70 =
7.71, P < 0.001; post hoc t tests, 7 days, P < 0.001; 14 days, P < 0.001; 28 days,
P = 0.001), and (C) immature (DCX+) neurons in the DG (n = 4 to 8 per group;
running × day, F4,34 = 3.17, P < 0.05; 7 days, P < 0.05; 14 days, P < 0.001; 28 days,
P < 0.05), as well as more (D) DCX+ LMTs in the CA3 (n = 4 per group; running × day,
F4,30 = 3.45, P < 0.05; 7 days, P = 0.001; 14 days, P < 0.05; 28 days, P < 0.05)
compared with sedentary controls. (E) Neurogenesis remodels DG-CA3 circuits.
www.sciencemag.org

Retrovirus-labeled presynaptic LMTs from new neurons (GFP+) in close apposition toexisting presynaptic LMTs from mature neurons (ZnT3+). Scale bar, 50 mm. Confocal
stacks used to reconstruct representative three-dimensional images of new LMTs
(green) in close contact with existing LMTs (red) in the CA3. (F) Adult mice ran orremained sedentary after contextual fear conditioning. (G and H) Running increased
neurogenesis (sedentary n = 8, running n = 8; LacZ+ cells; t14 = 2.81, P < 0.05) and
induced forgetting (sedentary n = 9, running n = 8; t15 = 2.75, P < 0.05). (I) Adult
mice ran or remained sedentary before contextual fear conditioning. (J and K)
Running increased neurogenesis (sedentary n = 7, running n = 8; t13 = 2.96, P <0.05) but did not affect formation of a context fear memory (sedentary n = 10,
running n = 9; P > 0.05). In all panels, cells/LMTs are expressed as number ofcells/LMTs per 1000 mm2. *P < 0.05.

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RESEARCH ARTICLESFig. 3. Forgetting depends on increased neurogenesis. (A) Adult
GAN-treated WT and TK+ mice remained sedentary or ran after contextual fear
conditioning. Running (B) increased neurogenesis (sedentary n = 6, running n =14; t18 = 2.81, P < 0.05) and (C) induced forgetting of a context fear memory in
WT mice (sedentary n = 16, running n = 14; t28 = 2.63, P < 0.05). By contrast, in
TK+ mice, both (B) the running-induced increase in neurogenesis (sedentary n = 8,
running n = 9; TK+ running versus WT sedentary, P > 0.05; WT running versus TK+
running, t21 = 3.43, P < 0.01) and (C) forgetting (TK+ sedentary n = 12, TK+
running n = 10; P > 0.05; genotype × running interaction, F1,48 = 4.88, P < 0.05)
were blunted. (D) Adult WT mice treated with MEM after contextual fear
conditioning showed (E) increased neurogenesis (vehicle n = 7, MEM n = 6; t11 =2.55, P < 0.05) and (F) forgetting of a context fear memory (vehicle n = 8, MEM n =8; t14 = 5.47, P < 0.001) relative to vehicle-treated controls. (G) Adult GAN-treated

WT and TK+ mice were treated with vehicle or MEM after contextual fear conditioning. MEM (H) increased neurogenesis (vehicle n = 8, MEM n = 8; t14 =2.25, P < 0.05) and (I) induced forgetting of a context fear memory in WT mice(vehicle n = 11, MEM n = 11; t20 = 2.23, P < 0.05). By contrast, in TK+ mice, both(H) the MEM-induced increase in neurogenesis (vehicle n = 8, MEM n = 8; TK+
vehicle versus TK+ MEM, P > 0.05; WT MEM versus TK+ MEM, t14 = 8.53, P < 0.001;
genotype × drug interaction, F1,28 = 4.69, P < 0.05) and (I) forgetting (vehicle n =13, MEM n = 14; TK+ vehicle versus TK+ MEM, P > 0.05; genotype × druginteraction, F1,45 = 5.41, P < 0.05) were attenuated. (J) Post-training tamoxifen
treatment (K) increased neurogenesis (WT n = 4, iKO-p53 n = 4; t6 = 4.39, P <0.01) and (L) induced forgetting of a context fear memory (WT n = 14, iKO-p53 n =9; t21 = 2.68, P < 0.05) in iKO-p53 mice relative to WT controls. In all panels, cellcounts are expressed as number of cells per 1000 mm2. *P < 0.05.

Fig. 4. Genetic and pharmacological decreases in neurogenesis mitigate forgetting in infant mice. (A) Infant GAN-treated WT or TK+ mice weretrained in contextual fear conditioning or placed in conditioning chambers
without foot shocks. TK+ mice had fewer (B) proliferating (Ki67+) cells (WTn = 9, TK+ n = 14; t21 = 3.08, P < 0.01) and (C) immature (DCX+) neurons (WT
n = 6, TK+ n = 6; t10 = 2.57, P < 0.05) in the DG than WT mice. (D) Shocked
WT and TK+ mice showed equivalent context fear memory 1 day after training(WT n = 9, TK n = 13; P > 0.05), and nonshocked mice showed low freezing(WT n = 7, TK n = 9). (E) A separate group of shocked WT mice showedforgetting of a context fear memory 7 days after training, whereas this forgetting was reduced in a separate group of TK+ mice (WT n = 9, TK+ n = 14;
t21 = 2.26, P < 0.05). Separate groups of nonshocked mice again showed

low freezing (WT n = 6, TK n = 7). (F) Inverse relationship between proliferation and memory persistence among shocked mice 7 days after training(r = –0.46, P < 0.05). (G) Infant mice were treated with vehicle or TMZ after
training in the incidental context learning paradigm (or were similarly treated
without foot shocks). TMZ-treated mice had fewer (H) proliferating (Ki67+)
cells (vehicle n = 30, TMZ n = 29; t57 = 3.57, P = 0.001) and (I) immature(DCX+) neurons (vehicle n = 5, TMZ n = 6; t9 = 2.29, P < 0.05) in the DG.
( J) Shocked TMZ-treated mice showed less forgetting of a context-only memory(vehicle n = 30, TMZ n = 29; t57 = 2.47, P < 0.05). Nonshocked mice showed
low freezing (vehicle n = 9, TMZ n = 9). (K) Inverse relationship between
proliferation and memory persistence among shocked mice (r = -0.31, P < 0.05).
In all panels, cells are expressed as number of cells per 1000 mm2. *P < 0.05.

continuous access to a running wheel in their home
cage or housed conventionally (i.e., sedentary;
Fig. 2F). Running increased neurogenesis in the
DG (Fig. 2G) and reduced context fear memory
when mice were tested 6 weeks later (Fig. 2H
and fig. S7). Access to a locked running wheel
did not induce forgetting (fig. S8), indicating thatforgetting was associated with running rather
than exposure to a novel object in the home cage.
Furthermore, running-induced forgetting of a con-600

text fear memory was reduced after a stronger
training protocol (i.e., additional foot shocks;
fig. S9), suggesting that the degree of forgetting
depends, in part, on initial memory strength.
As voluntary running induces several neuraland physiological changes apart from increasing
hippocampal neurogenesis (29), forgetting mightalternatively be mediated by these non-neurogenic
changes. Therefore, we first examined the impact of running before (rather than after) training

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VOL 344SCIENCE(Fig. 2I). Running before training similarly increased neurogenesis (Fig. 2J) but did not affectacquisition of a context fear memory (Fig. 2K),
indicating that running does not nonspecificallyalter freezing (e.g., by reducing anxiety).
Second, we tested whether preventing therunning-induced increase in neurogenesis would
prevent forgetting using transgenic mice in whicha nestin promoter/enhancer drives expression ofa modified herpes simplex virus (HSV) genewww.sciencemag.org

RESEARCH ARTICLESFig. 5. Precocial degus and guinea
pigs show low postnatal neurogenesis and persistent infantile
memories. (A) DCX+ cells in the DG
of infant and adult degus. (Left)
Low magnification. Scale bar, 200 mm.
(Right) High magnification. Scalebar, 25 mm. (B) DCX+ cells in the
DG of infant and adult guinea pigs.
(Left) Low magnification. Scale bar,
200 mm. (Right) High magnification.
Scale bar, 25 mm. Compared withmice (P17 n = 4 to 5, P60 n = 4),
degus (P17 n = 3, P60 n = 4 to 6)
and guinea pigs (GP; P17 n = 4,
P60 n = 4) showed reduced age-related declines in (C) proliferating (Ki67+)
cells and (D) immature (DCX+) neurons in the DG. (E) Infant and adult degus
were trained in contextual fear conditioning and tested 1 and 28 days later(P17 n = 7, P60 n = 10). (F) Both infant and adult degus showed persistentcontext fear memory (age × delay interaction and age main effect, Ps > 0.05).

(G) Separate groups of infant and adult guinea pigs were trained in a water
maze and tested 1 (P17 n = 8, P60 n = 8) or 28 days later (P17 n = 8, P60 n = 8).
(H) Both infant and adult guinea pigs showed persistent spatial memory
during probe tests (age × delay interaction, P > 0.05; age main effect, F1,28 =6.05, P < 0.05).

Fig. 6. Increasing neurogenesis promotes forgetting
in infant degus and guinea
pigs. (A) Infant degus weretrained in contextual fear conditioning and then remained
sedentary or given access toa running wheel for 28 days.
Running (B) increased neurogenesis (sedentary n = 4,
running n = 4; t6 = 4.74, P <0.01) and (C) induced forgetting of a context fear memory (sedentary n = 21, running
n = 16; t35 = 4.59, P < 0.001).
(D) Infant degus were trainedin contextual fear conditioning
and then treated with vehicle
or MEM for 28 days. MEM
treatment (E) increased neurogenesis (vehicle n = 8, MEM
n = 5; t11 = 4.41, P = 0.001)
and (F) induced forgetting ofa context fear memory (vehicle n = 12, MEM n = 11; t21 = 5.35, P < 0.001). (G) Infant guinea pigs were treatedwith vehicle or MEM after training in the water maze. MEM treatment (H) increased neurogenesis (vehicle n =3, MEM n = 3; t4 = 3.11, P < 0.05) and (I) induced forgetting of a spatial memory (vehicle n = 11, MEM n = 12;
t21 = 3.32, P < 0.01). In all panels, cells are expressed as number of cells per 1000 mm2. *P < 0.05.

encoding thymidine kinase (HSV-tk) (TK+ mice)(30). In TK+ mice, administration of ganciclovir(GAN) ablates only dividing cells expressing the
tk transgene. TK+ mice and their wild-type (WT)
littermates were trained in contextual fear conditioning and then given access to a running wheel
or housed conventionally for 6 weeks. During thisperiod, mice were treated with GAN to suppress
neurogenesis (Fig. 3A). GAN treatment in TK+
mice limited the running-induced increase in neurogenesis to WT sedentary levels (Fig. 3B) andprevented forgetting (Fig. 3C).
Third, nonrunning interventions that increaseneurogenesis might similarly induce forgettingof established memories. Administering the proneurogenic drugs memantine (MEM) (31) (Fig. 3,

D to F, and fig. S10) or fluoxetine (32) (fig. S11)
after training induced forgetting [see also (33)].
Both the increase in neurogenesis and forgetting
induced by MEM were blocked by activationof the tk transgene in TK+ mice (Fig. 3, G to I).
We also generated transgenic mice in which thetumor suppressor gene p53 was inducibly deleted from neural progenitor cells and their progeny during adulthood (iKO-p53 mice) (Fig. 3J).
Similar to previous studies examining global deletion of p53 (34), conditional deletion of p53
increased the number of proliferating (Ki67+)
cells (fig. S12) and immature (DCX+) neurons(Fig. 3K) in the DG. Furthermore, post-training
deletion of p53 induced forgetting of context fear
memory in adult mice (Fig. 3L).

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Finally, running also induced forgetting ofother hippocampus-dependent memories (incidental context learning, fig. S13; water maze,fig. S14). However, running did not induce forgetting of a conditioned taste aversion memory(fig. S15), which does not depend on the hippocampus (35).
Reducing Neurogenesis Increases Memory
Persistence in Infant Mice
Using genetic and pharmacological strategies, wenext examined whether decreasing neurogenesis
mitigates forgetting normally observed in infantmice (Fig. 1J). To genetically suppress neurogenesis, we administered GAN to infant TK+ and
WT mice (Fig. 4A). GAN treatment reduced thenumber of proliferating (Ki67+) cells and immature (DCX+) neurons in the DG of TK+ micecompared with WT littermates (Fig. 4, B and C).
When tested 1 day after contextual fear conditioning, WT and TK+ mice exhibited equivalentlevels of freezing (Fig. 4D), indicating normal
memory at this short retention delay. However,when separate groups of mice were tested 7 days
after training, TK+ mice froze more than WT
mice (Fig. 4E), and freezing levels were inversely
correlated with levels of neurogenesis (Fig. 4F).
GAN-treated WTand TK+ mice trained without footshocks showed little freezing when tested 7 days
after training (Fig. 4E). These low levels of freezing were similar to those observed in shocked WT
mice, indicating substantial forgetting in WT but
not TK+ mice. Furthermore, the absence of freezing in nonshocked TK+ mice suggests that suppressing neurogenesis (or GAN treatment) does
not simply increase the propensity to freeze.
Using temozolomide (TMZ), a DNA alkylating agent (36), to pharmacologically reduce hippocampal neurogenesis in infant WT mice, we
observed a similar attenuation of forgetting in an
incidental context learning paradigm. Infant mice
were preexposed to a context and then treatedwith TMZ or vehicle for 4 weeks (Fig. 4G). TMZ
treatment suppressed neurogenesis (Fig. 4, H

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RESEARCH ARTICLES
and I) and improved retention of the contextonly memory (Fig. 4J), and there was an inverse
relationship between hippocampal neurogenesis
and freezing (Fig. 4K). TMZ treatment did notdecrease the threshold for freezing, however, as
similar TMZ treatment before learning did notalter freezing levels (fig. S16). During infancy,high levels of proliferation are associated withhigh levels of apoptotic cell death in the subgranular zone (37). However, post-training pharmacological inhibition of cell death alone failed toattenuate forgetting (fig. S17).
Infantile Forgetting Is Absent in Precocial
Guinea Pigs and Degus
As guinea pigs have a longer (~65 days) gestation than mice (~21 days), they are more neurologically mature at birth and have reduced
postnatal hippocampal neurogenesis (38). This
led us to predict that guinea pigs (and possibly
other rodents with similarly extended gestation)
will not exhibit infantile forgetting. To test this,we examined hippocampal neurogenesis andmemory retention in guinea pigs [in which postnatal hippocampal neurogenesis has been described (38)] and degus, another precocial rodent(in which postnatal neurogenesis has not previously been studied). Whereas there is a considerable reduction in proliferating (Ki67+) cells andimmature (DCX+) neurons from P17 to P60 inmice, this reduction was much more modest in
degus and guinea pigs (Fig. 5, A to D). Unlike
infant mice that showed rapid forgetting, infantdegus showed normal retention of a context fear
memory for up to 1 month (Fig. 5, E and F), andinfant guinea pigs showed no change in spatial
memory as a function of retention delay (Fig. 5,
G and H), indicating that memories are persistent
in infant rodent species with low postnatal hippocampal neurogenesis.
Increasing Hippocampal Neurogenesis Is
Sufficient to Induce Forgetting in Infant Guinea
Pigs and Degus
If levels of hippocampal neurogenesis and forgetting are causally related, then increasing hippocampal neurogenesis in degus and guinea pigs
should be sufficient to induce infantile amnesia
in these precocial species. To test this, infant (P17)degus were trained in contextual fear conditioning
and then either housed conventionally, given
access to a running wheel, or treated with MEM
or vehicle for 4 weeks (Fig. 6, A and D). Bothrunning and MEM treatment increased neurogenesis (Fig. 6, B and E) and induced forgetting(Fig. 6, C and F). Similarly, forgetting of a spatial
memory was observed after MEM treatment ininfant guinea pigs (Fig. 6, G to I). These results
indicate that increasing hippocampal neurogenesis
using mechanistically distinct interventions induces
forgetting in precocial rodent species.
Discussion
The hippocampus encodes memories for places
and events (39). The observation that hippo-

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campal neurogenesis persists into adulthood led
to the idea that neurogenesis modulates hippocampal memory function (40). To our knowledge,
all previous studies examining the relationshipbetween hippocampal neurogenesis and memory
have used essentially the same design; they manipulated hippocampal neurogenesis before training and examined the impact of this manipulation
on subsequent memory formation (i.e., they investigated the anterograde effects of manipulating neurogenesis on memory) (40). The viewthat emerged from these studies is that, once
sufficiently mature, new neurons positively contribute to encoding of new hippocampus-dependent
memories, perhaps by providing new substrates
for memory storage (40). Here, we examined
the retrograde impact of similar manipulations ofneurogenesis on memory. Through a series ofstudies, we showed that high levels of neurogenesis disrupt established hippocampus-dependent
memories. As such, our findings reveal a novelrole for neurogenesis in forgetting or memory
clearance, in line with theoretical predictions(12, 14–16).
The hippocampus is thought to rapidly andautomatically encode experiences (41). Because
not all experiences are ultimately remembered,
it is likely that forgetting processes continuously
degrade or clear stored information from the
hippocampus. Our results identify neurogenesis
as one such process that promotes degradation ofhippocampus-dependent memories, most likely
by reconfiguring DG-CA3 circuits. Successful
memory retrieval may result from the reactivationof patterns of neural activity present at the timeof memory encoding (i.e., pattern completion)[e.g., (42–45)]. Because neurogenesis reconfigures hippocampal circuits, this may reduce
the ability of a given set of cues (or inputs) toreinvoke the same pattern of activity (i.e., patterncompletion failure) (46). During infancy, whenneurogenesis levels are elevated, high rates of
decay render hippocampus-dependent memories[that are declarative in nature (21)] inaccessible
at later time points. Reducing neurogenesis at thisdevelopmental stage can increase the persistenceof hippocampus-dependent memories. During
adulthood, when neurogenesis levels are lower,
memories are more resistant to decay. Artificially
increasing neurogenesis after learning, however,may be sufficient to induce forgetting.
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Acknowledgments: This work was supported by grants
from Brain Canada to P.W.F., the Canadian Institutes of
Health Research (CIHR) to P.W.F. (MOP86762) and S.A.J.
(MOP74650), the Centre for Brain and Behavior at the
Hospital for Sick Children to P.W.F. and S.A.J., and the Core
Research for Evolutional Science and Technology of Japan
Science and Technology Agency (JST-CREST) and Ministryof Education, Culture, Sports, Science and Technology
Grants-in-Aid for Scientific Research (KAKENHI) to T.M. K.G.A.
and H.-L.H. (CIHR), A.M.-C. (El Consejo Nacional de Ciencia yTecnología), A.P.Y. (Donald and Doris Milne Alzheimer’s
Disease Fellowship), A.L.W. (Ontario Mental HealthFoundation), and A.G. and B.A.R. (Natural Sciences andEngineering Research Council of Canada) were supported byfellowships. Data are archived in the Dryad repository(doi:10.5061/dryad.s7q3c).

Supplementary Materials
www.sciencemag.org/content/344/6184/598/suppl/DC1
Materials and Methods
Figs. S1 to S17
References (47–58)
25 November 2013; accepted 1 April 201410.1126/science.1248903

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