Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.
ABSTRACT Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
Article: Re-cycling Paradigms: Cell Cycle Regulation in Adult Hippocampal Neurogenesis and Implications for Depression.[show abstract] [hide abstract]
ABSTRACT: Since adult neurogenesis became a widely accepted phenomenon, much effort has been put in trying to understand the mechanisms involved in its regulation. In addition, the pathophysiology of several neuropsychiatric disorders, such as depression, has been associated with imbalances in adult hippocampal neurogenesis. These imbalances may ultimately reflect alterations at the cell cycle level, as a common mechanism through which intrinsic and extrinsic stimuli interact with the neurogenic niche properties. Thus, the comprehension of these regulatory mechanisms has become of major importance to disclose novel therapeutic targets. In this review, we first present a comprehensive view on the cell cycle components and mechanisms that were identified in the context of the homeostatic adult hippocampal neurogenic niche. Then, we focus on recent work regarding the cell cycle changes and signaling pathways that are responsible for the neurogenesis imbalances observed in neuropathological conditions, with a particular emphasis on depression.Molecular Neurobiology 03/2013; · 5.74 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: BACKGROUND:: Adult neurogenesis occurs in the hippocampus of most mammals, including humans, and plays an important role in hippocampal-dependent learning. This process is highly regulated by neuronal activity and might therefore be vulnerable to anesthesia. In this article, the authors investigated this possibility by evaluating the impact of propofol anesthesia on mouse hippocampal neurons generated during adulthood, at two functionally distinct maturational stages of their development. METHODS:: Adult-born hippocampal neurons were identified using the cell proliferation marker bromodeoxyuridine or a retroviral vector expressing the green fluorescent protein in dividing cells and their progenies. Eleven or 17 days after the labeling procedure, animals (n = 3-5 animals per group) underwent a 6-h-long propofol anesthesia. Twenty-one days after labeling, the authors analyzed the survival, differentiation, and morphologic maturation of adult-born neurons using confocal microscopy. RESULTS:: Propofol impaired the survival and maturation of adult-born neurons in an age-dependent manner. Anesthesia induced a significant decrease in the survival of neurons that were 17 days old at the time of anesthesia, but not of neurons that were 11 days old. Similarly, propofol anesthesia significantly reduced the dendritic maturation of neurons generated 17 days before anesthesia, without interfering with the maturation of neurons generated 11 days before anesthesia. CONCLUSIONS:: These results reveal that propofol impairs the survival and maturation of adult-born hippocampal neurons in a developmental stage-dependent manner in mice.Anesthesiology 01/2013; · 5.36 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Extinction of fear memory is a particular form of cognitive function that is of special interest because of its involvement in the treatment of anxiety and mood disorders. Based on recent literature and our previous findings (EMBO J 30(19):4071-4083, 2011), we propose a new hypothesis that implies a tight relationship among IGF signaling, adult hippocampal neurogenesis and fear extinction. Our proposed model suggests that fear extinction-induced IGF2/IGFBP7 signaling promotes the survival of neurons at 2-4 weeks old that would participate in the discrimination between the original fear memory trace and the new safety memory generated during fear extinction. This is also called "pattern separation", or the ability to distinguish similar but different cues (e.g., context). To understand the molecular mechanisms underlying fear extinction is therefore of great clinical importance.Cellular and Molecular Life Sciences CMLS 03/2013; · 6.57 Impact Factor
, 805 (2003);
et al.Luca Santarelli,
Behavioral Effects of Antidepressants
Requirement of Hippocampal Neurogenesis for the
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Requirement of Hippocampal
Neurogenesis for the Behavioral
Effects of Antidepressants
Luca Santarelli,1* Michael Saxe,1* Cornelius Gross,1
Alexandre Surget,2Fortunato Battaglia,3Stephanie Dulawa,1
Noelia Weisstaub,1James Lee,1Ronald Duman,4
Ottavio Arancio,3Catherine Belzung,2Rene ´ Hen1†
Various chronic antidepressant treatments increase adult hippocampal neurogen-
esis, but the functional importance of this phenomenon remains unclear. Here,
using genetic and radiological methods, we show that disrupting antidepressant-
receptor null mice were insensitive to the neurogenic and behavioral effects of
fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted
region of mouse brain containing the hippocampus prevented the neurogenic and
behavioral effects of chronic antidepressants may be mediated by the stimulation
of neurogenesis in the hippocampus.
Depression and anxiety disorders are com-
mon public health problems, with 10 to 20%
lifetime prevalence (1), yet the mechanisms
underlying their pathophysiology are still
poorly understood. Most antidepressant drugs
(ADs) increase levels of the monoamines se-
rotonin [5-hydroxytryptamine (5-HT)] and/or
noradrenaline (NA); this suggests that bio-
chemical imbalances within the 5-HT/NA
systems may underlie the pathogenesis of
these disorders—a theory also known as the
monoaminergic hypothesis of depression.
But although ADs produce a rapid increase in
extracellular levels of 5-HT and NA, the on-
set of an appreciable clinical effect usually
takes at least 3 to 4 weeks (1). This delay
suggests that slow neurochemical and struc-
tural changes take place within the limbic
target areas of monoaminergic projections.
Such changes may counteract neuropatho-
logical alterations that initiate or perpetuate
anxiety and depressive disorders. Indeed, re-
cent post mortem and brain imaging studies
have revealed atrophy or loss of neurons in
the prefrontal cortex and hippocampus of
both depressed and anxious patients (2–4),
and some of these alterations may be reversed
by ADs (5). In addition, stress—an environ-
mental factor capable of precipitating depres-
sive episodes in humans—causes cell death,
dendritic shrinkage, and decreased levels of
neurotrophins within the hippocampus (6–8),
as well as a reduction in hippocampal granule
cell neurogenesis (9). Although it is unclear
whether these events contribute to the patho-
genesis of depression, the recent observation
that adult hippocampal neurogenesis is de-
creased by stress and increased by chronic
antidepressants (9, 10) suggests that this pro-
cess may be involved in both the pathogene-
sis and treatment of mood disorders.
Adult neurogenesis—the production of
new neurons within the brain of an adult
organism—is primarily confined to two dis-
crete areas: the subventricular zone (SVZ),
and the subgranular zone (SGZ) of the den-
tate gyrus (11). In the hippocampus of both
rodents and primates, adult-generated neuro-
nal cells arise from progenitor cells in the
SGZ and migrate into the granule cell layer,
where they differentiate into granular neurons
(12). Recently, these cells were shown to be
capable of functional integration into the hip-
pocampal circuitry, as evidenced by their re-
sponsiveness to stimulation of the perforant
path and their ability to extend axonal pro-
jections to appropriate target areas (13). Al-
though the function of newly generated cells
in the adult hippocampus is still unclear, it
has been suggested that young granule cells
constitute a distinct population exhibiting a
greater degree of plasticity than mature neu-
rons (12). In the present study, we asked
whether an increase in neurogenesis is re-
quired for antidepressant action.
reliably demonstrate changes in mouse behav-
ior after chronic, but not acute, treatment with
ADs (14). We adapted the novelty-suppressed
feeding (NSF) test, previously used to assess
chronic antidepressant efficacy in rats (15), to
the 129/Sv mouse strain (16). We treated adult
mice orally with fluoxetine, imipramine, desi-
pramine, haloperidol, or vehicle for either 5 or
28 days before assessing latency to feed in the
NSF test (17). Mice treated with either fluox-
on latency to feed relative to vehicle-treated
mice, whereas all three antidepressants (but not
haloperidol) produced significant decreases in
latency to feed in mice treated for 28 days (Fig.
1A). The slow appearance of these changes
resembles the delay in the onset of AD efficacy
Because ADs are known to have various
effects on appetite, the feeding drive of each
mouse was assessed by returning it to the fa-
miliar environment of the home cage immedi-
ately after the test and measuring the amount of
food consumed over a period of 5 min. None of
the drugs tested produced a significant change
in food consumption after either subchronic or
chronic treatment (Fig. 1B).
Effects of fluoxetine.
pressant treatments, including fluoxetine, in-
crease neurogenesis in the dentate gyrus of
the rat hippocampus, as evidenced by an in-
1Center for Neurobiology and Behavior, Columbia
University, New York, NY 10032, USA.2Psychobiolo-
gie des Emotions, Universite ´ Franc ¸ois Rabelais, Tours
37200, France.3Nathan Kline Research Institute, New
York University School of Medicine, New York, NY
10016, USA.4Laboratory of Molecular Psychiatry, De-
partment of Psychiatry, Yale University, New Haven,
CT 06508, USA.
*These authors contributed equally to this work.
†To whom correspondence should be addressed. E-
Fig. 1. The NSF paradigm. (A) Treatment with
antidepressants, but not haloperidol, for 28
days resulted in a decreased latency to feed,
whereas treatment for 5 days was ineffective
(mean percentage of vehicle control latency ?
SEM), as shown by unpaired t tests between
vehicle (V) and fluoxetine (F), imipramine (I),
desipramine (D), or haloperidol (H) (*P ? 0.05,
**P ? 0.01; n ? 13 to 15 mice per group). (B)
None of the drugs tested produced a significant
change in home cage (h.c.) food consumption
(mean ? SEM).
www.sciencemag.orgSCIENCEVOL 3018 AUGUST 2003
on May 17, 2008
creased number of progenitor cells that incor-
porate the DNA synthesis marker 5-bromo-
2?-deoxyuridine (BrdU) and differentiate into
mature neurons (10). We thus treated adult
mice with either vehicle or fluoxetine for 5,
11, or 28 days; all mice were injected with
BrdU (4 ? 75 mg/kg) on the final day of
treatment and were killed 24 hours later. Flu-
oxetine caused a 60% increase in the number
of BrdU-positive cells in the dentate gyrus of
mice treated for 11 or 28 days, but it had no
effect after 5 days (Fig. 2, A and B).
Several studies have shown that cells born
in the SGZ of the adult rodent hippocampus
express markers of adult neurons as they differ-
entiate and mature (12). Mice were killed 4
weeks after injection of BrdU, and brain sec-
tions were colabeled with antibodies to BrdU
and a neuronal marker [neuron-specific nuclear
protein (NeuN)] or an astroglial marker [glial
fibrillary acidic protein (GFAP)] (Fig. 2, C and
D) to reveal the fate of BrdU-labeled cells after
chronic treatment with either fluoxetine or ve-
hicle. Analysis of the BrdU-positive cells
showed that 70 ? 2% expressed NeuN, where-
as only 15 ? 3% expressed GFAP. As previ-
ously reported, these proportions were not in-
fluenced by AD treatment (10).
Among the 14 known 5-HT receptor sub-
types, the 5-HT1Areceptor has been prominent-
ly implicated in the modulation of mood and
anxiety-related behaviors (18, 19). We com-
pared the effects of serotonin- and norepineph-
rine-enhancing ADs in wild-type (WT) mice
and in mice lacking this receptor [5-HT1Are-
ceptor knockout (KO) mice]. WT and KO mice
were treated with fluoxetine, imipramine, desi-
pramine, or vehicle for a period of 28 days
before being tested in the NSF paradigm. KO
mice displayed a higher latency than their lit-
termate controls to begin feeding (Fig. 3A), in
agreement with their increased levels of anxi-
ety-like behaviors (19). In addition, KO mice
were insensitive to the effects of chronic fluox-
etine but were still responsive to both imipra-
mine and desipramine (Fig. 3A).
5-HT1Areceptors is sufficient to alter NSF
behavior, we administered a 5-HT1A–selec-
tive agonist (8-OH-DPAT) for 28 days before
performing the test. 8-OH-DPAT significant-
ly decreased latency to feed in WT mice but
was ineffective in KO mice (Fig. 3B), indi-
cating that its effects were mediated by
WT and KO mice were injected with BrdU
after a 27-day treatment with fluoxetine, imip-
ramine, or vehicle. One group was killed 24
hours later to assess the effect of ADs on cell
proliferation. Fluoxetine caused a doubling of
BrdU-labeled cells in WT mice but had no
effect in KO mice (Fig. 3C). Further paralleling
the behavioral data (Fig. 3A), chronic treatment
with imipramine induced a significant increase
in BrdU-labeled cells in both WT and KO mice
(Fig. 3C). A second group of mice was killed 28
days after BrdU injection to determine whether
chronic AD treatment affects newborn cell sur-
vival. Similar to the pattern of responsiveness in
the proliferation experiment, fluoxetine had an
effect in WT but not KO mice, whereas imip-
These results indicate that 5-HT1Arecep-
tors are required for fluoxetine-induced but
not imipramine-induced neurogenesis. To
test whether activation of this receptor is
sufficient to enhance cell proliferation, we
treated WT and KO mice chronically with
8-OH-DPAT or vehicle before BrdU injec-
tion. In WT mice, 8-OH-DPAT caused an
increase in cell proliferation similar to that
seen after AD treatment (Fig. 3D). This effect
was not observed in KO mice, indicating that
the action of 8-OH-DPAT was specific to
Effects of hippocampal irradiation. To
test whether hippocampal neurogenesis par-
ticipates in the mechanism of action of ADs,
we sought to disrupt this process. Long-term
Fig. 2. Chronic fluoxetine treatment increases
BrdU uptake and neurogenesis in the dentate
gyrus. (A) The number of BrdU-positive cells was
significantly increased after 11 and 28 days of
treatment with fluoxetine (F) relative to vehicle
(V) (mean percentage of BrdU-positive cells in
vehicle mice ? SEM; Fisher post hoc analysis; n
? 7 to 10). (B) BrdU immunoreactivity in the
dentate gyrus after a 28-day treatment. Cell
counts were made in the granule cell layer (GCL)
and in the SGZ. Scale bar, 200 ?m. (C and D) Confocal micrographs of cells double-labeled for BrdU
(green) and NeuN or GFAP (red). Scale bar, 10 ?m.
Fig. 3. Requirement of 5-HT1Areceptors
for fluoxetine’s effects on anxiety-related
behaviors and hippocampal neurogenesis.
(A and B) Novelty-suppressed feeding. (A)
Fluoxetine, imipramine, and desipramine
(F, I, and D) decreased latency to feed,
relative to vehicle (V), in WT mice. Only
imipramine and desipramine were effective
in KO mice. Analysis of variance (ANOVA)
revealed significant effects of AD treat-
ment (F3,77? 5.8, P ? 0.0012), genotype
(F1,77? 33.3, P ? 0.0001), and an interac-
tion between the two [F3,77? 6.2, P ?
0.0008 (n ? 10 to 15)]. Differences be-
tween vehicle and treatment were calcu-
lated by Fisher post hoc test. (B) A 28-day
8-OH-DPAT (DPAT) regimen decreased la-
tency to feed in WT but not KO mice
(planned Fisher post hoc test, n ? 11 to
20). (C and D) BrdU uptake 24 hours after
injection. (C) After a 4-week treatment
with ADs or vehicle, imipramine increased
the number of BrdU-positive cells in both genotypes, but fluoxetine was effective only in WT mice.
ANOVA found significant effects of AD treatment (F2,30? 9.4, P ? 0.0006) and interaction between
treatment and genotype (F2,30? 3.2, P ? 0.05). Differences between vehicle and either fluoxetine or
imipramine were assessed by Fisher post hoc test (n ? 6 or 7). (D) WT but not KO mice showed
DPAT-induced increases in BrdU-labeled cells. ANOVA revealed an effect of DPAT treatment (F1,28?
4.3, P ? 0.046) and an interaction between treatment and genotype (F1,28? 5.8, P ? 0.02). Differences
between sham and DPAT-treated mice were assessed by Fisher post hoc analysis (n ? 7 to 9). Values
are means ? SEM (*P ? 0.05, **P ? 0.01).
R E S E A R C H A R T I C L E
8 AUGUST 2003VOL 301SCIENCEwww.sciencemag.org
on May 17, 2008
reductions in cell proliferation within the
dentate gyrus have previously been reported
after low-dose x-irradiation of the heads of
rats (20). To determine whether focal irradi-
ation can produce similar effects in mice, we
delivered fractionated, low doses of x-rays to
the hippocampus while sparing the body and
most of the brain (Fig. 4, A and B) (21).
Irradiation resulted in ?85% reduction in
BrdU-positive cells in the SGZ. This effect
persisted at the time of behavioral testing
(Fig. 4C) and lasted for at least 8 weeks after
delivery of the final x-ray dose.
The number of BrdU-positive cells in the
SVZ was unaltered by irradiation (Fig. 4C),
indicating that exposure to x-rays was con-
fined to the hippocampus and the overlying
and underlying structures. As shown earlier
(10), chronic treatment with fluoxetine had
no effect in the SVZ (Fig. 4C).
Previous studies in the rodent have shown
ablation of precursor cells by inducing apopto-
sis (22). We thus subjected a group of mice to
one 15-Gy dose of x-rays (the same cumulative
dose given in the behavioral experiments) and
killed them 10 hours later for TUNEL (terminal
ysis. Although few TUNEL-positive nuclei
were found in controls, irradiation caused a
marked increase in the number of apoptotic
nuclei, predominantly confined to the SGZ
(Fig. 4, D and E).
We subjected adult mice to x-rays as de-
with fluoxetine, imipramine, or vehicle, before
assessing their performance in the NSF test
(Figs. 4B and 5A). AD treatment caused a sig-
nificant reduction in latency to feed in sham
mice, but this effect was absent in irradiated
mice. Irradiation did not affect latency to feed in
vehicle-treated mice (Fig. 5A), and no change in
home cage food consumption resulted from ei-
ther drug or x-ray treatment (23). Therefore, the
lack of effect of ADs in the irradiated mice
cannot be explained by an alteration in the feed-
ing drive of these mice, or by a change in their
baseline behavior in the NSF test.
To determine whether the effect of irradia-
tion on antidepressant response specifically in-
volved the brain region containing the hip-
pocampus, rather than being due to a nonspecif-
ic response of the brain to radiological injury,
we designed a sliding lead shield that allows the
another neurogenic region just rostral to the
hippocampus (containing the SVZ), as well as
the nonneurogenic cerebellar region (CRB) cau-
dal to the hippocampus [see (21)]. Mice were
treated as shown in Fig. 4B. There was a signif-
icant main effect of drug treatment on latency
across all groups (Fig. 5B) and no effect of
x-ray, indicating that neither SVZ nor CRB
irradiation attenuates the response to ADs.
Again, no change in food intake as a result of
irradiation or drug treatment was detected in the
food consumption test.
We assessed whether hippocampal irradi-
ation also blocks the effects of fluoxetine in a
second behavioral test, the chronic unpredict-
ment: ablation of cell
exposing the SGZ, the
SVZ, or the cerebellum
(CRB) to x-rays. (B) Ex-
Gy were delivered on
days 1, 4, and 8, and
mice were concurrent-
ly treated with fluox-
etine, imipramine, or
vehicle before the NSF
test on day 28. BrdU
was injected on day 27
to assess cell prolifera-
drastically reduced cell
SGZ but had no effect
in the SVZ (S, sham; X,
x-ray; V, vehicle; F, flu-
and other groups were
assessed by Fisher post
hoc analysis (n ? 7 to
9; **P ? 0.01, †P ?
0.001). (D and E) X-ray
causes apoptosis selectively in the SGZ. Ten hours after x-ray, a large increase in the number
of apoptotic nuclei was observed in the SGZ. Scale bar, 100 ?m.
Fig. 5. X-ray of hippocampus
sponses to antidepressants.
(A and B) Novelty-suppressed
feeding. (A) A 28-day regimen
of fluoxetine (F) or imipra-
mine (I) reduced latency in
sham but not hippocampal-
irradiated mice (X-SGZ), as
indicated by significant ef-
(F2,176? 9.3, P ? 0.0001),
irradiation (F1,176? 9.4, P ?
0.0025), and an interaction
between the two [F2,176?
3.9, P ? 0.02 (ANOVA, n ?
25 to 35)]. Differences be-
tween vehicle (V) and fluox-
found by Fisher post hoc test.
(B) Irradiation of brain re-
gions rostral (X-SVZ) or cau-
dal (X-CRB) to the hippocam-
pus did not prevent the ef-
fects of AD treatment, as
shown by a significant main effect of AD treatment [F2,122? 12.2, P ? 0.0001 (ANOVA, n ?
13 to 15)]; differences between vehicle and fluoxetine or imipramine were assessed by Fisher
planned comparison. (C and D) Effects of CUS procedure. (C) Fluoxetine improved the state of
the coat in sham but not X-SGZ mice, as shown by a significant interaction between x-ray and
fluoxetine treatment [F1,24? 4.6, P ? 0.044 (ANOVA)]. Significant differences between the
fluoxetine-treated sham group and all the others were assessed by Fisher post hoc test (n ?
6 to 8). (D) In the grooming test, fluoxetine decreased latency in sham but not irradiated mice.
ANOVA revealed a significant main effect of fluoxetine (F1,24? 6.4, P ? 0.02) and an
interaction between fluoxetine and x-ray treatments [F1,24? 4.5, P ? 0.043 (n ? 6 to 8 mice
per group)]. Fisher post hoc analyses showed significant differences between the fluoxetine-
treated sham group and all the others. Values are means ? SEM (*P ? 0.05, **P ? 0.01).
R E S E A R C H A R T I C L E
www.sciencemag.orgSCIENCEVOL 3018 AUGUST 2003
on May 17, 2008
able stress (CUS) paradigm. This paradigm
results in a deterioration of the state of the
coat and an impaired grooming response that
can be reversed by chronic, but not acute, AD
treatment (24). Sham and irradiated mice
were subjected to CUS, during which fluox-
etine was administered to half of the mice in
each group. At the end of the stress period,
the state of each mouse’s fur was assessed
and assigned a score based on observations
from several body regions (21). Fluoxetine
treatment was continued for one more week,
after which we measured latency to begin
grooming after application of a sucrose solu-
tion to the snout. Fluoxetine significantly im-
proved the state of the fur in sham mice, and
this effect was absent in irradiated mice (Fig.
5C). Likewise, grooming latency was de-
creased by fluoxetine in sham mice but not in
irradiated mice (Fig. 5D).
We next subjected an independent group of
mice to hippocampal irradiation as described
above. Four weeks later, no discernible changes
in brain structure or integrity were found, as
assessed by Nissl staining and stereological cell
counts conducted within the superior and infe-
rior blades of the dentate gyrus (fig. S2).
To determine whether irradiation alters
the function of mature hippocampal neurons,
we assessed synaptic transmission and plas-
ticity in the CA1 region of hippocampal slic-
es. The input-output relationships between
the Schaffer collateral pathway and CA1 neu-
rons, as well as theta burst–induced long-
term potentiation (LTP), were not altered in
irradiated mice (fig. S3).
The brain area targeted by irradiation in-
cludes not only the hippocampus, but also
structures that are known to be involved in fear
and anxiety responses, such as the hypothala-
mus and the amygdala. To assess the possibility
that the behavioral effects observed after irradi-
ation result from damage to these structures,
rather than from a blockade of neurogenesis in
the hippocampus, we conducted two control
docrine response to stress, as assessed by serum
corticosterone before and after open-field
stress, was unchanged in irradiated mice (fig.
S3C). We next examined the effects of the
irradiation procedure on amygdala function by
means of a cued fear conditioning paradigm
(25). Sham and irradiated mice showed no sig-
nificant difference in percentage of time spent
freezing either before or during the conditioned
stimulus (fig. S3D).
Our data indicate that, in
mice, latency to feed in a novel environment is
decreased specifically by chronic, but not acute,
treatment with antidepressants that act through
either serotonergic or noradrenergic mecha-
nisms (Fig. 1A). A similar decrease in latency
to feed was obtained by chronic activation of
5-HT1Areceptors with the direct agonist 8-OH-
DPAT (Fig. 3B). This observation is consistent
with the clinical use of the partial 5-HT1Aag-
onist buspirone for the treatment of generalized
anxiety disorder and in combination with sero-
tonin selective reuptake inhibitors (SSRIs) for
the treatment of depression (26). Interestingly,
5-HT1Areceptor KO mice responded to the
tricyclic antidepressants (TCAs) imipramine
in the NSF test; this finding suggests that acti-
vation of 5-HT1Areceptors is a critical compo-
nent in the mechanism of action of SSRIs but
not TCAs (Fig. 3A). These results indicate that
serotonin- and norepinephrine-enhancing ADs
act via independent molecular pathways. In-
deed, there is both preclinical and clinical evi-
dence supporting this interpretation (27, 28).
The fact that deletion of the 5-HT1Are-
ceptor resulted in a blockade of both the
behavioral and neurogenic effects of fluox-
etine suggests that these two phenomena may
be causally related. Further support for this
hypothesis comes from the fact that disrupt-
ing hippocampal neurogenesis with x-irradi-
ation blocked the effects of chronic AD treat-
ment. It is unlikely that the lack of AD effect
was due to nonspecific disruption of limbic
circuits caused by irradiation, as evidenced
by normal behavioral and neurochemical re-
sponses to fearful or stressful stimuli, as well
as normal synaptic plasticity in the LTP par-
adigm (fig. S3).
Although our data show a strong correspon-
dence between behavior and neurogenesis, we
(i) 5-HT1AKO mice show higher levels of
anxiety-related behaviors in the NSF test, as
well as in a number of other conflict tests (Fig.
3A) (29), but have WT levels of basal neuro-
genesis; and (ii) a 28-day ablation of neurogen-
esis in vehicle-treated mice does not produce
any behavioral deficit in either the NSF or CUS
test (Fig. 5). Concerning the first point, we have
previously shown that the anxious-like pheno-
type of the 5-HT1AKO mice results from the
lack of expression of this receptor during the
early postnatal period (19); therefore, it is likely
that the mechanisms underlying this phenotype
are developmentally determined and indepen-
dent of adult hippocampal neurogenesis. Re-
garding the second point, it is possible that a
longer period of ablation is necessary to reveal
behavioral deficits in the NSF and CUS para-
digms and thereby uncover a potential role of
basal hippocampal neurogenesis. Alternatively,
the functional properties of neurons that are
different from those of cells generated in base-
line conditions. In either case, the lack of effect
of irradiation on basal behavioral responses in
the NSF and CUS suggests that our focal x-ray
procedure does not elicit a nonspecific behav-
ioral impairment. The specificity of the effects
of hippocampal irradiation is also supported by
the fact that the irradiation of other brain re-
gions does not alter the behavioral response to
ADs in the NSF test (Fig. 5B). These results
strengthen our hypothesis that neurogenesis
contributes to the effects of antidepressants, but
we cannot exclude the possibility that other
consequences of hippocampal irradiation con-
tribute to the lack of effect of antidepressants.
The hippocampus has long been associated
with learning and memory processes, but there
is increasing evidence that this structure is also
involved in the modulation of emotional re-
sponses (30–33). Lesions of the ventral hip-
pocampus or local administration of pharmaco-
logical agents result in altered behavior in a
number of rodent models of anxiety (32, 34–
38). Recently, a double dissociation was found
regarding the roles of the dorsal and ventral
hippocampus in spatial learning versus hypo-
neophagia, an anxiety test that is similar to the
NSF test used in the present study. Specifically,
whereas dorsal hippocampal lesions had an ef-
fect on spatial learning but not on hyponeopha-
gia, ventral lesions decreased hyponeophagia
but had no effect on learning (39). Thus, a
functional differentiation of the hippocampus
may exist along its dorsoventral axis.
In further support of the hippocampus’s in-
volvement in mood regulation are recent re-
ports that manipulations of transcription or neu-
rotrophic factors in this structure can produce
an antidepressant-like effect (40). Moreover,
there is evidence in both the rodent and human
literatures that chronic stress and depression
result in hippocampal atrophy, and that these
effects can be reversed by certain antidepres-
sants (5, 6, 41). Our results suggest that strate-
gies aimed at stimulating hippocampal neuro-
genesis could provide novel avenues for the
treatment of anxiety and depressive disorders.
References and Notes
1. M. L. Wong, J. Licinio, Nature Rev. Neurosci. 2, 343
2. T. V. Gurvits et al., Biol. Psychiatry 40, 1091 (1996).
3. P. J. Shah, K. P. Ebmeier, M. F. Glabus, G. M. Goodwin,
Br. J. Psychiatry 172, 527 (1998).
4. Y. I. Sheline, P. W. Wang, M. H. Gado, J. G. Csernansky,
M. W. Vannier, Proc. Natl. Acad. Sci. U.S.A. 93, 3908
5. B. Czeh et al., Proc. Natl. Acad. Sci. U.S.A. 98, 12796
6. B. S. McEwen, Annu. Rev. Neurosci. 22, 105 (1999).
7. R. S. Duman, G. R. Heninger, E. J. Nestler, Arch. Gen.
Psychiatry 54, 597 (1997).
8. R. Sapolsky, Stress, the Aging Brain and the Mecha-
nism of Neuron Death (MIT Press, Cambridge, MA,
9. E. Gould, P. Tanapat, B. S. McEwen, G. Flugge, E.
Fuchs, Proc. Natl. Acad. Sci. U.S.A. 95, 3168 (1998).
10. J. E. Malberg, A. J. Eisch, E. J. Nestler, R. S. Duman,
J. Neurosci. 20, 9104 (2000).
11. J. M. Garcia-Verdugo, F. Doetsch, H. Wichterle, D. A.
Lim, A. Alvarez-Buylla, J. Neurobiol. 36, 234 (1998).
12. E. Gould, C. G. Gross, J. Neurosci. 22, 619 (2002).
13. H. van Praag et al., Nature 415, 1030 (2002).
14. J. F. Cryan, A. Markou, I. Lucki, Trends Pharmacol. Sci.
23, 238 (2002).
15. S. R. Bodnoff, B. Suranyi-Cadotte, D. H. Aitken, R. Quirion,
M. J. Meaney, Psychopharmacology 95, 298 (1988).
16. The NSF is a conflict test that elicits competing moti-
vations: the drive to eat and the fear of venturing into
the center of a brightly lit arena. Latency to begin eating
has been used as an index of anxiety-like behavior
because classical anxiolytic drugs decrease it.
R E S E A R C H A R T I C L E
8 AUGUST 2003VOL 301SCIENCEwww.sciencemag.org
on May 17, 2008
17. Fluoxetine is an SSRI. Imipramine is a TCA that
blocks the reuptake of both 5-HT and NA. Desi-
pramine is a TCA that selectively blocks NA re-
uptake. Haloperidol is a neuroleptic devoid of an-
18. P. A. Sargent et al., Arch. Gen. Psychiatry 57, 174
19. C. Gross et al., Nature 416, 396 (2002).
20. E. Tada, J. M. Parent, D. H. Lowenstein, J. R. Fike,
Neuroscience 99, 33 (2000).
21. See materials and methods on Science Online.
22. R. Nagai, S. Tsunoda, Y. Hori, H. Asada, Surg. Neurol.
53, 503 (2000).
23. L. Santarelli et al., data not shown.
24. G. Griebel et al., Proc. Natl. Acad. Sci. U.S.A. 99, 6370
25. J. E. LeDoux, P. Cicchetti, A. Xagoraris, L. M. Romanski,
J. Neurosci. 10, 1062 (1990).
26. J. M. Gorman, J. Clin. Psychiatry 63, 17 (2002).
27. P. L. Delgado et al., Biol. Psychiatry 46, 212 (1999).
28. M. E. Page, M. J. Detke, A. Dalvi, L. G. Kirby, I. Lucki,
Psychopharmacology 147, 162 (1999).
29. S. Ramboz et al., Proc. Natl. Acad. Sci. U.S.A. 95,
30. N. McNaughton, Pharmacol. Biochem. Behav. 56, 603
31. H. Eichenbaum, Curr. Biol. 9, R482 (1999).
32. J. A. Gray, N. MaNaughton, The Neuropsychology of
Anxiety (Oxford Univ. Press, Oxford, ed. 2, 2000).
33. G. Kempermann, Bipolar Disord. 4, 17 (2002).
34. J. Menard, D. Treit, Behav. Pharmacol. 9, 93 (1998).
35. S. E. File, P. J. Kenny, S. Cheeta, Pharmacol. Biochem.
Behav. 66, 65 (2000).
36. J. Menard, D. Treit, Brain Res. 888, 163 (2001).
37. R. M. Deacon, D. M. Bannerman, J. N. Rawlins, Behav.
Neurosci. 116, 494 (2002).
38. A. Degroot, D. Treit, Brain Res. 949, 60 (2002).
39. D. M. Bannerman et al., Behav. Neurosci. 116, 884
40. Y. Shirayama, A. Chen, S. Nakagawa, D. Russell, R.
Duman, J. Neurosci. 22, 3251 (2002).
41. G. J. Moore et al., Lancet 356, 1241 (2000).
42. We thank J. Malberg, A. Dhilla, and G. Johnson for their
help; W. Dauer, M. Groszer, E. Kandel, P. Rakic, G.
Fishbach, F. Gage, A. Kriegstein, and J. Goldman for
comments and suggestions; and N. Annenberg for his
support. Supported by grants from the National Insti-
tute on Drug Abuse (R.H.), National Institute of Mental
Health (R.H.), and National Alliance for Research on
Schizophrenia and Depression (R.H. and L.S.).
Supporting Online Material
Materials and Methods
Figs. S1 to S3
We demonstrated Rabi oscillations between
the exciton and biexciton states that are similar
to the excited-state Rabi oscillations observed
in atomic systems. This work builds on earlier
demonstrations of the ground-state-to-exciton
Rabi oscillations in QDs (6–9). The result is
important in that the ? pulse in this experiment
plays a critical role in quantum information
processing. It transforms a factorizable state
into an entangled state: ?00? ? ?10? 3 ?00? ?
?11?. It can also be used as the operational pulse
for the CROT. When we combine this result
with the exciton Rabi oscillations, the truth
table of a CROT gate can be mapped out in this
two-bit system. The performance of the gate is
11 February 2003; accepted 27 June 2003
An All-Optical Quantum Gate in
a Semiconductor Quantum Dot
Xiaoqin Li,1Yanwen Wu,1Duncan Steel,1* D. Gammon,2
T. H. Stievater,2D. S. Katzer,2D. Park,2C. Piermarocchi,3
L. J. Sham4
Rabi flopping in an isolated atom. The pulse control of the biexciton dynamics,
serves as the physical basis for a two-bit conditional quantum logic gate. The truth
for the gate operation. Such experimental capability is essential to a scheme for
The rapid evolution of quantum dot (QD) studies
has opened up the possibility of building devices
particular, biexciton transitions in QDs have been
proposed as the physical realization of universal
quantum logic gates (1–3). In a single QD, quan-
tum confinement greatly enhances the higher or-
der Coulomb interaction, leading to the formation
of a bound state of two orthogonally polarized
excitons. The excitation of one exciton affects the
the characteristic conditional quantum dynamics
that are needed for quantum computing.
Fig. 1, A and B, shows the mapping from
the single-particle picture of the two exciton
transitions in a single QD to the excitation-
level diagram. This simplest two-bit system
involves the crystal ground state (?00?), two
distinguishable excitonic states with orthog-
onal polarizations (?01? and ?10?), and the
biexciton state (?11?), where the value 0 (or 1)
represents the absence (or presence) of an
exciton. In a controlled rotation (CROT) gate,
the target bit (the second bit) is rotated
through ? (i.e., from state 0 to 1 or vice
versa) if and only if the control bit (the first
bit) is 1. The unitary transformation matrix of
the CROT shown in Fig. 1C operates on the
input wave function defined in the compu-
tational basis and yields the output wave
function. The CROT gate is equivalent to
the standard controlled-NOT (CNOT) gate,
despite the slight difference in the minus-
sign placement in their matrix representa-
tions (4). Unitary rotations like the CROT
are much easier to realize than the CNOT
operations (4, 5).
1Frontiers in Optical Coherent and Ultrafast Science
(FOCUS), Harrison M. Randall Laboratory of Physics,
The University of Michigan, Ann Arbor, Michigan
Washington, DC 20375–5347, USA.3Department of
Physics and Astronomy, Michigan State University,
East Lansing, MI 48824–2320, USA.4Department of
Physics, The University of California, San Diego, La
Jolla, CA 92093–0319, USA.
2Naval Research Laboratory,
*To whom correspondence should be addressed. E-
Fig. 1. (A) Two exciton transitions in a single
QD. (B) Excitation-level diagram, where ?00?,
?01? and ?10?, and ?11? denote the ground state,
the excitons, and the biexciton, respectively.
The optical selection rules for various transi-
orthogonally and linearly polarized lights. ?
represents the binding energy. (C) The trans-
formation matrix for a CROT gate.
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