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REVIEW
Hippocampal neurogenesis: a biomarker for depression
or antidepressant effects? Methodological considerations
and perspectives for future research
Arnaud Tanti &Catherine Belzung
Received: 26 February 2013 /Accepted: 8 March 2013 / Published online: 18 April 2013
#Springer-Verlag Berlin Heidelberg 2013
Abstract Whereas animal models of depression are associ-
ated with decreased adult hippocampal neurogenesis, anti-
depressant treatments, including pharmacotherapy but also
electroconvulsive therapy, have the opposite action, as they
stimulate cell proliferation and the survival and maturation
of newborn dentate gyrus neurons. Although the lack of
these new cells is not causally involved in depression, as
their absence does not trigger a depressive-episode per se,
their loss has been shown to be causally involved in the
ability of chronic monoaminergic antidepressants to achieve
remission. However, the process by which the stimulation of
hippocampal neurogenesis can elicit recovery after a
depressive-like episode is poorly understood. The accepted
view is that hippocampal newborn neurons integrate into the
hippocampal network and thus participate in hippocampal
cognitive functions crucial for remission. The hippocampus
is associated with a wide range of such functions, including
spatial navigation, pattern separation, encoding of new con-
textual information, emotional behavior and control over the
hypothalamic-pituitary-adrenal axis. The present review aims
at discussing each of these functions and tries to identify the
process by which newborn cells participate in remission after
successfultherapy. Finally, future directionsare proposed for a
better understanding of these mechanisms.
Keywords Neurogenesis .Antidepressants .Depression .
Stress .Hippocampus
Introduction
Since the discovery that chronic treatment with antidepres-
sant drugs elicits an increase in cell proliferation in the
hippocampus (Malberg et al. 2000), a growing body of
research and enthusiasm has been generated regarding the
contribution of adult-generated new hippocampal neurons in
major depression and in the mechanisms involved in remis-
sion after successful therapy. Interest in this field became
even higher with the discovery, in 2003, that these new
neurons are crucial for the action of the antidepressants, as
ablation of these cells via focal irradiation of the dentate
gyrus of the hippocampus suppresses the ability of chronic
monoaminergic antidepressants to induce recovery in mice
(Santarelli et al. 2003). Indeed, this showed that the link
between hippocampal neurogenesis and the therapeutic ac-
tion of the antidepressant is not solely correlative but rather
causal. Later on, additional data supported this hypothesis.
For example, the pro-neurogenic action of treatments
endowed with beneficial effects in the treatment of
depressive-like states has been demonstrated not to be re-
stricted to the classical monoaminergic-acting antidepres-
sants, as similar findings have been observed with other
drugs eliciting antidepressant-like effects in animal models,
including tianeptine (Czéh et al. 2001; McEwen et al. 2002),
CRF
1
or vasopressin V
1b
receptor antagonists (Alonso et al.
2004), glutamatergic agents (Yoshimizu and Chaki 2004),
endocannabinoid ligands (Jiang et al. 2005), or a melanin-
concentrating hormone antagonist (David et al. 2007). Fur-
thermore, the mood stabilizers lithium and valproate also
increase both proliferation and survival of newborn hippo-
campal neurons (Chen et al. 2000; Hanson et al. 2011a; Hao
et al. 2004; Silva et al. 2008). Finally, non-pharmacological
therapies of major depression, such as electroconvulsive
A. Tanti :C. Belzung (*)
UFR Sciences et Techniques, Université François Rabelais
& INSERM 930, Parc Grandmont,
37200 Tours, France
e-mail: catherine.belzung@univ-tours.fr
Cell Tissue Res (2013) 354:203–219
DOI 10.1007/s00441-013-1612-z
therapy (Malberg et al. 2000) or vagal nerve stimulation,
also share the ability to increase hippocampal neurogenesis
(Revesz et al. 2008). All this evidence seems convergent on
the general idea that an increase in the number of newborn
neurons of the hippocampus during adulthood is a property
shared by all treatments enabling remission to be achieved,
even if some data suggest that the picture is not fully
homogeneous, results that have somewhat reduced initial
enthusiasm in this field. For example, repetitive transcra-
nial magnetic stimulation, which is also effective in
achieving recovery, only partly abolishes the stress-
induced decrease of cell proliferation, whereas it sup-
presses the survival rate of proliferating cells (Czéh et
al. 2002). Further, the dual orexin receptor antagonist
almorexant restores behavioral alterations that occur
after chronic stress and normalizes the hypothalamis-
pituitary-adrenal (HPA) axis function but, at the same
time, decreases cell proliferation and neurogenesis with-
in the ventral hippocampus (Nollet et al. 2012). The
clinical relevance of this body of evidence obtained
from preclinical data has also been debated (Gass and
Henn 2009). Indeed, research with human subjects is
difficult to undertake, as no tools that enable the in vivo
imaging of new hippocampal neurons in patients are
available and so their characterization entails post-
mortem immunohistochemistry. This is extremely difficult
to carry out in human subjects, as it requires not only access
to hippocampal samples of humans that have newly died but
also the phenotypic characterization of these patients (e.g.,
whether they used antidepressant medication, or if they
were depressed). Therefore, only a few studies have
been undertaken. Interestingly, some of these studies
have confirmed the preclinical data, as pro-neurogenic
effects of antidepressants have been found in humans
(Boldrini et al. 2012; Boldrini et al. 2009), whereas others
have not (Reif et al. 2006).
The objective of this paper is not to review the literature
on this subject extensively, as such reviews have recently
been published (Bambico and Belzung 2012; David et al.
2010; Hanson et al. 2011b; Petrik et al. 2012; Tanti and
Belzung 2010a) but rather to try to provide a frame enabling
us to understand the way that these new hippocampal neu-
rons can contribute crucially to the etiopathogeny of major
depression or to the ability of drugs to achieve remission.
Indeed, major depression is a complex disorder related to a
complex set of symptoms such as sadness, anhedonia, mo-
tivational decline, apathy and appetite changes that are not
usually related to a defect of hippocampal functions. Fur-
ther, this disease also elicits alterations of the morphology
and the function of a set of brain areas, including of course
the hippocampus but also other areas such as the amygdala,
the lateral habenula, the nucleus accumbens, the cingulate
cortex and several parts of the prefrontal cortex (for reviews,
see Tanti and Belzung 2010b; Willner et al. 2012) together
with alterations in the regulation of the HPA axis (Belzung
and Billette de Villemeur 2010)andinseveralneuro-
transmitter systems (serotonin, noradrenalin, dopamine,
glutamate, gamma amino butyric acid [GABA] and sev-
eral neuropeptides). So, how can new neurons that are
restricted to the dentate gyrus of the hippocampus par-
ticipate in the recovery of a set of symptoms and of
dysfunctions related to such a global brain network?
Does the restoration of a normal level of hippocampal
neurogenesis restore a crucial process that is dysfunc-
tional in depression? What function that is so important
for remission is achieved by the newborn hippocampal
neurons? This review will try to answer these questions.
However, before we can understand which of the functions
related to hippocampal neurogenesis can explain its critical
importance for recovery, we have to analyze, in a more de-
tailed way, the findings regarding the impact of the new
hippocampal cells in affective disorders and therapeutic ef-
fects. Indeed, do the current findings point to an involvement
of neurogenesis (1) in the precipitation of a depressive epi-
sode, (2) in the vulnerability of subjects to depression, or (3) in
the recovery after therapy? Before answering this question, we
have to understand more precisely the way in which antide-
pressants act on newborn neurons and, particularly, whether
they target a specific stage of the maturation of these cells. We
should therefore first detail the process leading to the genera-
tion of newborn neurons.
Generation of newborn hippocampal neurons
New hippocampal neurons do not arise spontaneously. They
are the result of a long maturation process starting with the
proliferation of neural progenitors termed Type-1 progeni-
tors (sometimes also defined as neural stem cells), which are
located in the most inner part of the granule cell layer of the
dentate gyrus of the hippocampus (for a review, see Duan et
al. 2008). These cells express glial fibrillary acidic protein
(GFAP), as do astrocytes but they can be distinguished from
the latter by their lack of expression of S100βand by their
co-expression of brain lipid-binding protein, MUSASHI-1
(an RNA-binding protein), Nestin and Sry-related HMG
box transcription factor Sox2. These cells are capable of
self-renewal but can also generate Type-2 progenitors (also
sometimes referred to as intermediate progenitors) that no
longer express GFAP and possess the ability to generate
Type 3 neural progenitors (neuroblasts) that are still mitotic
cells. This linear model is however sometimes questioned,
as it appears that Type 1 progenitors can also be generated
from Type 2 progenitors (Suh et al. 2007). All three types of
progenitors are capable of self-renewal. Fate determination
occurs after the Type 2 stage, as in Type 3 progenitors the
204 Cell Tissue Res (2013) 354:203–219
aptitude to differentiate into glial cells is lost. The next stage
corresponds to immature neurons. At this stage, cells ex-
press the microtubule-associated protein doublecortin
(DCX), the polysialated form of the neural cell adhesion
molecule (PSA-NCAM) and Prox 1. Immature neurons are
post-mitotic cells that start tangential migration in the gran-
ule cell layer; during this process, they develop dendritic
arborization, contact afferents from the entorhinal cortex
and output mostly on pyramidal cells in the CA3 region of
the hippocampus. By 8 weeks after cell birth, the process
has enabled the generation of mature neurons. Immature
neurons show some unique properties, probably related to
the function of these cells (see below). For example, in these
cells, the neurotransmitter GABA induces depolarization
instead of hyperpolarization that is seen in adult neurons;
this is related to a specific pattern of expression of some
ionic co-transporters. Further, these immature neurons show
enhanced excitability and a low long-term potentiation
(LTP) induction threshold indicating that they possess spe-
cific properties associated with plasticity. At the same time,
they undergo glutamatergic-related competitive survival; if
these cells are not able to integrate into a functional network,
they die. Later on (when 4–6 weeks old), these neurons
display a larger LTP amplitude (Schmidt-Hieber et al.
2004). At approximately 7–8 weeks after the first division,
the newborn cells become functionally indistinguishable
from mature granule cells (Mongiat and Schinder 2011;
Zhao et al. 2008).
Various methodologies enable us to assess each stage of
this maturation process. A first approach consists in labeling
the cells with bromodeoxyuridine (BrdU). Depending upon
the time between the BrdU injection and the killing of the
animals, one can assess proliferation (if BrdU has been
administered 24 h before death) or the survival of the
newborn cells (for example, if the injection occurred 4 weeks
before death). However, this does not reveal the phenotype
(glial or neural) of these cells, the demonstration of which
requires double-labeling with a neuronal marker (for exam-
ple NeuN) or the use of different combinations of endoge-
nous markers. Interpretation of the data is sometimes
difficult. For example, an increase in the number of
immature neurons can be masked by an acceleration of
the maturation of the neurons, the first resulting in an
increase in the number of DCX-positive (DCX+)cells
and the second having the opposite action. In this case,
alternative methods consist in studying the proportion of
DCX+cells exhibiting tertiary/quaternary dendrites,
which is an index of maturation. Assessment of the
proportion of new neurons expressing immediate early
genes after a given stimulation is also possible; as only
themorematurecellswillexpress the immediate early
gene, this proportion indicates the maturation speed
(Snyder et al. 2009).
Do animal models of depression or antidepressant
therapies alter a specific stage of the process leading
to the generation of new neurons in the dentate gyrus?
Two recent reviews have carefully analyzed the literature
(David et al. 2010; Hanson et al. 2011b). Indeed, various
protocols considered as models of depression, including
bulbectomy, chronic stress, or chronic corticosterone admin-
istration, have been applied and the consequences on cell
proliferation or survival have been assessed. On the forty-
eight studies that have been considered by Hanson et al.
(2011b), half determined a decrease in cell proliferation and
an equivalent number did not describe any modification.
One study even attempted a more precise characterization
and showed that the effects of the selective serotonin reup-
take inhibitor fluoxetine were restricted to Type 2 and not
Type 1 progenitor cells (Encinas et al. 2006). The same
picture was found with regard to the effects of chronic
treatments with antidepressant drugs or electroconvulsive
therapy ; half of the studies showed an increase in cell
proliferation, whereas the others found no effect. For sur-
vival, the view is again balanced when considering the
effects of models of depression, as more than half of the
models of stress induced a decrease of survival, whereas a
large majority of studies investigating the effects of treat-
ment found the opposite, i.e., an increase. These variations
are probably related to many factors, including the age of
the animals (for example, chronic fluoxetine does not mod-
ify cell proliferation in middle-aged rodents; Couillard-
Despres et al. 2009), the strain of the mice, the experimental
models used to induce depressive-like behavior and the
antidepressant drug used. Other studies have investigated
the number of immature neurons by using DCX. Interest-
ingly, although chronic fluoxetine treatment increased cell
proliferation and cells expressing mature markers, it did not
alter the number of DCX+ cells suggesting that it accelerat-
ed the maturation of progenitors into neurons (Wang et al.
2008). Similar findings were described by David et al.
(2010) who used a Sholl analysis that enabled them to
distinguish cells according to their dendritic morphology
as DCX+cells without tertiary dendrites and DCX+cells
with tertiary dendrites. They found that chronic treatment
with fluoxetine increased the proportion of DCX+cells
exhibiting tertiary dendrites indicating that the antidepres-
sant treatment accelerated their maturation. This means that
probably more cells enter the DCX+stage but that, as the
maturation rate is increased by the treatment, they will
remain for a shorter time in this stage, resulting in an
apparent absence of effect on the total number of DCX+
cells. A possible interpretation is that the antidepressants
have facilitated a function related to the new hippocampal
cells and that this improves their incorporation into the
corresponding functional network, thereby increasing their
Cell Tissue Res (2013) 354:203–219 205
maturation and survival. If this is true, the ablation of
hippocampal neurogenesis should deteriorate the corre-
sponding function, thus inducing a behavioral or a cog-
nitive phenotype. In this case, loss of these cells could, for
example, modify the behavior of subjects when faced with
particular conditions in which this function is required.
Here, we aim to explore whether these newborn neurons
are involved in functions related to depressive symptomatol-
ogy. However, does ablation of newborn neurons alter
depression-related behaviors?
Can the absence of new hippocampal neurons trigger
depressive-like behaviour?
Nineteen experiments investigated the effects of the loss of
new hippocampal neurons on depressive-like behavior of
rodents (Table 1) that were not subjected to manipulations
usually triggering depressive-like states. They thus assessed
the intrinsic effects of the ablation of the newborn neurons.
Suppression of neurogenesis was carried out by various
strategies, including focal irradiation of the hippocampus
(which only destroys newborn neurons of the hippocam-
pus), peripheral injection of the anti-mitotic agent
methylazoxymethanol (MAM), or genetic strategies
(hGFAPtk or nestin-Bax mice; the latter two strategies sup-
press adult neurogenesis in the whole brain). The behavioral
outcome was then assessed by using the forced swim test
(eight studies), coat state deterioration (two studies), splash
test (one study), sucrose consumption or preference (five
studies), tail suspension (one study), cookie test (one study),
or social interactions (one study). Only four experiments
(21%) revealed behavioral alteration after neurogenesis ab-
lation, whereas the large majority showed no effect (79%).
Notably, the common point of these four studies was that
they were all undertaken in rodents that had been subjected
to ablation not only of hippocampal neurogenesis but also of
olfactory bulb neurogenesis (hGFAPtk mice in two experi-
ments and MAM-treated mice in two other experiments).
Thus, relating the effects that were observed to a specific
impact of the loss of the hippocampal new neurons is
difficult, as these rodents also lacked new born neurons of
the olfactory bulbs, a deficit that might play an important
role in some behaviors that involve olfaction, such as feed-
ing or drinking. Further, olfactory bulbectomy has also been
used as an animal model of depression (Song and Leonard
2005), which might complicate the interpretation of these
four studies. Taken together, most of these studies point to a
consensus toward a lack of impact of neurogenesis ablation
per se on depression-like behavior. However, the loss of
newborn neurons might not trigger a depressive-like episode
but rather alter vulnerability to the effects of factors in-
volved in the etiology of depression. In this case, a
double-hit (ablation of neurogenesis+triggering factor)
would be necessary to observe a phenotype.
Does ablation of hippocampal new neurons affect
vulnerability to depression?
The effects of the ablation of newborn hippocampal neurons
on vulnerability to depression can be investigated by using
two different experimental strategies. (1) We can study the
effects of ablation of hippocampal neurogenesis on behav-
iors or factors associated with the onset of depression, such
as increased anxiety (see Table 1) or a defect in the regula-
tion of the HPA axis, which regulates the release of stress
hormones. Indeed, heightened anxiety has been shown to
precipitate depressive episodes and anxiety disorders are
highly comorbid with major depression. Further, a de-
fect in the regulation of the HPA axis, such as in
Cushing disease, increases the rate of major depression
episodes. (2) We can associate the ablation of hippocampal
neurogenesis with other factors involved in the onset of de-
pression, such as chronic stress. Here the idea is to study the
addition of two vulnerability factors (a double-hit combining
the loss of newborn neurons and stress) at the onset of a
depressive-like episode with the view that the second hit will
precipitate the onset of the symptoms or potentiate pre-
existing infra-clinic symptoms. An analysis of the studies
based on this second approach is presented in Table 2.
Studies investigating the basal corticosterone levels
after neurogenesis ablation did not show any effect in
basal (non-stressful) situations (Santarelli et al. 2003;
Schloesser et al. 2009;Snyderetal.2011;Surgetet
al. 2011) indicating that newborn neurons do not impact
on the HPA functions in cases in which a subject has
not been challenged by a stressful situation. However, if
the animal is subjected to a challenge, such as a new
situation or an acute restraint, differences appear both at
the neuroendocrine and at the behavioral levels. Indeed,
if mice are introduced into a brightly lighted new arena
or are restrained, animals with a defect in neurogenesis
show increased corticosterone levels (Schloesser et al.
2009; Snyder et al. 2011) and this parallels behavioral
results. Moreover, anxiety-like behavior (Table 1)has
been investigated in a range of test situations based on
forced confrontation of rodents with novelty (novelty-
induced suppression of feeding; 11 experiments), elevat-
ed plus maze (five experiments), light/dark boxes (five
experiments), open field (4 experiments), O-maze (three ex-
periments), novelty-induced hypophagia (two experiments),
marble burying (one experiment) and predator avoidance (one
experiment)). Interestingly, seven of these 32 experiments
(again 21%) revealed an anxiogenic-like effect. This percent-
age remains low.
206 Cell Tissue Res (2013) 354:203–219
Table 1 Does suppression of neurogenesis lead to a depressive/anx-
ious-like phenotype? Studies investigating the behavioral effects of
neurogenesis ablation are listed according to the behavioral paradigms
used, the method of ablation and whether suppression of neurogenesis
leads to increased anxious/depressive-like behavior (Yes) or no change
(No) in naive animals
Cell Tissue Res (2013) 354:203–219 207
The second approach consists in combining a deficit
in adult neurogenesis with factors conferring a vulnera-
bility to depression, such as chronic stress or chronic
corticosterone. The results are summarized in Table 2
and show a clear picture. Indeed, if we focus on
studies that associate suppression of neurogenesis, vul-
nerability factors and assessment of depressive-related
behaviors or on studies that combined the suppression
of neurogenesis, stress and anxiety behavior, we find a
totalof23experiments(15ondepression-relatedbehav-
iors and eight on anxiety-relate behaviors). Interestingly,
none of the 15 experiments focusing on depression-
related behavior have found a behavioral alteration,
while two of the eight experiments on anxiety behavior
revealed an effect of the ablation of neurogenesis,
both using non-specific suppression of newborn cells
(in the hippocampus and in the olfactory bulbs). This
indicates that the idea that the ablation of hippocampal
neurogenesis might sensitize the subjects to subsequent
stressors does not receive strong experimental support as
(1) the percentage of experiments revealing an effect of
the ablation of newborn neurons on anxiety-behavior
is quasi the same when mice are placed in basal condi-
tions and when they have been challenged by experimen-
tal manipulations mimicking vulnerability factors; (2) a
complete loss of brain neurogenesis, including not only
hippocampal neurogenesis but also neurogenesis in the
olfactory bulbs seems necessary to trigger such effects.
Table 2 Does suppression of neurogenesis precipitate or amplify the
behavioral effects of stress or animal models of depression? Studies
investigating the behavioral effects of neurogenesis ablation are listed
according to the behavioral paradigms used, the method of ablation and
whether suppression of neurogenesis precipitated/increased the depres-
sive/anxious-like phenotype induced by stress exposure or animal
models of depression (Yes) or did not modify the behavioral outcome
of such models (No)
208 Cell Tissue Res (2013) 354:203–219
The ablation of olfactory bulbs has also sometimes been
considered as an animal model of depression. Even if
chronic stress associated to the loss of neurogenesis does
not induce convincing and reproducible behavioral mod-
ifications, chronic stress can indeed elicit an alteration of
the HPA axis responsiveness at higher amplitude in ani-
mals showing a defect of neurogenesis (Snyder et al. 2011)
supporting the idea that a combination of various suscepti-
bility factors induces modifications relevant for the
depressive-like phenotype.
Taken together, these studies suggest a small and not
convincing trend toward an involvement of the newborn
dentate gyrus neuron in vulnerability/resilience to de-
pression, rather than in triggering depressive episodes
per se. The other side of the coin concerns remission
after effective therapy.
Is hippocampal neurogenesis crucial for recovery?
Strong evidence has been obtained regarding the impact of
adult newborn neurons on the ability of chronic monoamin-
ergic antidepressant drugs to achieve recovery. These stud-
ies were undertaken either on naive rodents that had not
been subjected to experimental manipulations to induce a
depressive-like state (Table 3) or on animals in which a
depressive-like state had been induced (Table 4). With re-
gard to the first category, all experiments were performed
after focal irradiation and did not provide strong evidence
that the loss of hippocampal newborn neurons suppressed
the ability of monoaminergic drugs to achieve remission;
indeed, two experiments showed that the effects of fluoxe-
tine and imipramine were suppressed in the novelty-
suppression feeding test and one showed the opposite. The
picture is also balanced concerning the forced swimming
test. However, the relevance of these studies is unclear, since
monoaminergic antidepressant drugs do not elicit recovery
in clinical situations in non-depressed subjects. If one ex-
plores the effect of these compounds in animals that have
been stressed, strong evidence emerges indicating that the
ability to achieve remission is suppressed after the focal
suppression of hippocampal newborn neurons; indeed,
antidepressant-like effects are suppressed in seven studies
out of eight. The sole exception concerns an experiment
involving the forced swim test, which is probably not
relevant for depression but is instead a bio-assay. Anxi-
olytic effects of monoaminergtic compounds were also
suppressed in three studies out of four after the suppression
of neurogenesis induced either by irradiation or by anti-
mitotic drugs. Hence, here, the picture seems monolithic, with
however one exception: the antidepressant-like effects of
monoaminergic antidepressants were not suppressed after
antimitotic-induced suppression of neurogenesis, probably
because the used protocol suppressed only extremely young
cells (see below).
An important point to be addressed here concerns the
developmental stage at which new neurons contribute to the
therapeutic effects of monoaminergic antidepressants. In-
deed, as can be seen from above, the process leading to
the generation of adult-generated newborn neurons is long,
lasting 6-8 weeks. Neural progenitors are unlikely to con-
tribute to the recovery from depression; this might rather be
a property of immature neurons or of neurons that have
reached maturity recently. However, is there any experimen-
tal evidence for this? The first studies investigating the
contribution of new neurons to the effects of fluoxetine used
focal irradiation of the hippocampus. As this methodology
can also elicit neuro-inflammation, the experiments usually
tested the animals several weeks after the irradiation. For
example, in the study of Surget et al. (2011), the behavioral
experiments were undertaken 12 weeks after the focal irra-
diation of the hippocampus, so that most dentate gyrus
neurons aged 0-12 weeks at the time of testing were miss-
ing. This does not provide a tight temporal window. How-
ever, other experiments have provided more precise
information. For example, some studies used an immediate
early gene (e.g., fos) to reveal the activity of precise
populations of new neurons. This was performed by Surget
et al. (2011) who found that fluoxetine increased the recruit-
ment of 4-week-old cells to restore the normal function of
the HPA axis (which is dysfunctional in depressive sub-
jects). Two other studies have provided interesting results
in this regard. First, Bessa et al. (2009)usedMAMto
suppress adult-generated neurons of the hippocampus and
assessed the effects of chronic fluoxetine and imipramine at
2 weeks after the MAM injection. In this case, they found
that the behavioral effects of the two monoaminergic drugs
were not suppressed in the forced swimming test and in the
sucrose preference test, suggesting a lack of impact of
2-week-old cells. These cells were probably too young to
have any impact on the recovery after treatment with mono-
aminergic antidepressants. However, if the impact of MAM
administration was studied on long-term recovery (for ex-
ample, if the behavioral tests are applied 1 month after its
administration), the effects of fluoxetine on the chronic
stress-induced defects in anxiety-like behavior and in work-
ing memory were found to be absent after MAM injection
(Mateus-Pinheiro et al. 2013). This indicates that newborn
cells have to reach the age of 4-6 weeks to impact recovery
after this pharmacological treatment. Remarkably the same
profile can be found regarding the impact of new hippo-
campal neurons in depressive-like behavior; an effect in the
forced swimming test is only found if 4-week-old cells are
suppressed. These findings are also interesting with regard
to the observation that antidepressants stimulate the matu-
ration of new hippocampal cells. These drugs might
Cell Tissue Res (2013) 354:203–219 209
therefore facilitate the recruitment of these neurons for
precise functions, an event that might accelerate their mat-
uration and facilitate their functional integration into the
network and thus decrease their apoptosis.
If 4–to 6-week-old newborn hippocampal neurons con-
tribute to the ability of monoaminergic-acting (and particu-
larly serotoninergic) antidepressant drugs to achieve
remission, little data has been found with respect to putative
drugs acting via non-monoaminergic mechanisms (Tables 3,
4). Indeed, regarding non-aminergic-drugs endowed with
putative antidepressant-like effects, the sole causal evidence
has been obtained with the CB1 (cannabinoid receptor 1)
agonist HU210, as this compound elicits increased
neurogenesis together with antidepressant-like effects that
are abolished after hippocampal irradiation (Jiang et al
2005). However, a similar picture is not found regarding
the involvement of hippocampal neurogenesis in the effects
of CRH-1 (corticotropin-releasing hormone receptor type 1)
, V1b (vasopressin type 1b receptor; Surget et al. 2008), or
MCHR1 (melanocortin hormone receptor 1) ligands (David
et al. 2007). Indeed, six studies have investigated the causal
involvement of dentate gyrus neurogenesis in the
antidepressant-like effects of these molecules and five have
not detected its contribution, as the suppression of these
cells does not abolish the effects of these molecules. Of
course, one can argue that these drugs are in fact not anti-
depressant drugs, as despite a number of preclinical studies
suggesting an antidepressant-like profile of these com-
pounds, little clinical evidence has been found in Phase II
trials with, for example, CRH1 antagonists or V1b antago-
nists (Griebel et al. 2012; Griebel and Holsboer 2012). The
anxiolytic effects of these treatments provide more evidence
in this regard, as out of four such studies, three have shown
that the anxiolytic-like effects of the compounds are
abolished after the suppression of the new neurons.
Finally, hippocampal neurogenesis interestingly also
causally contributes to the antidepressant-like effects of
non-pharmacological treatments of depressive-like pheno-
types, such as environmental enrichment, adrenalectomy, or
hypoxia. Indeed, if we consider only the studies that have
explored this aspect of animal models of depression, we can
observe that eight studies have been undertaken, all leading
to positive effects as the antidepressant-like or anxiolytic-
like effects of these different manipulations are all prevented
after ablation of new neurons. A common denominator of
these and pharmacological treatments could be the
Table 3 Does suppression of neurogenesis lead to a blunted behav-
ioural response to antidepressants in naive animals? Studies investigat-
ing the behavioral effects of antidepressant therapy following
suppression of neurogenesis in naive animals are listed according to
the behavioral paradigms used, the type of antidepressant/mood-im-
proving manipulation used (listed in parentheses following each
reference) and whether arrest of neurogenesis leads to decreased
(Yes ) or intact (No) antidepressant efficacy. No study to our knowledge
has investigated the efficacy of antidepressant treatment following the
arrest of neurogenesis by anti-mitotic drug administration or genetic
manipulation
210 Cell Tissue Res (2013) 354:203–219
Table 4 Does suppression of neurogenesis lead to a blunted behav-
ioural response to antidepressants in animals exposed to a model of
depression? Studies investigating the behavioral effects of antidepres-
sant therapy following suppression of neurogenesis in animals exposed
to a model of depression are listed according to the behavioral
paradigms used, the method of ablation, the type of antidepressant/
mood-improving manipulation used (listed in parentheses following
each reference) and whether arrest of neurogenesis leads to decreased
(Yes ) or intact (No) antidepressant efficacy
Cell Tissue Res (2013) 354:203–219 211
activation of the transcription factor, cAMP response
element-binding protein and the growth factor, brain-
derived neurotropic factor (Gass and Riva 2007).
Which function?
If we consider that neurogenesis in the hippocampus, even if
not causally involved in triggering depressive episodes or in
participating in the vulnerability to depression, is nonetheless
crucial for the ability of monoaminergic antidepressants to
achieve remission, we have now to determine the process by
which this action might occur. Little data is however available
on this subject, which also questions, in a more general way,
the function of dentate gyrus neurogenesis. Indeed, to date,
only a limited understanding of its function is available, as
reflected by a list of factors, including executive functions,
pattern separation, spatial/contextual memory, regulation of
the HPA axis and behavioral coping with stressful situations
(see Fig. 1). The view is that newborn hippocampal neurons
enable the generation of a neural reserve that might be used in
the performance of any of these functions in case the network
underlying has been disturbed.
Neurogenic reserve
Kempermann (2008) has proposed the “neurogenic reserve
hypothesis”. This theory derives from the “neural reserve
theory”promoted by R. Katzman and P. Satz (Katzman
1993; Satz 1993; Stern 2003), which posits that, when faced
with challenging situations that can disrupt normal cognitive
function, the organism can adapt by recruiting specific neu-
rons or networks that can thus be considered a neural re-
serve, enabling plasticity and adaptation. According to
Kemperman (2008), the newborn hippocampal neurons
(even when immature, i.e., during their critical time win-
dow) can be recruited to allow adaptation of the hippocam-
pal network to situations that are experienced for the first
time at moments in the life of the subject in which plasticity
is lower, such as in older age. A prediction related to this
theoretical framework is that the ablation of neurogenesis
might have no direct consequences in normal situations,
whereas it will have a huge impact in cases in which the
subject has been placed in challenging situations such as
chronic stress. One can thus hypothesize that, in such situ-
ations, increased hippocampal neurogenesis would also bet-
ter enable the subject to face changes occurring within their
surroundings, thus increasing adaptability to a challenging
environment. Within this framework, newborn neurons gen-
erated throughout the life of the subject would allow im-
proved coping with stressful situations occurring at older
ages and better resilience during confrontations with envi-
ronmental stress. According to this view, antidepressants
would promote the generation of new neurons to compen-
sate a loss of the neural reserve.
Executive functions
According to theoretical frameworks in the field of cognitive
psychology, executive functions include three fully dissocia-
ble aspects: inhibition, task shifting and updating (Miyake et
al. 2000). As is well established both from clinical and from
preclinical research, the processing of executive functions is
related to the prefrontal cortex (Kesner and Churchwell 2011).
However, the hippocampus is also involved in this function to
some extent and this has relevance to the field of depression
research as, in depressed patients, the executive dysfunction
correlates with the hippocampal volume (Frodl et al. 2006).
Interestingly, the prefrontal cortex and the hippocampus are
highly connected through reciprocal direct or indirect projec-
tions (Godsil et al. 2013; Laroche et al. 2000) and one can thus
propose that the involvement of the hippocampus in this
function partly relies on its connections with the prefrontal
areas. However, little data is available on the involvement of
dentate gyrus neurogenesis in this process, partly also because
of the lack of relevant rodent tests of executive functions.
Indeed, few tasks specific to the inhibition or to flexibility
have been developed in rodents. One can however mention
one study that involved a variant of the active place avoid-
ance task in which an aversive zone was switched from
one place to another (mice have thus to inhibit a learned
response and to shift to a new task); this study showed that
ablation of the newborn hippocampal neurons decreased
performance (Burghardt et al. 2012). One can thus hypoth-
esize that hippocampal neurogenesis deficit induces de-
creased executive performance, which causes non-response
to antidepressant therapy. Indeed, in patients, decreased
executive functions have been related to non-response to
fluoxetine (Dunkin et al. 2000). However, these results
have to receive further experimental and theoretical support.
Pattern separation
The idea that the main function of hippocampal neurogenesis
is to enable pattern separation (the ability to discriminate
among similar experiences, thus transforming identical mem-
ories into non-overlapping representations) has gained much
popularity in last few years, first because this process is unique
in having been related specifically to the dentate gyrus
(Leutgeb et al. 2007) and second because it hasreceived strong
experimental support from studies assessing the effects of
decreased or increased neurogenesis, which respectively have
found a deterioration or improvement of pattern separation
(Clelland et al. 2009; Nakashiba et al. 2012; Sahay et al.
2011;Troneletal.2012). However, the relationship between
pattern separation and depression or the effects of an
212 Cell Tissue Res (2013) 354:203–219
antidepressant remains unclear. First, no clinical or preclinical
evidence reporting that antidepressant therapy modifies perfor-
mance in tasks related to pattern separation in depression has
been published as yet. The same applies to major depression or
depression models in rodents, as no study has shown a deficit
in this process under these conditions. Second, as noticed
above, pattern separation enables two resembling contexts to
be distinguished. Major depression is characterized by a focus
on negative stimuli and by poor processing of hedonic
information. A deficit in pattern separation should elicit an
over-generalization for negative and for positive information;
if the first of these two phenomenon can precipitate depressive-
like behaviors, because it can induce a cognitive bias for
negative events, the second should induce the opposite effect
and one can hardly imagine a way in which this can participate
in the onset of depression or in the ability of treatments to
achieve remission. Future experiments should thus investigate
the effects of stress, of depression and of antidepressants on
Fig. 1 Potential involvement of hippocampal neurogenesis in the
behavioral effects of antidepressants. By promoting the functional
integration of newborn neurons into the hippocampal network, antide-
pressants might strengthen various hippocampus-related functions in
which neurogenesis has been shown to participate. This could in return
facilitate antidepressant-induced remission. According to the neuro-
genic reserve hypothesis, by increasing the pool of newborn
hippocampal neurons, antidepressants might allow the (re)generation
of a neural reserve that could be used to strengthen any of these
functions and to enable better coping and resilience to stress when
confronted with a challenging environment, such as during severe
stress exposure and depression (+,–indicate, respectively, the
strengthening and weakening of the hippocampus contribution to the
listed functions
Cell Tissue Res (2013) 354:203–219 213
pattern separation concerning emotionally relevant positive and
negative information to further determine the way that in-
creased pattern separation might contribute to recovery.
Processing of contextual information
The involvement of the hippocampus in the processing of
contextual (particularly spatial) information and in declarative
memory is well established. A logical proposal is thus that
dentate gyrus neurogenesis might be involved in one or an-
other of these processes. Interestingly, the suppression of
hippocampal neurogenesis has been shown to worsen this
process, whereas new hippocampal neurons are preferentially
activated during spatial or contextual tasks. For example, use
of the Morris water maze, the Barnes maze, or associative
learning, such as contextual fear conditioning, has shown that
the ablation of newborn hippocampal neurons induces a de-
cline of performance (Deng et al. 2009;Dupretetal.2008;
Farioli-Vecchioli et al. 2008; Garthe et al. 2009; Jessberger et
al. 2009; Shors et al. 2001), even if failure to see such effects
has also been observed in some studies (for a review, see
Marín-Burgin and Schinder 2012). Further, by using immedi-
ate early gene immunohistochemistry, increased recruitment
of these new cells when compared to more mature granule
cells of the dentate gyrus has also been described in relation to
learning (Kee et al. 2007; Ramirez-Amaya et al. 2006;
Sandoval et al. 2011; Trouche et al. 2009). These findings
seem relevant to the topic of depression, as models of depres-
sion such as chronic stress have been found to impair perfor-
mance in several hippocampus-dependent learning tasks or to
induce a shift from spatial-based strategies to cued-based
strategies (for a review, see Conrad 2010). Similar findings
have been established by clinical studies assessing
hippocampus-related learning in patients with major depres-
sion (Nissen et al. 2010). Finally, the cognitive decline in-
duced by chronic stress can be prevented by antidepressant
treatment (Elizalde et al. 2008). However, the mechanisms by
which an increase of the processing of contextual information
or of encoding of declarative memories participates in remis-
sion remains to be discovered. The increased number of new
neurons might enable a shift from habit-based strategies asso-
ciated with chronic stress and/or major depression to more
flexible and adaptive strategies and this might, at the same
time but independently, increase performance in declarative
memory and elicit recovery from depressive-like behaviors.
HPA axis
As is well established, the hippocampus, together with other
brain areas such as the prefrontal cortex, participates in neg-
ative feedback over the HPA axis (for a review, see Belzung
and Billette de Villemeur 2010). However, under basal condi-
tions, the involvement of hippocampal neurogenesis in this
function is probably not prominent, as shown by the absence
of HPA alterations after the removal of newborn neurons
(Santarelli et al. 2003; Schloesser et al. 2009;Snyderetal.
2011; Surget et al. 2011), probably because the other brain
areas involved in HPA regulation compensate the
neurogenesis-related loss of function. A different picture is
found after mild stress as, in this case, ablation of
neurogenesis can compromise normal HPA function. Indeed,
in this situation, corticosterone levels have been demonstrated
to require more time to return to pre-stress levels and HPA
regulation is blunted (Snyder et al. 2011). Notably, in this
case, the function of other areas negatively regulating the
HPA axis, such as the prefrontal cortex, is also compromised,
whereas the function of areas positively regulating the HPA,
such as the amygdala, is increased (McEwen 2002). In this
instance, all the systems enabling the compensation for the
loss of the hippocampal system are defective. Therefore, the
recruitment of newborn neurons can be facilitated by antide-
pressant drugs (Surget et al. 2011), which might enable the
loss of function related to the alteration in the other brain areas
participating in this regulation to be compensated. This is
certainly sufficient to explain the way that these cells can
enable antidepressants drugs to achieve recovery. Newborn
neurons are well established as synapsing on CA3 pyramidal
cells and do not directly project to the paraventricular nucleus
of the hypothalamus, the nucleus in which the endocrine stress
axis initiates the process leading to the release of glucocorti-
coids. This action occurs via multisynaptic projections on
relay areas such as the lateral septum, the bed nucleus of the
stria terminalis and several hypothalamic nuclei (Surget et al.
2011).
Behavioural coping with stressful situations; anxiety
behavior
Heightened anxiety might contribute to the onset or to
the maintenance of depressive symptomatology and sup-
pression of anxiety behavior by antidepressants might
thus participate in recovery. The effect of neurogenesis
loss on anxiety behavior occurs in part through connec-
tions arising from the basolateral amygdala. Indeed, ac-
tivity within the basolateral nucleus of the amygdala has
been shown to regulate the activity pattern of hippocam-
pal newborn neurons, as lesions of this brain structure
block the recruitment of new hippocampal neurons in a
contextual fear conditioning task (Kirby et al. 2012). As
high anxiety behavior is reversed by chronic antidepres-
sant drugs (Guilloux et al. 2011), the treatment, by
preventing the anxiety associated with the depressive
symptomatology, might participate in remission. Interest-
ingly, the presence of comorbid anxiety disorders in
depressed patients predicts poor treatment outcome
(Souery et al. 2007).
214 Cell Tissue Res (2013) 354:203–219
We have just reviewed the various functions that have
been proposed to rely on hippocampal neurogenesis. Inter-
estingly, recent evidence suggests that the hippocampus,
even if long considered as being rather functionally homo-
geneous, displays functional dissociation along its septo-
temporal axis, some hippocampal-dependant functions rely-
ing on the septal sub-regions and others on the more tem-
poral sub-regions. For example, use of the Morris water
maze, which enables the measurement of spatial learning,
has shown that the amplitude of the decrease in performance
in this test parallels the magnitude of dorsal (septal) hippo-
campal lesions (Moser et al. 1993,1995). Similarly, lesions
restricted to the dorsal hippocampal have been demonstrated
to interfere with the acquisition of the tone-shock associa-
tion in contextual fear conditioning, which is another
hippocampus-dependant learning task (Kim and Fanselow
1992; Yoon and Otto 2007). Such effects have not been
observed after a lesion restricted to the more ventral part
of the hippocampus, a result that has led to the idea that
only the dorsal hippocampus is involved in spatial or
contextual learning. However, this does not mean that
the ventral part has no functional contribution. Indeed,
specific effects after an ablation restricted to the ventral
hippocampus have also been observed, revealing that this
subpart is instead associated with emotional behaviour.
Moreover, in cases of a specific lesion of the ventral sub-
region, the lesion elicits modified anxiety-like behaviour
in various situations such as novelty suppression of feed-
ing (Bannerman et al. 2002; Burns et al. 1996; McHugh
et al. 2004), exposure to predator-related stimuli
(Blanchard et al. 2005; Pentkowski et al. 2006), elevated
plus maze (Degroot and Treit 2004; Kjelstrup et al. 2002;
Trivedi and Coover 2004) and tone fear conditioning
(Hunsaker and Kesner 2008; Maren and Holt 2004).
Interestingly, lesions of the dorsal hippocampus do not
induce such effects, indicating a double dissociation. These
differences between the two sub-regions are probably related
to a different pattern of inputs/ouputs of the dorsal and
ventral sub-regions.
Therefore, a possible approach for clarifying the func-
tions of the hippocampal newborn neurons relating to de-
pression or to recovery might involve an exploration of
whether animal models of depression or treatment with anti-
depressant compounds impact specifically on septal/dorsal or
on temporal/ventral neurogenesis.
Is there a regional specificity of the impact of depression
models and/or antidepressant treatment on hippocampal
neurogenesis?
Some studies have investigated whether stress or more
generally animal models of depression can impact newborn
neurons specifically in a subpart of the hippocampus. This
has been recently reviewed (A. Tanti and C. Belzung, sub-
mitted). Interestingly, most studies have shown that the
effects are restricted to the more ventral part of the hippo-
campus. One can hypothesize that this might alter functions
related to the ventral part of the hippocampus, as the new-
born neurons located in this sub-region might have a pattern
of input/outputs enabling them to interfere with the activity
of the ventral hippocampus. However, strangely enough, a
mirror picture is not obtained after pharmacotherapy with
monoaminergic antidepressants. Indeed, chronic treatment
with these molecules produces an increase in the number
of newborn neurons not only in the ventral sub-region but
also in the dorsal sub-region, whatever the state of the
animals (irrespective of whether they have been subjected
to experimental manipulations inducing a depressive-like
state before application of the treatment). However, when
focusing on the effects of putative non-monoaminergic anti-
depressants, the picture becomes more precise. For example,
agomelatine induces an increase in neurogenesis that is re-
stricted to the ventral sub-region, indicating that an action on
neurogenesis in this sub-region is sufficient to induce
recovery.
Concluding remarks and future directions
This review clearly underlines the idea that hippocampal
neurogenesis, while not causally involved in the onset of
depression-like symptomatology, is related to the ability
of chronic monoaminergic antidepressants to achieve
recovery. However, the cognitive or the biological mecha-
nism explaining this phenomenon is still poorly understood
and requires further investigations. Newborn neurons func-
tionally integrate into the dentate gyrus network and thus
participate in hippocampal functions crucial for remission.
Several functions have been related to neurogenesis, including
spatial navigation, pattern separation, processing of contex-
tual information, neurogenic reserve, executive func-
tions, anxiety behavior and control over the HPA axis.
Even if experimental data strongly support some of
these hypotheses (for example, the HPA axis), convinc-
ing evidence regarding the other processes is still miss-
ing. This action might in some cases not occur directly
as a result of the deficit of the function of the dentate
gyrus but rather indirectly, through connections of the
hippocampus with other brain areas, such as the amyg-
dala or areas of the HPA axis (Eisch and Petrik 2012).
As the dorsal and the ventral sub-regions of the hippo-
campus have highly distinct patterns of connections, the
impact of models of depression and antidepressants on
dorsal or ventral sub-regions of the hippocampus might
provide some interesting information in this regard.
Cell Tissue Res (2013) 354:203–219 215
Decisive progress in this field is unfortunately ham-
pered by the lack of specific methodology. First, clinical
investigations are hindered by the lack of tools enabling
in vivo neuroimaging of neurogenesis. Therefore, the
few studies that have explored neurogenesis changes in
relation to depression or antidepressants have involved
post-mortem immunohistochemistry, which does not per-
mit the establishment of a comprehensive symptomatic
phenotyping of the patients. Future research should devel-
op radiopharmaceutical molecules tagged with positron-
emitting isotopes that could specifically label proteins
expressed in newborn neurons from various maturation
stages. Some proposals have been made (Couillard-Despres
and Aigner 2011) in this regard. Second, preclinical research
lacks behavioral test situations allowing the easy targeting of
some cognitive processes, such as executive functions. Some
experimental protocols have been designed, such as the go/no
go task to assess inhibition in mice (Gomez et al. 2007)orthe
attentional-set-shifting task to measure aspects of flexibility
(Colacicco et al. 2002; McAlonan and Brown 2003) but all
require long training procedures, so that an assessment of the
contribution of newborn neurons of a precise maturation stage
is not possible. Third, in the clinic, several subtypes of depres-
sion have been described, such as melancholic and atypical
depression. These entities are related to different (sometimes
opposite) cognitive and biological features, including differ-
ences in HPA axis abnormalities, coping styles, sleep pattern
and memory. The availability of animal models of all the sub-
types would certainly help to unravel the contribution of the
new hippocampal cells in these different phenotypes. Finally, a
more precise characterization of the involvement of dorsal or
ventral neurogenesis would undoubtedly improve our under-
standing of the function of neurogenesis with regard to depres-
sion and recovery, possibly pin-pointing specific patterns of
projections of these sub-regions.
References
Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K (2007)
High-speed imaging reveals neurophysiological links to behavior
in an animal model of depression. Science 317:819–823
Alonso R, Griebel G, Pavone G, Stemmelin J, Le Fur G, Soubrié P
(2004) Blockade of CRF(1) or V(1b) receptors reverses stress-
induced suppression of neurogenesis in a mouse model of depres-
sion. Mol Psychiatr 9:278–286
Bambico FR, Belzung C (2012) Novel insights into depression and anti-
depressants: a synergy between synaptogenesis and neurogenesis?
Curr Top Behav Neurosci (in press)
Bannerman DM, Deacon RMJ, Offen S, Friswell J, Grubb M, Rawlins
JNP (2002) Double dissociation of function within the hippocam-
pus: spatial memory and hyponeophagia. Behav Neurosci
116:884–901
Belzung C, Billette de Villemeur E (2010) The design of new antide-
pressants: can formal models help? A first attempt using a model
of the hippocampal control over the HPA-axis based on a review
from the literature. Behav Pharmacol(in press)
Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA,
Almeida OF, Sousa N (2009) The mood-improving actions of
antidepressants do not depend on neurogenesis but are associated
with neuronal remodeling. Mol Psychiatr 14:764-773
Blanchard DC, Canteras NS, Markham CM, Pentkowski NS,
Blanchard RJ (2005) Lesions of structures showing FOS expres-
sion to cat presentation: effects on responsivity to a cat, cat odor,
and nonpredator threat. Neurosci Biobehav Rev 29:1243–1253
Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John
Mann J, Arango V (2009) Antidepressants increase neural progen-
itor cells in the human hippocampus. Neuropsychopharmacology
34:2376–2389
Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann
JJ, Arango V (2012) Hippocampal angiogenesis and progenitor
cell proliferation are increased with antidepressant use in major
depression. Biol Psychiatry 72:562–571
Burghardt NS, Park EH, Hen R, Fenton AA (2012) Adult-born hippo-
campal neurons promote cognitive flexibility in mice. Hippocampus
22:1795–1808
Burns LH, Annett L, Kelley AE, Everitt BJ, Robbins TW (1996) Effects
of lesions to amygdala, ventral subiculum, medial prefrontal cortex,
and nucleus accumbens on the reaction to novelty: implication for
limbic-striatal interactions. Behav Neurosci 110:60–73
Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK (2000)
Enhancement of hippocampal neurogenesis by lithium. J Neurochem
75:1729–1734
Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A,
Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey
TJ (2009) A functional role for adult hippocampal neurogenesis in
spatial pattern separation. Science 325:210–213
Colacicco G, Welzl H, Lipp HP, Wurbel H (2002) Attentional set-
shifting in mice: modification of a rat paradigm, and evidence for
strain-dependent variation. Behav Brain Res 132:95–102
Conrad CD (2010) A critical review of chronic stress effects on spatial
learning and memory. Prog Neuropsychopharmacol Biol Psychiatry
34:742–755
Couillard-Despres S, Aigner L (2011) In vivo imaging of adult
neurogenesis. Eur J Neurosci 33:1037–1044
Couillard-Despres S, Wuertinger C, Kandasamy M, Caioni M,
Stadler K, Aigner R, Bogdahn U, Aigner L (2009) Ageing
abolishes the effects of fluoxetine on neurogenesis. Mol Psychiatry
14:856–864
Czéh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen
M, Bartolomucci A, Fuchs E (2001) Stress-induced changes in
cerebral metabolites, hippocampal volume, and cell proliferation
are prevented by antidepressant treatment with tianeptine. Proc
Natl Acad Sci USA 98:12796–12801
Czéh B, Welt T, Fischer AK, Erhardt A, Schmitt W, Müller MB, Toschi
N, Fuchs E, Keck ME (2002) Chronic psychosocial stress and
concomitant repetitive transcranial magnetic stimulation: effects
on stress hormone levels and adult hippocampal neurogenesis.
Biol Psychiatry 52:1057–1065
David DJ, Klemenhagen KC, Holick KA, Saxe MD, Mendez I, Santarelli
L, Craig DA, Zhong H, Swanson CJ, Hegde LG, Ping XI, Dong D,
Marzabadi MR, Gerald CP, Hen R (2007) Efficacy of the MCHR1
antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-
piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847)
in mouse models of anxiety and depression following acute and
chronic administration is independent of hippocampal neurogenesis.
J Pharmacol Exp Ther 321:237–248
David DJ, Samuels BA, Rainer Q, Wang J-W, Marsteller D, Mendez I,
Drew M, Craig DA, Guiard BP, Guilloux J-P, Artymyshyn RP,
Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R
(2009) Neurogenesis-dependent and -independent effects of
216 Cell Tissue Res (2013) 354:203–219
fluoxetine in an animal model of anxiety/depression. Neuron
62:479–493
David DJ, Wang J, Samuels BA, Rainer Q, David I, Gardier AM, Hen
R (2010) Implications of the functional integration of adult-born
hippocampal neurons in anxiety-depression disorders. Neuroscientist
16:578–591
Degroot A, Treit D (2004) Anxiety is functionally segregated within
the septo-hippocampal system. Brain Res 1001:60–71
Deng W, Saxe MD, Gallina IS, Gage FH (2009) Adult-born hippo-
campal dentate granule cells undergoing maturation modulate
learning and memory in the brain. J Neurosci 29:13532–13542
Duan X, Kang E, Liu CY, Ming G-L, Song H (2008) Development of
neural stem cell in the adult brain. Curr Opin Neurobiol 18:108–115
Dunkin JJ, Leuchter AF, CookIA, Kasl-Godley JE, Abrams M, Rosenberg-
Thompson S (2000) Executive dysfunction predicts nonresponse to
fluoxetine in major depression. J Affect Disord 60:13–23
Dupret D, Revest J-M, Koehl M, Ichas F, De Giorgi F, Costet P, Abrous
DN, Piazza PV (2008) Spatial relational memory requires hippo-
campal adult neurogenesis. PLoS One 3:e1959
Eisch AJ, Petrik D (2012) Depression and hippocampal neurogenesis:
a road to remission? Science 338:72–75
Elizalde N, Gil-Bea FJ, Ramirez MJ, Aisa B, Lasheras B, Del Rio J,
Tordera RM (2008) Long-lasting behavioral effects and recogni-
tion memory deficit induced by chronicmild stress in mice: effect of
antidepressant treatment. Psychopharmacology (Berl) 199:1–14
Encinas JM, Vaahtokari A, Enikolopov G (2006) Fluoxetine targets
early progenitor cells in the adult brain. Proc Natl Acad Sci USA
103:8233–8238
Farioli-Vecchioli S, Saraulli D, Costanzi M, Pacioni S, Cina I, Aceti M,
Micheli L, Bacci A, Cestari V, Tirone F (2008) The timing of
differentiation of adult hippocampal neurons is crucial for spatial
memory. PLoS Biol 6:e246
Frodl T, Schaub A, Banac S, Charypar M, Jäger M, Kümmler P,
Bottlender R, Zetzsche T, Born C, Leinsinger G, Reiser M, Möller
H-J, Meisenzahl EM (2006) Reduced hippocampal volume corre-
lates with executive dysfunctioning in major depression. J Psychia-
try Neurosci 31:316–323
Fuss J, Ben Abdallah NM, Hensley FW, Weber K-J, Hellweg R, Gass P
(2010) Deletion of running-induced hippocampal neurogenesis by
irradiation prevents development of an anxious phenotype in
mice. PLoS One 5:e12769
Garthe A, Behr J, Kempermann G (2009) Adult-generated hippocam-
pal neurons allow the flexible use of spatially precise learning
strategies. PLoS One 4:e5464
Gass P, Henn FA (2009) Is there a role for neurogenesis in depression?
Biol Psychiatry 66:3–4
Gass P, Riva MA (2007) CREB, neurogenesis and depression.
Bioessays 29:957–961
Godsil BP, Kiss JP, Spedding M, Jay TM (2013) The hippocampal-
prefrontal pathway: the weak link in psychiatric disorders? Eur
Neuropsychopharmacol (in press)
Gomez P, Ratcliff R, Perea M (2007) A model of the go/no-go task. J
Exp Psychol Gen 136:389–413
Griebel G, Holsboer F (2012) Neuropeptide receptor ligands as drugs
for psychiatric diseases: the end of the beginning? Nat Rev Drug
Discov 11:462–478
Griebel G, Beeske S, Stahl SM (2012) The vasopressin V(1b) receptor
antagonist SSR149415 in the treatment of major depressive and
generalized anxiety disorders: results from 4 randomized, double-
blind, placebo-controlled studies. J Clin Psychiatry 73:1403–1411
Guilloux J-P, David DJP, Xia L, Nguyen HT, Rainer Q, Guiard BP,
Repérant C, Deltheil T, Toth M, Hen R, Gardier AM (2011)
Characterization of 5-HT(1A/1B)-/- mice: an animal model sen-
sitive to anxiolytic treatments. Neuropharmacology 61:478–488
Hanson ND, Nemeroff CB, Owens MJ (2011a) Lithium, but not
fluoxetine or the corticotropin-releasing factor receptor 1 receptor
antagonist R121919, increases cell proliferation in the adult den-
tate gyrus. J Pharmacol Exp Ther 337:180–186
Hanson ND, Owens MJ, Nemeroff CB (2011b) Depression, antidepres-
sants, and neurogenesis: a critical reappraisal. Neuropsychopharmacol
Off Publ Am Coll Neuropsychopharmacol 36:2589–2602
Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK,
Chen G (2004) Mood stabilizer valproate promotes ERK
pathway-dependent cortical neuronal growth and neurogenesis. J
Neurosci 24:6590–6599
Holick KA, Lee DC, Hen R, Dulawa SC (2008) Behavioral
effects of chronic fluoxetine in BALB/cJ mice do not require
adult hippocampal neurogenesis or the serotonin 1A receptor.
Neuropsychopharmacology 33:406–417
Hunsaker MR, Kesner RP (2008) Dissociations across the dorsal-ventral
axis of CA3 and CA1 for encoding and retrieval of contextual and
auditory-cued fear. Neurobiol Learn Mem 89:61–69
Jayatissa MN, Henningsen K, West MJ, Wiborg O (2009) Decreased
cell proliferation in the dentate gyrus does not associate with
development of anhedonic-like symptoms in rats. Brain Res
1290:133–141
Jessberger S, Clark RE, Broadbent NJ, Clemenson GD Jr, Consiglio A,
Lie DC, Squire LR, Gage FH (2009) Dentate gyrus-specific
knockdown of adult neurogenesis impairs spatial and object rec-
ognition memory in adult rats. Learn Mem 16:147–154
Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji S-P, Bai G, Zhang X
(2005) Cannabinoids promote embryonic and adult hippo-
campus neur ogenesis and produce anxiolytic- and antidepressant-
like effects. J Clin Invest 115:3104–3116
Katzman R (1993) Education and the prevalence of dementia and
Alzheimer’s disease. Neurology 43:13–20
Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential
incorporation of adult-generated granule cells into spatial memory
networks in the dentate gyrus. Nat Neurosci 10:355–362
Kempermann G (2008) The neurogenic reserve hypothesis: what is
adult hippocampal neurogenesis good for? Trends Neurosci
31:163–169
Kesner RP, Churchwell JC (2011) An analysis of rat prefrontal cortex in
mediating executive function. Neurobiol Learn Mem 96:417–431
Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of
fear. Science 256:675–677
Kirby ED, Friedman AR, Covarrubias D, Ying C, Sun WG, Goosens
KA, Sapolsky RM, Kaufer D (2012) Basolateral amygdala regu-
lation of adult hippocampal neurogenesis and fear-related activa-
tion of newborn neurons. Mol Psychiatry 17:527–536
Kjelstrup KG, Tuvnes FA, Steffenach H-A, Murison R, Moser EI,
Moser M-B (2002) Reduced fear expression after lesions of the
ventral hippocampus. Proc Natl Acad Sci USA 99:10825–10830
Lagace DC, Donovan MH, DeCarolis NA, Farnbauch LA, Malhotra S,
Berton O, Nestler EJ, Krishnan V, Eisch AJ (2010) Adult hippo-
campal neurogenesis is functionally important for stress-induced
social avoidance. Proc Natl Acad Sci USA 107:4436–4441
Laroche S, Davis S, Jay TM (2000) Plasticity at hippocampal to
prefrontal cortex synapses: dual roles in working memory and
consolidation. Hippocampus 10:438–446
Lehmann ML, Brachman RA, Martinowich K, Schloesser RJ,
Herkenham M (2013) Glucocorticoids orchestrate divergent effects
on mood through adult neurogenesis. J Neurosci 33:2961–2972
Leutgeb JK, Leutgeb S, Moser MB, Moser EI (2007) Pattern separation in
the dentate gyrus and CA3 of the hippocampus. Science 315:961–966
Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antide-
pressant treatment increases neurogenesis in adult rat hippocam-
pus. J Neurosci 20:9104–9110
Maren S, Holt WG (2004) Hippocampus and Pavlovian fear condi-
tioning in rats: muscimol infusions into the ventral, but not dorsal,
hippocampus impair the acquisition of conditional freezing to an
auditory conditional stimulus. Behav Neurosci 118:97–110
Cell Tissue Res (2013) 354:203–219 217
Marín-Burgin A, Schinder AF (2012) Requirement of adult-born neu-
rons for hippocampus-dependent learning. Behav Brain Res
227:391–399
Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND,
Monteiro S, Patricio P, Almeida OF, Sousa N (2013) Sustained
remission from depressive-like behavior depends on hippocampal
neurogenesis. Transl Psychiatry 3:e210
McAlonan K, Brown VJ (2003) Orbital prefrontal cortex mediates
reversal learning and not attentional set shifting in the rat. Behav
Brain Res 146:97–103
McEwen BS (2002) Sex, stress and the hippocampus: allostasis, allostatic
load and the aging process. Neurobiol Aging 23:921–939
McEwen BS, Magarinos AM, Reagan LP (2002) Structural plasticity
and tianeptine: cellular and molecular targets. Eur Psychiatry 17
(Suppl 3):318–330
McHugh SB, Deacon RMJ, Rawlins JNP, Bannerman DM (2004)
Amygdala and ventral hippocampus contribute differentially to
mechanisms of fear and anxiety. Behav Neurosci 118:63–78
Meshi D, Drew MR, Saxe M, Ansorge MS, David D, Santarelli L,
Malapani C, Moore H, Hen R (2006) Hippocampal neurogenesis
is not required for behavioral effects of environmental enrichment.
NatNeurosci9:729–731
Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager
TD (2000) The unity and diversity of executive functions and their
contributions to complex “frontal lobe”tasks: a latent variable
analysis. Cogn Psychol 41:49–100
Mongiat LA, Schinder AF (2011) Adult neurogenesis and the plasticity
of the dentate gyrus network. Eur J Neurosci 33:1055–1061
Moser E, Moser MB, Andersen P (1993) Spatial learning impairment
parallels the magnitude of dorsal hippocampal lesions, but is
hardly present following ventral lesions. J Neurosci 13:3916–
3925
Moser MB, Moser EI, Forrest E, Andersen P, Morris RG (1995) Spatial
learning with a minislab in the dorsal hippocampus. Proc Natl
Acad Sci USA 92:9697–9701
Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL,
McHugh TJ, Rodriguez Barrera V, Chittajallu R, Iwamoto KS,
McBain CJ, Fanselow MS, Tonegawa S (2012) Young dentate
granule cells mediate pattern separation, whereas old granule cells
facilitate pattern completion. Cell 149:188–201
Nissen C, Holz J, Blechert J, Feige B, Riemann D, Voderholzer U,
Normann C (2010) Learning as a model for neural plasticity in
major depression. Biol Psychiatry 68:544–552
Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S (2012)
Neurogenesis-independent antidepressant-like effects on behavior
and stress axis response of a dual orexin receptor antagonist in a
rodent model of depression. Neuropsychopharmacology
37:2210–2221
Onksen JL, Brown EJ, Blendy JA (2011) Selective deletion of a cell cycle
checkpoint kinase (ATR) reduces neurogenesis and alters responses
in rodent models of behavioral affect. Neuropsychopharmacology
36:960–969
Pentkowski NS, Blanchard DC, Lever C, Litvin Y, Blanchard RJ
(2006) Effects of lesions to the dorsal and ventral hippocampus
on defensive behaviors in rats. Eur J Neurosci 23:2185–2196
Perera TD, Dwork AJ, Keegan KA, Thirumangalakudi L, Lipira CM,
Joyce N, Lange C, Higley JD, Rosoklija G, Hen R, Sackeim HA,
Coplan JD (2011) Necessity of hippocampal neurogenesis for the
therapeutic action of antidepressants in adult nonhuman primates.
PLoS One 6:e17600
Petrik D, Lagace DC, Eisch AJ (2012) The neurogenesis hypothesis of
affective and anxiety disorders: are we mistaking the scaffolding
for the building? Neuropharmacology 62:21–34
Ramirez-Amaya V, Marrone DF, Gage FH, Worley PF, Barnes CA
(2006) Integration of new neurons into functional neural net-
works. J Neurosci 26:12237–12241
Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP
(2006) Neural stem cell proliferation is decreased in schizophre-
nia, but not in depression. Mol Psychiatry 11:514–522
Revest JM, Dupret D, Koehl M, Funk-Reiter C, Grosjean N, Piazza
PV, Abrous DN (2009) Adult hippocampal neurogenesis is
involved in anxiety-related behaviors. Mol Psychiatry 14:959–
967
Revesz D, Tjernstrom M, Ben-Menachem E, Thorlin T (2008) Effects
of vagus nerve stimulation on rat hippocampal progenitor prolif-
eration. Exp Neurol 214:259–265
Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA,
Burghardt NS, Fenton AA, Dranovsky A, Hen R (2011) Increas-
ing adult hippocampal neurogenesis is sufficient to improve pat-
tern separation. Nature 472:466–470
Sandoval CJ, Martinez-Claros M, Bello-Medina PC, Perez O,
Ramirez-Amaya V (2011) When are new hippocampal neurons,
born in the adult brain, integrated into the network that processes
spatial information? PLoS One 6:e17689
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S,
Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R
(2003) Requirement of hippocampal neurogenesis for the behav-
ioral effects of antidepressants. Science 301:805–809
Satz P (1993) Brain reserve capacity on symptom onset after brain
injury: a formulation and review of evidence for threshold theory.
Neuropsychology 7:273–295
Saxe MD, Battaglia F, Wang J-W, Malleret G, David DJ, Monckton JE,
Garcia ADR, Sofroniew MV, Kandel ER, Santarelli L, Hen R,
Drew MR (2006) Ablation of hippocampal neurogenesis impairs
contextual fear conditioning and synaptic plasticity in the dentate
gyrus. Proc Natl Acad Sci USA 103:17501–17506
Schloesser RJ, Manji HK, Martinowich K (2009) Suppression of adult
neurogenesis leads to an increased hypothalamo-pituitary-adrenal
axis response. Neuroreport 20:553–557
Schloesser RJ, Lehmann M, Martinowich K, Manji HK, Herkenham M
(2010) Environmental enrichment requires adult neurogenesis to
facilitate the recovery from psychosocial stress. Mol Psychiatry
15:1152–1163
Schmidt-Hieber C, Jonas P, Bischofberger J (2004) Enhanced synaptic
plasticity in newly generated granule cells of the adult hippocam-
pus. Nature 429:184–187
Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001)
Neurogenesis in the adult is involved in the formation of trace
memories. Nature 410:372–376
Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E (2002)
Neurogenesis may relate to some but not all types of hippocampal-
dependent learning. Hippocampus 12:578–584
Silva R, Mesquita AR, Bessa J, Sousa JC, Sotiropoulos I, Leão P,
Almeida OFX, Sousa N (2008) Lithium blocks stress-induced
changes in depressive-like behavior and hippocampal cell fate:
the role of glycogen-synthase-kinase-3beta. Neuroscience 152:656–
669
Singer BH, Jutkiewicz EM, Fuller CL, Lichtenwalner RJ, Zhang H,
Velander AJ, Li X, Gnegy ME, Burant CF, Parent JM (2009)
Conditional ablation and recovery of forebrain neurogenesis in
the mouse. J Comp Neurol 514:567–582
Snyder JS, Choe JS, Clifford MA, Jeurling SI, Hurley P, Brown A,
Kamhi JF, Cameron HA (2009) Adult-born hippocampal neurons
are more numerous, faster maturing, and more involved in behav-
ior in rats than in mice. J Neurosci 29:14484–14495
Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA (2011) Adult
hippocampal neurogenesis buffers stress responses and depressive
behaviour. Nature 476:458–461
Song C, Leonard BE (2005) The olfactory bulbectomised rat as a
model of depression. Neurosci Biobehav Rev 29:627–647
Souery D, Oswald P, Massat I, Bailer U, Bollen J, Demyttenaere K,
Kasper S, Lecrubier Y, Montgomery S, Serretti A, Zohar J,
218 Cell Tissue Res (2013) 354:203–219
Mendlewicz J, Group for the Study of Resistant D (2007) Clinical
factors associated with treatment resistance in major depressive
disorder: results from a European multicenter study. J Clin Psy-
chiatry 68:1062–1070
Stern Y (2003) The concept of cognitive reserve: a catalyst for re-
search. J Clin Exp Neuropsychol 25:589–593
Suh H, Consiglio A, Ray J, Sawai T, D’Amour KA, Gage FH (2007) In
vivo fate analysis reveals the multipotent and self-renewal capac-
ities of Sox2+ neural stem cells in the adult hippocampus. Cell
Stem Cell 1:515–528
Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, Griebel G,
Hen R, Belzung C (2008) Drug-dependent requirement of hippo-
campal neurogenesis in a model of depression and of antidepres-
sant reversal. Biol Psychiatry 64:293–301
Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C,
Palme R, Griebel G, Ibarguen-Vargas Y, Hen R, Belzung C (2011)
Antidepressants recruit new neurons to improve stress response
regulation. Mol Psychiatry 16:1177–1188
Tanti A, Belzung C (2010a) Neurogenic basis of antidepressant action:
recent advances. In: Cryan JF, Leonard BE (eds) Modern trends in
pharmacopsychiatry, vol 27. Karger, Basel, pp 224–242
Tanti A, Belzung C (2010b) Open questions in current models of
antidepressant action. Br J Pharmacol 159:1187–1200
Trivedi MA, Coover GD (2004) Lesions of the ventral hippocampus,
but not the dorsal hippocampus, impair conditioned fear expres-
sion and inhibitory avoidance on the elevated T-maze. Neurobiol
Learn Mem 81:172–184
Tronel S, Belnoue L, Grosjean N, Revest JM, Piazza PV, Koehl M,
Abrous DN (2012) Adult-born neurons are necessary for extended
contextual discrimination. Hippocampus 22:292–298
Trouche S, Bontempi B, Roullet P, Rampon C (2009) Recruitment of
adult-generated neurons into functional hippocampal networks
contributes to updating and strengthening of spatial memory. Proc
Natl Acad Sci USA 106:5919–5924
Wang J-W, David DJ, Monckton JE, Battaglia F, Hen R (2008) Chronic
fluoxetine stimulates maturation and synaptic plasticity of adult-
born hippocampal granule cells. J Neurosci 28:1374–1384
Willner P, Scheel-Krüger J, Belzung C (2012) The neurobiology
of depression and antidepressant action. Neurosci Biobehav
Rev (in press)
Yoon T, Otto T (2007) Differential contributions of dorsal vs. ventral
hippocampus to auditory trace fear conditioning. Neurobiol Learn
Mem 87:464–475
Yoshimizu T, Chaki S (2004) Increased cell proliferation in the adult
mouse hippocampus following chronic administration of group II
metabotropic glutamate receptor antagonist, MGS0039. Biochem
Biophys Res Commun 315:493–496
Zhao C, Deng W, Gage FH (2008) Mechanisms and functional impli-
cations of adult neurogenesis. Cell 132:645–660
Zhu X-H, Yan H-C, Zhang J, Qu H-D, Qiu X-S, Chen L, Li S-J, Cao X,
Bean JC, Chen L-H, Qin X-H, Liu J-H, Bai X-C, Mei L, Gao T-M
(2010) Intermittent hypoxia promotes hippocampal neurogenesis
and produces antidepressant-like effects in adult rats. J Neurosci
30:12653–12663
Cell Tissue Res (2013) 354:203–219 219
