Neuropharmacology 62 (2012) 21e34

Contents lists available at SciVerse ScienceDirect

Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Review

The neurogenesis hypothesis of affective and anxiety disorders:

Are we mistaking the scaffolding for the building?
David Petrika, Diane C. Lagaceb, Amelia J. Eischa, *
a
Department of Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9070, USA
b
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Hypotheses are scaffoldings erected in front of a building and then dismantled when the building is finished.
Received 4 August 2011 They are indispensable for the workman; but you mustn’t mistake the scaffolding for the building. Johann
Received in revised form Wolfgang von Goethe. The neurogenesis hypothesis of affective disorders e in its simplest form e postulates
3 September 2011
that the generation of neurons in the postnatal hippocampal dentate gyrus is involved in the etiology and
Accepted 6 September 2011
treatment efficacy of major depressive disorder (MDD). The hypothesis was established in the 1990s but
was built on a broad foundation of earlier research on the hippocampus, serotonin and MDD. It has gone
Keywords:
through several growth phases fueled by discoveries both correlative and causative in nature. Recently, the
Hippocampus
Dentate gyrus
hypothesis has also been broadened to also include potential relevance for anxiety disorders, like post-
Adult neurogenesis traumatic stress disorder (PTSD). As any hypothesis should be, it has been tested and challenged, sometimes
Depression vigorously. Here we review the current standing of the neurogenesis hypothesis of affective and anxiety
Anxiety disorders, noting in particular how a central postulate e that decreased neurogenesis results in depression
Post-traumatic stress disorder or anxiety e has, in general, been rejected. We also review the controversies on whether treatments
for these disorders, like antidepressants, rely on intact neurogenesis for their efficacy, and the existence of
neurogenesis-dependent and -independent effects of antidepressants. In addition, we review the implica-
tions that the hypothesis has for the response to stress, PTSD, and the neurobiology of resilience, and
highlight our own work showing that adult-generated neurons are functionally important for the behavioral
response to social stress. We conclude by emphasizing how advancements in transgenic mouse technology,
rodent behavioral analyses, and our understanding of the neurogenesis process will allow us to refine our
conclusions and perform ever more specific experiments. Such scrutiny is critical, since if we “mistake the
scaffolding for the building” we could overlook opportunities for translational impact in the clinic.
This article is part of a special Issue entitled ‘Anxiety and Depression’.
Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction people, but there is an unacceptable percentage of diagnosed

patients with mood disorders who never receive pharmacological
1.1. The problem and it’s existing scaffolding relief, who relapse, or who commit suicide (Tanti and Belzung,
2010; Taylor et al., 2011). Clinical and preclinical research with
Affective and anxiety disorders, like major depressive disorder animal models of these disorders are beginning to unravel their
(MDD), are devastating and staggering in their personal, societal, neurobiological underpinnings, and current progress indicates
financial costs. The existing treatments benefit a great number of promising paths for treatment and perhaps even prevention
(Krishnan and Nestler, 2008, 2011).
Affective and anxiety disorders are distinct diagnostic cate-
gories, but they share key similarities. Like all psychiatric disorders,
Abbreviations: AVb1, arginine vasopressin receptor type 1b; BrdU, bromodeox-
yuridine; CMS, chronic mild stress; Cort, corticosterone; CRF1, corticotropin they have complex etiologies, with a range of genetic, epigenetic,
releasing hormone type 1 receptor; DG, dentate gyrus; GFAP, glial fibrillary acidic neuroanatomical, and experiential causes or triggers under
protein; MAM, methylazoxymethanol acetate; MDD, major depressive disorder; consideration (Covington et al., 2010; Cryan and Slattery, 2010;
PTSD, post-traumatic stress disorder; SGZ, subgranular zone; SS, social defeat Karten et al., 2005; Pittenger and Duman, 2008). Diagnosis of
stress; SSRI, selective serotonin reuptake inhibitor; tk, thymidine kinase; UCMS,
unpredictable chronic mild stress.
these disorders is made based on descriptive, not etiologically-
* Corresponding author. Tel.: þ1 214 648 5549; fax: þ1 214 645 9549. based, symptoms that often overlap and are still widely debated
E-mail address: [email protected] (A.J. Eisch). (American Psychiatric Association, 2000). The essential central

0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropharm.2011.09.003
22 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34

nervous system diagnostic symptoms include depressed mood and several other factors. First, as summarized in Section 2.1, the neu-
anhedonia for affective disorders and anxiety for anxiety disorders. rogenesis hypothesis has gone through several growth phases
The high frequency of comorbidity and similarities between other fueled by correlative research findings (e.g. antidepressants
associated symptoms (such as cognitive function, changes in increase and stress decreases neurogenesis) and very recent caus-
appetite) suggest also that depression and anxiety may have ative research findings (e.g. role of adult-generated hippocampal
a shared etiology. This is also supported by many treatments being neurons in key aspects of the stress response and in cognition). We
indicated for both depression and anxiety. The symptoms of these feel these growth phases and their corresponding results deserve
disorders also indicate the involvement of limbic circuitry, discussion and wider dissemination than they have already
including the hippocampus (Dere et al., 2010; Nemeroff et al., 2006; received. Second, there have been notable advancements made
Perera et al., 2008; Seminowicz et al., 2004; Sheline et al., 2002). In recently in transgenic mouse technology, rodent behavioral anal-
addition, the gastrointestinal, cardiovascular, endocrine, and yses, and our understanding of the neurogenesis process (e.g.
immune systems are also notably affected (e.g. O’Mahony et al., Aasebo et al., 2011; Aimone and Gage, 2011; Dhaliwal and Lagace,
2011; Savignac et al., 2011; Tsigos and Chrousos, 2002). Such 2011; Imayoshi et al., 2011; Kempermann, 2011b; Marin-Burgin
complex, multifaceted disorders likely require equally complex, and Schinder, 2011; Sierra et al., 2011). We feel it is important to
multifaceted hypotheses about their cause and the best avenues for look at past publications relevant to the neurogenesis hypothesis
treatment and even prevention. Some of the most prominent and their respective conclusions with the fresh eye allowed by
hypotheses about the neural and physiological underpinnings of these recent advances. Finally, the surge of work on the neuro-
affective and anxiety disorders involve dysregulation of neuro- genesis hypothesis indicates it is an optimal time to encourage
transmitters (especially monoamines and serotonin) or neuropep- discussion on how the neurogenesis hypothesis can interdigitated
tides; of the endocrine system (especially corticosteroid signaling); with pre-existing “scaffolding” e the hypotheses that have long
or of inflammatory responses (especially cytokines) (e.g. Brown driven our research into and understanding of affective and anxiety
et al., 2004; Luscher et al., 2011; Schwarzer, 2009). disorders.
As an extension of Goethe’s quote offered in the abstract, these Here we combine historical and recent literature review on the
many diverse hypotheses form the “scaffolding” from which neurogenesis hypothesis to briefly review the fundamental infor-
researchers have been trying to gain enough perspective to target mation that non-neurogenesis researchers should know about
treatment and even prevention of mood-related disorders. neurogenesis in general (Section 2.1), and the origin and current
However, as with other psychiatric disorders (e.g. Fernando and status of this hypothesis and its main postulates in particular
Robbins, 2011; Frankland et al., 2008; Gottesman and Gould, (Sections 2.2, 3.1 and 3.2). We also discuss the relevance of this
2003), depression-related disorders may actually be a range of hypothesis for our understanding of the neurobiology of resilience
similar disorders that result from many different factors and thus (Section 3.3). Finally, in Section 4 we propose a restructuring of the
require a range of preclinical and clinical research tactics (Cryan neurogenesis hypothesis and suggest how it may interdigitate well
and Slattery, 2007; Touma, 2011). In addition, depression-related with the many disparate hypotheses of affective and anxiety
disorders may actually represent one major behavioral phenotype disorders.
that results from different etiologies and thus require a range of
research hypotheses. 2. The neurogenesis hypothesis of depression: an overview
Thus, a solitary hypothesis may be insufficient to explain all
cases of the mood-related disorders. Fortunately, with the rapid 2.1. Keystones of adult neurogenesis
rate of research and technical advances in neuroscience, even more
scaffolding e in the form of new, complementary but distinct To understand the neurogenesis hypothesis of affective and
hypotheses e is being erected to help guide the treatment and anxiety disorders, it is necessary to understand the fundamentals,
prevention of these disorders. or keystones, of adult neurogenesis. There are several detailed
reviews on this subject for the reader that requires more depth or
1.2. New scaffolding support from new neurons? more specific knowledge (e.g. Abrous et al., 2005; Balu and Lucki,
2009; Christie and Cameron, 2006; Curtis et al., 2011; Gould,
The focus of this review is one of the newer hypothesis of 2007; Kaneko and Sawamoto, 2009; Kempermann, 2011a; Koehl
affective and anxiety disorders: the neurogenesis hypothesis. In its and Abrous, 2011; Li et al., 2009; Ming and Song, 2011; Suh et al.,
simplest form, the neurogenesis hypothesis states that the gener- 2009; Toni and Sultan, 2011), but the essential information
ation of neurons in the postnatal brain is important for under- needed is provided in this section and in Fig. 1.
standing and treating depression. More recently, the hypothesis has Briefly, neurogenesis occurs throughout life in several regions of
been broadened to also include potential relevance for anxiety the brain. The region that has received the most attention for its
disorders, like post-traumatic stress disorder (PTSD), and thus may involvement in the neurogenesis hypothesis of affective and
hold hope for helping understand diverse response to stress and anxiety disorders is the hippocampal dentate gyrus (DG; Fig. 1AeC).
the neurobiology of resilience. As discussed in detail in Section 3, The DG is host to the subgranular zone (SGZ), the main neurogenic
the neurogenesis hypothesis has two main postulates: decreased region of the hippocampus. The SGZ contains a range of cell types
neurogenesis results in depression or anxiety; and effective phar- that represent different stages of cell and neuron maturity. The
macological or environmental treatment for affective or anxiety maturation of cell lineage in the SGZ is thought to be relatively
disorders requires intact neurogenesis. linear. Many studies have demonstrated that the Type-1 putative
As the neurogenesis hypothesis and its accompanying postu- neural stem cells (also called radial glial cells, Type B, or quiescent
lates have received extensive discussion in recent years (Abrous neural progenitors) give rise to rapidly dividing progenitors, which
et al., 2005; David et al., 2010; Kempermann et al., 2008; in turn divide and give rise to immature neurons, which, if they
Lucassen et al., 2006; Malberg and Schechter, 2005; McEwen survive, become mature DG granule cells (e.g. Encinas et al., 2006;
et al., 2002; Perera et al., 2008; Sahay et al., 2007; Samuels and Kempermann et al., 2004; Seri et al., 2001). Evidence strongly
Hen, 2011; Schmidt and Duman, 2007; Warner-Schmidt and suggests that adult-generated hippocampal neurons incorporate
Duman, 2006), this present review was prompted not by a need to into hippocampal circuitry via projections in the mossy fiber
provide a comprehensive review of existing literature but rather by pathway, and contribute to hippocampal functions relevant to
 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34 23

Fig. 1. Adult hippocampal neurogenesis and the neurogenesis hypothesis of depression. (A) Dissection of the rodent telecephalon reveals a cross-section through the hippocampus
(colored lines) with the dentate gyrus e the site of adult-generated hippocampal neurons e depicted in red. (B) Enlarged schematic of the dentate gyrus shows the superior and
inferior blades of the granule cell layer (GCL, brown) and the subgranular zone (SGZ, red) where the hippocampal neurogenesis occurs in the postnatal period through adulthood.
(C) Higher magnification of the boxed region from (B) displays the phases of adult hippocampal neurogenesis as a function of time. The neural stem cells (NSCs, green) putatively
give rise to the transiently-amplifying progenitors (blue and violet) whose progeny differentiate into immature neurons (dark violet) and finally into fully mature dentate gyrus GC
neurons (red). (D) Under normal, physiological conditions, the process from NSCs to mature GC takes approximately 4e6 weeks. (E) The first postulate of the neurogenesis
hypothesis of depression states that reduced neurogenesis should result in a depressive phenotype. (F) The second postulate of the neurogenesis hypothesis of depression states
that antidepressants require adult neurogenesis for effects in improving mood. As discussed in the text, Fig. 2, and Tables 1 and 2, published work supports aspects of the second,
but not the first, hypothesis.

mood and memory. Neurogenesis is an extremely dynamic process, only when examining many of these contemporary reviews
as the number of cells in each “stage” of neurogenesis can change together that the entire neurogenesis hypothesis of depression and
with pharmacological, environmental, and physiological stimuli. As it’s current postulates emerge.
described in the next section, it is the responsiveness of adult The field of adult neurogenesis also had many breakthroughs
neurogenesis to stimuli that first drew the attention of depression around this time. For example, mammalian hippocampal neuro-
and anxiety researchers and led to the development of the neuro- genesis was demonstrated in humans (Eriksson et al., 1998). Also,
genesis hypothesis of affective and anxiety disorders. the newly formed neurons were proven to incorporate into existing
circuitry and expressed indices of functional neurons (Eckenhoff
2.2. Keystones of the neurogenesis hypothesis of affective and Rakic, 1988; Hastings and Gould, 1999; Markakis and Gage,
and anxiety disorders 1999; Rozental et al., 1995; Stanfield and Trice, 1988; van Praag
et al., 2002). There was also reasonable evidence that adult-
The neurogenesis hypothesis of depression was stated formally generated neurons were functionally important in the mamma-
in the last decade, but it has deep roots. There is almost a century of lian olfactory system and in the avian brain (Alvarez-Buylla and
work on the hippocampus, stress, monoamines, MDD (Conrad, Kirn, 1997; Bottjer and Arnold, 1997). However, in the early
2008; Hirschfeld, 2000; Lopez-Munoz and Alamo, 2009; McEwen, 2000’s, the functional relevance of adult-generated hippocampal
2000; Sapolsky, 2000; Sheline, 2000), and almost fifty years of neurons was not clear. There were many correlative studies sug-
work on postnatal neurogenesis in the mammalian brain (Altman, gesting its importance in learning and memory (e.g. Derrick et al.,
1962). These research lines began to intersect in the 1990’s when 2000; Dobrossy et al., 2003; Gould et al., 1999; Kempermann
it was discovered that stress and stress hormones robustly decrease et al., 1997; van Praag et al., 1999a), and a few studies using
the generation of hippocampal neurons and increased cell death constitutive knockout mice (Feng et al., 2001), but no study had
(Gould et al., 1992, 1991) and depletion of serotonin inhibited inducibly and specifically decreased neurogenesis to explore its
adult neurogenesis (Brezun and Daszuta, 1999). Soon after came functional relevance.
a seminal paper showing that chronic but not acute antidepressant Inducible ablation of adult neurogenesis was first done in
treatment increased SGZ proliferation and neurogenesis (Malberg studies using cranial irradiation or antimitotics agents (Madsen
et al., 2000). Importantly, this finding generalized to different et al., 2003; Mizumatsu et al., 2003; Monje et al., 2002; Parent
classes of antidepressants pharmacotherapeutics (such as tricyclic et al., 1999; Peissner et al., 1999; Raber et al., 2004; Shors et al.,
and selective serotonin reuptake inhibitors), as well as electro- 2002; Snyder et al., 2001; Uberti et al., 2001). As a whole, these
convulsive shock therapy (ECS) and environment interventions that studies showed the functional importance of adult hippocampal
are antidepressant, like running (Madsen et al., 2000; Malberg neurogenesis in learning and memory and in seizure induction.
et al., 2000; Manev et al., 2001; Santarelli et al., 2003; van Praag Most relevant for this review, in 2003, a publication in Science
et al., 1999b). Spurred by these and other research papers, it was appeared whose title formulated one of the main postulates of the
around this time that review publications began to address the neurogenesis hypothesis of depression: Requirement of adult
potential importance of neurogenesis to our understanding of hippocampal neurogenesis for the efficacy of antidepressants
hippocampal plasticity and psychiatric disorders, MDD in particular (Santarelli et al., 2003). Using irradiation-induced ablation of adult-
(Blows, 2000; Brown et al., 1999; Duman et al., 1999; Eisch, 2002; generated hippocampal neurons, Hen and colleagues found that
Jacobs et al., 2000; Perera and Lisanby, 2000). While Jacobs et al. irradiated mice no longer responded behaviorally to antidepres-
(2000) nicely articulated key aspects of the neurogenesis hypoth- sants like fluoxetine. These data suggested that adult neurogenesis
esis of depression e proposing that the “waxing and waning of might be related to the pathophysiology of depression, and that
neurogenesis [are important causal factors in depression]” e it is enhanced hippocampal neurogenesis is required for the beneficial
24 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34

effects of the antidepressant treatment. There was a strong 3.1.1. Effect of decreasing neurogenesis on depression- and anxiety-
“anxiety” component to the behavioral testing in Santarelli et al., like behaviors in non-stressed animals
thus raising questions about whether in fact antidepressant treat- So does decreasing adult hippocampal neurogenesis in “naïve”
ments themselves (vs. antianxiety treatments) required neuro- laboratory animals result in a depressive or anxious phenotype
genesis. However, MDD and anxiety are comorbid in humans, so (Fig. 1DeF)? One of the most striking observations from this
taken together with subsequent work these data suggested that the summary of 19 publications (yellow rows, Table 1) is that there is no
neurogenesis hypothesis may apply to both affective and anxiety effect of ablating neurogenesis in 32 of the 42 mood-related tests
disorders (e.g. David et al., 2010; Tanti and Belzung, 2010). (76% of studies) completed in naïve or non-stressed rodents. This
The neurogenesis hypothesis was highly attractive for many lack of effect is particularly clear from the large number of studies
reasons. It offered a novel perspective on etiology of MDD, but one using tests of NSF and FST, which across many (but not all) studies
that fit with the existing “scaffolding”: the concept of MDD as show no effect of neurogenesis disruption on these behavioral tests.
a limbic disorder marked by hippocampus maladaptations. The This argues strongly against the postulate that in solely decreasing
hypothesis also helped to explain the delay of several weeks neurogenesis e and not invoking any aspect of stress or utilizing an
between the initiation of antidepressant treatment and onset of animal model of depression e induces a depressive-like phenotype.
their effects (Lavergne and Jay, 2010), since the maturation of the Because of the challenge posed by separating depression- from
hippocampal progenitors into mature DG granule neurons and anxiety-like behaviors (Crawley, 1999; Cryan and Holmes, 2005;
their incorporation into circuitry also takes about 3e4 weeks Kalueff et al., 2010), it remains unclear from the current literature
(Encinas et al., 2006; Kee et al., 2007; Kempermann et al., 2004). what effect disruption of neurogenesis has specifically on anxiety-
The tractability of the hypothesis, along with the rapid rate of related behaviors. Consider the comparison of nestin-Bax and ATR
discovery about neural stem cells, stages of neurogenesis, and novel mice in Table 1, both mouse models in which neurogenesis can be
ways to track, label and manipulate adult-generated neurons inducibly decreased to about a similiar extent (nestin-Bax by
(e.g. Dhaliwal and Lagace, 2011; Imayoshi et al., 2008) led to overexpressing Bax specifically in nestin-expressing cells, and ATR
a massive surge in publications in this area (e.g. “depression” and by either inducibly knocking out this cell cycle checkpoint gene
“neurogenesis” resulted in 8 items for the year 2000, and 79 already throughout the body or removing it solely from differentiated cells
July, 2011). But is the hypothesis still valid? The next section in the hippocampus). Non-stressed nestin-Bax mice display
addresses its component parts and their current status. increased anxiety in three separate anxiety-related behavioral tests
(elevated plus maze, lightedark, and predator avoidance (Revest
et al., 2009)). In contrast, non-stressed ATR mice that display
3. Postulates of the neurogenesis hypothesis of affective
reduced anxiety in three anxiety-related tests: marble burying,
and anxiety disorders
novelty-induced hypophagia, and zero maze (Onksen et al., 2011). It
is likely these differences are in part reliant on technical aspects e
While the neurogenesis hypothesis of depression remains
e.g. the cell specificity of the gene overexpression (Bax in nestin-
attractive, how does it and it’s two main postulates hold up after
expressing cells) or deletion (ATR from whole body or from all
almost a decade of intense research? Here we will review these two
differentiated cells in the hippocampus), the resulting selectivity of
postulates: 1) Decreased adult neurogenesis results in depressive
disruption of neurogenesis, the timing of the decrease in neuro-
or anxious phenotypes (Fig. 1DeF, Table 1); 2) Effective treatments
genesis relative to the behavioral testing, and to changes that are
for these disorders require intact hippocampal neurogenesis (Fig. 2,
not directly related to changes in neurogenesis (e.g. ATR mice fail to
Table 2). We will also explore how the current state of the
show antidepressant-induced increase in spine density in a non-
hypothesis informs our current understanding of the response to
neurogenic part of the hippocampus). However, the fact that
stress, PTSD, and the related concept of the neurobiology of
disruption of neurogenesis via two different inducible transgenic
resilience.
mouse models results in alterations in anxiety-like behaviors
contrasts with the fact that disruption of neurogenesis via more
3.1. Does decreased adult hippocampal neurogenesis result global approaches ablation (e.g. irradiation and MAM) does not
in depressive or anxious phenotypes? alter anxiety-like behaviors. Thus, this encourages the application
of more specific genetic models (e.g. inducible and cell-specific
Since the early studies on the neurogenesis hypothesis, such as manipulations which directly target adult neurogenesis) to more
Malberg et al. (2000) and Santarelli et al. (2003), there have been closely assess the possibility that neurogenesis is a regulator of
many correlative and causal studies that explore whether anxiety-like behaviors. This also encourages development of
decreased hippocampal neurogenesis results in depression or approaches to specifically enhance adult neurogenesis, a concept
anxiety. As shown in Table 1, there are currently 21 publications we will return to in Section 3.2.1. Future work should also consider
that have examined the depression- and anxiety-related behavioral the possibility that depression- and anxiety-relevant behaviors
consequences of decreasing neurogenesis in laboratory animals may be differently associated with hippocampal neurogenesis (e.g.
(Airan et al., 2007; Bessa et al., 2009; David et al., 2009; Fuss et al., Uchida et al., 2011).
2010a; Holick et al., 2008; Jayatissa et al., 2009; Lagace et al., 2010;
Meshi et al., 2006; Noonan et al., 2010; Onksen et al., 2011; Revest 3.1.2. Effect of decreasing neurogenesis on depression- and anxiety-
et al., 2009; Santarelli et al., 2003; Saxe et al., 2006; Schloesser like behaviors in animal models of depression
et al., 2010; Shors et al., 2002; Singer et al., 2009; Snyder et al., Section 3.1.1 addressed whether decreasing neurogenesis in
2011; Surget et al., 2008, 2011; Wang et al., 2008; Zhu et al., “naïve” laboratory animals results in a depressive or anxiety
2010). For ease of categorization, Table 1 groups these studies by phenotype. However, it is possible that the importance of neuro-
behavioral test e novelty suppressed feeding (NSF), forced swim genesis is only revealed when the animal is in a depressive-like
test (FST), tail suspension test (TST), etc. In addition, the studies are state (Kempermann, 2008). To address this possibility, many
discussed below in two distinct sections based on whether the groups have inducibly ablated neurogenesis in animal models of
effect of decreasing neurogenesis was tested in non-stressed depression e animals that have received injections of corticoste-
rodents (Section 3.1.1) or in one of several animal models of rone (CORT) or exposure to social defeat stress (SS), unpredictable
depression (Section 3.1.2). chronic mild stress (UCMS), and restraint stress e and then
 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34 25

Table 1
Effect of ablation of adult neurogenesis on depression- and anxiety-related behaviors. Inspired by Dr. Jason Synder’s online catalog of papers relevant to neurogenesis (www.
functionalneurogenesis.com/blog/), Table 1 highlights studies that have genetically (via knockout mouse) or inducibly ablated neurogenesis (via irradiation, MAM, or inducible
transgenic mice) and assessed how specific behavioral tests have been used in various mood-related rodent models. Depression- and anxiety-related behavior tasks that have
been assessed in studies that have ablated or disrupted adult neurogenesis are listed in chronological order and divided by two categories. Yellow highlighted studies were
performed in “naïve” or non-stressed animals (e.g. suppression of neurogenesis was employed but no animal model of depression, n ¼ 19 publications cited, 42 individual test
results shown). Light green highlighted studies were performed using animal model of depression or anxiety (Unpredictable Chronic Mild Stress, UCMS; Corticosterone
Treatment, Cort; social stress, SS; or Restraint stress, Restraint, n ¼ 8 publications cited, 19 individual test results shown). In answer to the question “How is depression/anxiety-
related behavior altered by disrupted neurogenesis?” (Column 2), behavioral test results are classified as no change (nc) or increased or decreased depression/anxiety-related
behavior. As the focus of this table is on depression- and anxiety-related behaviors, it does not address other aspects of physiology that have been linked to neurogenesis and
the stress response (e.g. corticosterone levels in serum or fecal boli (e.g. Surget et al., 2011), body weight (e.g. Surget et al., 2011), and normalization of corticosterone levels after
stress or dexamethasone suppression (e.g. Snyder et al., 2011; Surget et al., 2011)).
26 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34

Fig. 2. Is the efficacy of antidepressants reliant on intact adult hippocampal neurogenesis? (A) This question is often addressed by depletion adult-generated neurons by cranial
irradiation or antimitotic agents (methylazoxymethanol or MAM is shown; see Tables 1 and 2 for more approaches) and subsequent administration of antidepressant compounds or
environmental manipulations known to have antidepressant efficacy (like running or environmental enrichment). As highlighted in Table 2, the results from these studies are
conflicting. Some studies show that after disruption of neurogenesis, antidepressants still produce antidepressant or antianxiety effects in behavioral tests, here summarized as
“improved mood”. However, other studies show that after disruption of neurogenesis, antidepressants fail to result in antidepressant or antianxiety effects in behavioral tests, here
summarized as “impaired mood”. (B) The conflicting results summarized in (A) may in part be explained by the many factors that influence whether adult-generated neurons are
required for antidepressant efficacy or not. Stress or anxiety levels of the experimental animals, difference in animal strain that may influence the basal level of adult neurogenesis,
and the type of ablation strategy utilized (such as gancyclovir in tkþ mice) are just some of the factors that appear to influence whether or not antidepressants influence mood
regulation via adult-generated neurons.

examined the effect on mood-related behaviors. This approach has 3.2. Do antidepressant or antianxiety therapeutics require
been used in 8 publications (light green rows, Table 1) for a total of adult hippocampal neurogenesis for their effects?
19 behavioral tests in animal models of depression. Generally these
studies find no behavioral effect of ablating neurogenesis (15 of the The second postulate of the neurogenesis hypothesis (Fig. 2) was
19, or 79%, of tests show no change). This suggests that as in non- first hinted at in a study showing that antidepressants reversed the
stressed animals, decreasing neurogenesis in animal models of decrease in proliferation induced by the learned helplessness
depression is not sufficient to result in or exacerbate a depressive- model of depression (Malberg and Duman, 2003). The reliance of
or anxiety-like phenotype. antidepressant efficacy on intact neurogenesis was also supported
However, Table 1 also lists 4 of the 19 published tests (21%) in in the NSF test in non-stressed mice with ablated neurogenesis
which decreasing neurogenesis in animal models of depression is (Santarelli et al., 2003). As shown in Table 2, there are 14 publica-
sufficient to drive a depressive- or anxiety-like phenotype. What tions that have examined the requirement for neurogenesis in
might explain these conflicting data? One explanation is that the antidepressant or antianxiety efficacy in behavioral tasks via abla-
relationship between behavioral performance on mood-related tion approaches (Airan et al., 2007; Bessa et al., 2009; David et al.,
tests and adult neurogenesis may be dependent on the method, 2009; Fuss et al., 2010b; Holick et al., 2008; Jiang et al., 2005; Meshi
timing, or extent of neurogenesis disruption. A good example of et al., 2006; Perera et al., 2011; Santarelli et al., 2003; Schloesser
behavioral performance being reliant on the method, timing, or et al., 2010; Surget et al., 2008, 2011; Wang et al., 2008; Zhu
extent of neurogenesis disruption is evident from review of et al., 2010). As with Table 1, the publications in Table 2 are
publications that inducibly alter neurogenesis and then examine grouped by behavioral test, with each publication appearing
behavior on the NSF test. When neurogenesis was ablated via multiple times for each test examined. However, here an additional
cranial irradiation prior to the start of UCMS, there was no change column is added to allow presentation of animal models of
in latency to feed in the NSF test (Surget et al., 2008). In contrast, depression, antidepressant/antianxiety therapeutics and manipu-
when neurogenesis was ablated via MAM treatment 3 weeks after lations, and the combined approach.
the onset of UCMS, there was an increased latency to feed (Bessa
et al., 2009). The contradictory nature of these results could be 3.2.1. Is intact neurogenesis required for efficacy of antidepressants?
due the non-specific nature of the experimental interventions Studies in non-stressed animals
(e.g. systemically administered MAM disrupts cell division So far a total of 10 studies (pink rows, Table 2) have used naïve
throughout the body in contrast to cranially-delivered radiation) animals, disrupted neurogenesis, and explored whether adult-
and encourages for development of more specific ways to ablate generated neurons are required for antidepressant efficacy of
neurogenesis. However since most transgenic approaches result antidepressant compounds like fluoxetine or antidepressant
in less efficient ablation than more global approaches like irra- stimuli like environmental enrichment or running. In the studies
diation, it remains to be seen how the quantity and extent of that assess performance on the NSF and FST (9 publications, 10
ablation will also influence behavioral responses in animals. individual tests reported), there is 80% consensus that neurogenesis
These conflicting data could also be due to differences in the lag is required for antidepressant-induced alterations in behavior.
time between testing for functional deficits and the time after These data from the NSF and FST suggest that, in general, intact
UCMS or ablation of neurogenesis. Another area that warrants neurogenesis is required for the antidepressant effects that can be
additional study is whether these studies are all utilizing similar produced by either pharmacological (antidepressants) or environ-
measures of neurogenesis, and whether there are cell stage- mental (environmental enrichment) manipulation. When all the
specific changes that are currently unappreciated. One example behavioral tests are considered (e.g. all pink rows, Table 2), there is
of this is with another animal model of depression, social isola- less agreement. For example, there are 6 tests across three publi-
tion. Dranovsky and colleagues found that social isolation induced cations that show antidepressant efficacy is not reliant on intact
an accumulation of the putative Type 1 neural stem cells in the neurogenesis: environmental enrichment in the NSF (Meshi et al.,
mouse hippocampus, but not neurons (Dranovsky et al., 2011). 2006), fluoxetine in the FST and novelty-induced hypophagia
This emphasizes the need to continually advance our under- (Holick et al., 2008), and running in the open field, light/dark, and
standing of neurogenesis. O maze (Fuss et al., 2010b). While inclusion of running here as an
 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34 27

Table 2
Effect of ablation of adult neurogenesis on the efficacy of antidepressant compounds and antidepressant physiological manipulations in depression- and anxiety-related
behavior task. As with Table 1, Table 2 was inspired by Dr. Jason Synder’s online catalog of papers relevant to neurogenesis (www.functionalneurogenesis.com/blog/).
However, this table specifically addresses the question “is antidepressant efficacy diminished by disrupted neurogenesis”? Depression- and anxiety-related behavior tasks that
have been assessed in studies that have ablated or disrupted adult neurogenesis (via irradiation, MAM, or inducible transgenic mice) are listed in chronological order and
divided into two categories. In pink highlighted studies, animals were given a compound or manipulation that has antidepressant efficacy (e.g. antidepressant compounds
including fluoxetine, imipramine, AV1b or CRF1 receptor antagonists; environmental enrichment; the cannabinoid receptor [CB] agonist HU210; intermittent hypoxia; and
running,) in addition to the disruption of neurogenesis (n ¼ 10 publications, 14 individual test results shown). Purple highlighted studies were performed using animal models
of depression or anxiety (Unpredictable Chronic Mild Stress, UCMS; Corticosterone Treatment, Cort; Chronic Mild Stress, CMS; social stress, SS; or Restraint stress, Restraint),
and also received an additional treatment such as a pharmacological treatment or environmental modification (n ¼ 8 publications, 38 individual test results shown). In answer
to the question “Is antidepressant efficacy diminished by disrupted neurogenesis?” (Column 3), behavioral test results are classified as No or Yes. As the focus of this table is on
the reliance of the behavioral effects of antidepressant on intact neurogenesis, it does not address other aspects of physiology that have been linked to neurogenesis and the
stress response (e.g. antidepressant-induced synaptic plasticity, Wang et al., 2008).
28 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34

“antidepressant” is controversial, since in this particular study et al., 2009; Snyder et al., 2011; Surget et al., 2011). Second,
running induced an anxious and depressive phenotype (Fuss et al., behavioral tests appear sensitive to the animal strain used
2010b), it remains notable that irradiation did not influence the (Alahmed and Herbert, 2008), and animal strains have long been
performance on tests of depression or anxiety. Still, when all the known to display enormous differences in levels of hippocampal
pink rows in Table 2 are considered together, there is a slight proliferation and adult neurogenesis (Kempermann, 2002;
majority e 57% e of behavioral data that support the second Kempermann and Gage, 2002), which fits with strain-dependent
postulate: intact adult neurogenesis is required for antidepressant differences in brain morphology and metabolism (e.g. Penet et al.,
efficacy, at least in the basal context (e.g. not in animal models of 2006). Therefore, it is important to consider mouse strain when
depression). The next section will address whether the second interpreting basic research studies that examine the relationship
postulate holds in animal models of depression. between neurogenesis, stress, and antidepressants (e.g. Table 1 in
David et al., 2010). A final hypothesis is that the ablation approaches
3.2.2. Is intact neurogenesis required for efficacy of themselves might produce confounds in these behavioral experi-
antidepressants? Studies in animal models of depression ments. Adult-generated neurons for example provide more than
The dependency of antidepressant action on intact adult neu- just new hippocampal neurons; they also provide structural
rogenesis also has been assessed in many studies using a variety of support and cellecell contact, and ablation of new neurons is akin
animal models of depression, such as UCMS, CMS, SS, and Cort to pulling a support beam out from a scaffolding platform in that it
(purple rows, Table 2, 8 publications, 38 individual tests reported). can have wide reaching and unintended effects no matter how cell-
There is support for the second postulate in animal models of specific the ablation strategy is. This possibility can be resolved by
depression, with 20 of the 38 tests (53%) showing the reliance of a gain of function approach, which, opposite to ablation of neuro-
antidepressant efficacy on intact neurogenesis in the context of genesis, induces a specific upregulation of adult neurogenesis.
animal models of depression. For example, antidepressants fail to Excitingly, recent work showed specific upregulation of adult
“work” in the NSF test an animal model of depression (UCMS) after neurogenesis using a genetic approach resulted in improved
cranial irradiation; fluoxetine, for example, does not lead to pattern separation in spatial memory in mice (Sahay et al., 2011).
decreased latency to feed in the NSF test in stressed, irradiated mice Highly relevant for this review, this same publication showed a lack
(Surget et al., 2008). This is similar to the original finding that of effect of increasing neurogenesis on NSF, FST, and another test
antidepressants fail to work in the NSF test after just cranial irra- relevant for anxiety (open field exploration in both low and high
diation (Santarelli et al., 2003). anxiety conditions) (Sahay et al., 2011). As this study was per-
However, 18 of 38 individual tests (47%) from a variety of formed in non-stressed animals (e.g. not in an animal model of
publications do not support the idea that adult neurogenesis is depression), it will be important to see if selective increase in
required for antidepressant-associated changes in behavior in neurogenesis in an animal model of depression results in normal-
animal models of depression. For example, latency to feed in the ized mood-related behaviors or response to antidepressants. It is
NSF test was reduced in MAM-treated animals even when antide- also possible that the antidepressant aspects of neurogenesis come
pressants were administered (Bessa et al., 2009), suggesting that from normalization of levels, not increasing levels neurogenesis
antidepressants can improve mood independently of adult neuro- beyond basal levels. This is in part supported by post-mortem work
genesis. In addition, genetic ablation of adult neurogenesis in showing the level of proliferation in patients with MDD on anti-
nestin-tkþ mice did not prevent antidepressant action in the TST depressants (SSRIs) was higher than in patients with MDD not on
(Singer et al., 2009). These studies, which are cited in Table 2, fit antidepressants, but not significantly different from age-matched
with other studies that did not inducibly ablate neurogenesis. For healthy controls (Boldrini et al., 2009). Clearly, more work with
example, a study the same year as Malberg and Duman (2003) such selective and inducible manipulation of neurogenesis is war-
reported that a reduced number of actively dividing progenitors ranted to more fully understand how increasing e or decreasing e
did not correlated with performance in the learned helplessness hippocampal neurogenesis influences antidepressant responsivity.
task (Vollmayr et al., 2003). Similarly in BALB/cJ mice, which have One particularly interesting tool in this regard is application of
high levels of basal anxiety, the behavioral effects of antidepres- inducible yet reversible reduction in neurogenesis (e.g. Massa et al.,
sants (chronic fluoxetine) also did not require adult neurogenesis 2011). It will also be important to explore the signaling and
and were not associated with changes in proliferation or differen- molecular mechanisms mediating antidepressant-induced regula-
tiation (Holick et al., 2008; Huang et al., 2008). Taken together, tion of neurogenesis and behavior. One molecular candidate in this
Table 2 shows that there is an almost even division between those regard is TrkB, the receptor for the neurotrophin BDNF (Li et al.,
results that support and those that oppose a role for intact neuro- 2008). Interestingly, inducible ablation of TrkB from nestin-
genesis in antidepressant efficacy when using an animal model of expressing cells and their progeny did not decrease basal levels of
depression (purple rows). neurogenesis, but rather prevented the antidepressant-induced
While there are only 14 publications total in Table 2, there are increase in indices of neurogenesis and antidepressant-induced
sufficient results to ask the question: what might explain these alterations in behavior on the NSF and TST (Li et al., 2008). Given
differing perspectives on whether or not antidepressants require the long line of research linking BDNF, antidepressant efficacy, and
intact neurogenesis in laboratory animals? One hypothesis is that neurogenesis, deeper exploration of how precisely TrkB on adult-
the basal level of anxiety or activation of the stress axis plays generated neurons mediates antidepressant-induced changes in
a critical role in whether or not antidepressants rely on intact neurogenesis and behavior is warranted.
neurogenesis. Indeed, antidepressants increased adult neuro- If adult-generated neurons do indeed play a critical role in
genesis in animals subjected to stress (David et al., 2009); however, antidepressant efficacy, there are some interesting clinical impli-
fail to do so in unstressed ones (Couillard-Despres et al., 2009). cations. For example, adult neurogenesis decreases with age (Kuhn
Similarly, stressed non-human primates who lack neurogenesis fail et al., 1996). If antidepressant action requires neurogenesis, one
to show the behavioral response of antidepressants (Perera et al., could reason that antidepressants should not be as effective in aged
2011). The hippocampus itself has long been known to be impor- individuals as in young ones. This seems to be true, as aging abol-
tant in regulation of the stress axis, and even more recent data have ishes the positive effects of fluoxetine of hippocampal proliferation
begun to elegantly dissect the role of adult-generated neurons in and pro-neuronal differentiation in mice (Couillard-Despres et al.,
stress-induced surges in serum and fecal corticosterone (Schloesser 2009). Also, antidepressant efficacy decreases dramatically in
 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34 29

elderly patients (Schatzberg and Roose, 2006; Tollefson et al., 1995), enhanced neurogenesis and hippocampal-dependent memory as
and antidepressants fail to stimulate adult neurogenesis in old age well as diminished depressive- and anxiety-like behaviors (Parihar
(Lucassen et al., 2010b; however, see Zhao et al., 2008b). This aspect et al., 2011). These studies suggest that as in humans, predictability
of the neurogenesis hypothesis of depression also raises important confers a positive aspect to stress, and that successful coping with
considerations for anti-cancer chemotherapy that targets mitoti- a stressor may actually serve to enhance brain function. In contrast,
cally active cells, including the hippocampal neuronal progenitors unpredictable stressors are potentially more damaging and difficult
(Fig. 1). Since adult neurogenesis is proposed to be critical for mood to cope with.
control (DeCarolis and Eisch, 2010), anti-cancer therapies may have A second, related message relevant to the neurogenesis
direct effects on affect and mood. Consistent with this, antide- hypothesis evident from another recent study is the importance of
pressant treatment was able to reverse memory and proliferation the behavioral response to stress. In humans, some “susceptible”
impairments after chemotherapy in rats (Lyons et al., 2011). individuals exposed to stress develop symptoms of MDD and PTSD,
while other “resilient” individuals do not. There are some person-
3.3. Implications of the neurogenesis hypothesis of affective ality traits (optimism) and situational variables (whether the stress
and anxiety disorders for the understanding is controllable) that appear to be important in determining
of the neurobiology of resilience whether someone is either susceptible or resilient to a given stress
(Duman, 2009; Feder et al., 2009). Assessment of “resilience” can
One tenet of the neurogenesis hypothesis is that a stress- also be examined in preclinical research. The social defeat model,
induced decrease in neurogenesis may contribute to the onset or for example, is a model of stress-induced social avoidance that
exacerbate stress-related disorders (e.g. Bremner et al., 2008), produces multiple features of stress susceptibility in approximately
making decreased neurogenesis a “vulnerability factor” for disor- half of subjects (Krishnan et al., 2007). In mice exposed to this
ders like PTSD. In support of this, stress is used to mimic clinically- prolonged stressful psychosocial experience, susceptible mice will
relevant symptoms in animals models of MDD or PTSD (Greenwood display behavioral and physiological indices reminiscent of MDD
and Fleshner, 2008; Krishnan and Nestler, 2008; Stam, 2007; and PTSD and will avoid an aggressor mouse in a social environ-
Takemura and Kato, 2008), in models as diverse as the social ment, while resilient mice will not. A notable difference between
defeat stress (e.g. Van Bokhoven et al., 2011) and UCMS (e.g. Surget the social defeat model and other animal models of stress is the
et al., 2009). SGZ proliferation and neurogenesis are robustly ability to measure the behavioral response to stress. In other tests,
inhibited in these and other stress models and after administration like separation or restraint stress, the animal is merely exposed to
of stress hormones (e.g. Gould and Tanapat, 1999; Joels, 2007; Joels the stress. In the social defeat model, the animal’s behavioral
et al., 2008; Pittenger and Duman, 2008; Schmidt and Duman, response to stress is calculated by their performance on an inter-
2007; Van Bokhoven et al., 2011; Zhao et al., 2008a). Several action test with an aggressor. As such, it is an ideal model in which
correlative studies have also suggested that stress is associated to probe the neural mechanisms contributing to an organism’s
with decreased hippocampal neurogenesis and depressive- or response to chronic severe stress.
anxious-like phenotypes (e.g. Ho and Wang, 2010; Lucassen et al., Using the mouse model of social defeat, and exploiting the
2010a; Pittenger and Duman, 2008; Vollmayr et al., 2007), and diversity of stress response in this model, we recently discovered
that antidepressants can reverse the behavioral or cellular pheno- that adult hippocampal neurogenesis is functionally important for
type (e.g. Dagyte et al., 2011; Veena et al., 2011). The message from stress-induced social avoidance (Lagace et al., 2010). There are two
most of these studies is that “stress decreases neurogenesis”. key findings from this study that are relevant to the neurogenesis
However, a growing number of publications suggest the hypothesis of affective disorders. First, we found that enhanced
message is much more complex than “stress decreases neuro- neuronal survival occurs only in mice with persistent social
genesis”. For example, while there is decreased SGZ proliferation avoidance. We did not see this effect when all defeated mice were
during or immediately after stress, there is no change in survival of analyzed irrespective of behavioral response to this stressor. This
cells that were dividing prior to stress (Heine et al., 2004). In emphasizes the importance of considering the behavioral response
addition, decreased neurogenesis might be thought to result in to stress, rather than just exposing an animal to stress, as is
decreased hippocampal volume; however, there is no change in common with animal models of depression. It is possible that some
granule cell layer volume reported in many stress studies (Czeh of the studies presented in Tables 1 and 2 would yield a different
et al., 2001; Jayatissa et al., 2006; Yap et al., 2006). Also, there are answer if the animal’s response to stress was taken into consider-
many correlative studies in which stress-induced decrease in some ation. Second, using focused cranial X-Ray irradiation to ablate
index of neurogenesis does not correlate with an anhedonic or neurogenesis, we found that decreased neurogenesis led to
anxious phenotype (e.g. Jayatissa et al., 2010). Finally, there are a greater proportion of the mice displaying resilience. This
a few recent studies that suggest stress does not decrease neuro- emphasizes that the time window after cessation of stress is
genesis but actually can increase neurogenesis, and that this a critical period for the establishment of persistent cellular and
increase in functionally relevant (Lagace et al., 2010; Lyons et al., behavioral responses to stress, and therefore is a very good target
2010; Parihar et al., 2011). What do these recent findings mean for therapeutic intervention. If, as our data suggest, adult-generated
for the neurogenesis hypothesis of affective and anxiety disorders? neurons store the memory of a stressful experience, targeting
There are two messages that these recent studies have for us adult-generated neurons after a stressful experience may provide
about the neurogenesis hypothesis. First, contrary to stress always some translational approaches to dealing with abnormally strong
being “bad”, it has long been appreciated that stress has an or stressful memories.
important biological role, and recent research supports that some Two additional intriguing speculations emerge from our work in
amount of stress at the right time is actually useful for learning and regards to treatment of or even prevention of PTSD. Since the
memory (Joels et al., 2006). For example, in a study of non-human survival of adult-generated neurons is functionally important in
primates, successful coping with intermittent social stress was social avoidance, it is possible that modern approaches to visualize
associated with enhanced neurogenesis (as assessed by BrdU given neurogenesis in the living brain (e.g. Manganas et al., 2007) could
during the stressor) and hippocampal function (as assessed be used to help correlate behavioral responses to stress in humans
by spatial learning, Lyons et al., 2010). A study in rats came to and levels of neurogenesis. With this information, strategies
a similar conclusion, where predictable chronic mild stress could be used to selectively increase or decrease neurogenesis
30 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34

appropriately to help augment or diminish particular memories of Onksen et al., 2011)? Are the experimental animals living in non-
stressful experiences, similar to those approaches suggested for enriched environment the best model for the neurogenesis
other brain neuroadaptations (e.g. Blundell et al., 2008; Ressler hypothesis of depression since their neurogenesis may be under-
et al., 2004). In regards to treatment, there are several novel scored by non-stimulating environment (Hauser et al., 2009)? Why
strategies that have been shown to prevent the behavioral response do antidepressant effects on adult neurogenesis influence only
to stress in laboratory animals, including exercise and regulation of some depression-like behavior tests and not others? Is it because
diet (e.g. Finger et al., 2011a,b; Greenwood and Fleshner, 2008), many of the behavioral tests for estimating depression and anxiety
which are also known to alter hippocampal neurogenesis. It would are not mutually compatible (Belzung and Le Pape, 1994) or were
be interesting to dissect the involvement of hippocampal neuro- developed for drug screening (Krishnan and Nestler, 2008) and
genesis in these protective strategies. thus do not reflect the complex etiology of depression and/or
anxiety? Or is it possible that differences in results came from
4. New scaffolding needed to keep up with construction experimental differences in animal species and handling, timing of
the antidepressant administration and other factors as it was
When reviewed as a whole, the published literature relevant to shown before (Crabbe et al., 1999; Wahlsten et al., 2003)?
the neurogenesis hypothesis of affective and anxiety disorders has As we near the end of this review it is worth stressing a point we
been built logically, study by study, with many of the results sup- made in the introduction: depression and anxiety are not defined or
porting prior work and allowing a true hypothesis-driven approach diagnosed via etiology but rather by symptom presentation. Indeed,
to test whether new neurons are important in mood disorders. In depression and anxiety may share etiology. This is an additional
addition, the work on this topic is not complete, so there is no sense factor that has likely made it difficult to delineate the role of neu-
in dismantling the scaffolding of the hypothesis now; this is when rogenesis through the lens of depression or anxiety models. With
the workers need the support provided by these hypotheses the this in mind, it is also important to stress that a common approach
most. However, the great speed at which these studies are being for many studies in this field e inducible ablation of adult neuro-
generated puts the field at risk for, in Goethe’s words, mistaking the genesis e itself will alter the neuronal circuitry responsible for
scaffolding for the building. What can we learn from examining the controlling mood. Indeed, very recent results show the particular
scaffolding e the neurogenesis hypothesis of depression and power that adult-generated neurons have over physiological
anxiety e that might help us restructure it to best guide future response to stress (Snyder et al., 2011), thus providing a functional
studies? link to the long-known anatomical connections between the
It seems we have discounted the first postulate that decrease in hippocampus and the stress axis, and provides a mechanistic avenue
hippocampal adult neurogenesis is related to the pathophysiology of to explore how new neurons might regulate mood. This work by
depression in the “basal” or non-stressed state. Indeed, as summa- Cameron’s group also clarifies how the first postulate should be
rized in Table 1 and Fig. 2, most studies do not find that reduced adult stated in the future: reduced neurogenesis may result in increased
neurogenesis yields depression behavior (Bessa et al., 2009; Jayatissa depressive-like behavior when the individual is stressed. However,
et al., 2009; Meshi et al., 2006; Shors et al., 2002). This fits with since the neurobiology of depression relies on many different aspects
human post-mortem work that does not find decreased neuro- of brain functioning and involves many proposed cellular and
genesis in the hippocampi of depressed patients (e.g. Boldrini et al., molecular mechanisms including changes in neurotrophic factors,
2009; Reif et al., 2006). The lack of a clear-cut effect e decreased synaptic plasticity, and even cell proliferation and survival outside of
neurogenesis leads to depression e also fits with the fact that even hippocampus (Castro et al., 2010; Krishnan and Nestler, 2008;
though adult neurogenesis is dramatically decreased in older age Lavergne and Jay, 2010), it is unlikely that the adult hippocampal
(Hwang et al., 2007; Jinno, 2011; Knoth et al., 2010; Kuhn et al., 1996; neurogenesis would influence them all. Similarly, antidepressants
McDonald and Wojtowicz, 2005), the majority of aged animals and modulate a wide spectrum of brain functions and processes besides
elderly patients are not depressed. The work on the neurobiology of adult neurogenesis (Berton et al., 2006). While it is likely that adult-
resilience from our laboratory and others also fits into this; a stress- generated neurons play some role in antidepressant efficacy (e.g.
induced decrease in neurogenesis may not result in depression, but it Li et al., 2008), it is highly unlikely that all antidepressants would
could influence the behavioral response to future stressors and the have a single common denominator in requirement of adult neuro-
ability to cope with them in an adaptive manner. genesis. This fits well with the concept of a circuit- or behavioral-
The second postulate proposing that hippocampal neurogenesis level endophenotype of depression and anxiety (e.g. Airan et al.,
is required for the behavioral effects of antidepressants is and will 2007; Cryan and Slattery, 2007; Garner et al., 2009; Leuner and
likely remain a great source of controversy and intensive research. Gould, 2010), where hippocampal plasticity as a whole is dis-
As shown in Table 2 and Fig. 2, while many studies support a role for rupted, and neurogenesis is just one facet that can help normalize
intact neurogenesis in antidepressant efficacy, others do not. Thus this disruption. This concept has worked well with other complex
additional research is needed to resolve these differences. In psychiatric disorders (Frankland et al., 2008; Kobayashi, 2009;
addition, the entire field is challenged e or perhaps distracted e by Tamminga et al., 2010; Yamasaki et al., 2008), and can be applied
the fact that “antidepressants” are for the most part mono- to depression-related disorders. It may also help to explain some
aminergic modulating agents that are effective for a wide variety of discrepancies in results, for example, as adult neurogenesis is
disorders (and arguably more effective for anxiety disorders than capable of compensating for some endophenotypes but not others.
depression), and “models of depression” are actually models of We believe that taking this hard look at the current structure of
stress. This type of generalization or simplification has been the neurogenesis hypothesis will result in a beneficial restructuring
extremely beneficial for some aspects of research in the field, but of it. For example, we posit that the neurogenesis hypothesis is not
likely is holding back progress in other areas. Nevertheless, the at odds with the complexity of affective and anxiety disorders, nor
studies that provided conflicting evidence to the original hypoth- is it in conflict with the pre-existing scaffolding or hypotheses that
esis that hippocampal neurogenesis is required for the behavioral have long supported active and fruitful research into these disor-
effects of antidepressants raise several interesting questions. For ders, such as the neurotransmitter and endocrine hypotheses.
example, how does the basal anxiety level affect adult neurogenesis Instead the neurogenesis hypothesis fits extremely well with
if the anxiety level is important for the adult neurogenesis to confer overarching “neuroplasticity” hypothesis of affective and anxiety
antidepressant effects (e.g. David et al., 2009; Fuss et al., 2010a,b; disorders (e.g. Fossati et al., 2004; Fuchs et al., 2004; Kempermann,
 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34 31

2011a; McEwen and Chattarji, 2004; Nissen et al., 2010). In fact, the Airan, R.D., Meltzer, L.A., Roy, M., Gong, Y., Chen, H., Deisseroth, K., 2007. High-speed
imaging reveals neurophysiological links to behavior in an animal model of
neurogenesis hypothesis is well positioned to be interdigitated into
depression. Science 317, 819e823.
other existing hypotheses, particularly the hypotheses that involve Alahmed, S., Herbert, J., 2008. Strain differences in proliferation of progenitor cells
the endocrine and stress systems, providing a broader and more in the dentate gyrus of the adult rat and the response to fluoxetine are
flexible base from which to work toward improving our under- dependent on corticosterone. Neuroscience 157, 677e682.
Altman, J., 1962. Are new neurons formed in the brains of adult mammals? Science
standing of these disorders. The current challenge is for scientists 135, 1127e1128.
working from distinct scaffolding to continue their work upwards Alvarez-Buylla, A., Kirn, J.R., 1997. Birth, migration, incorporation, and death of vocal
but also work across hypotheses to construct a clinically-relevant control neurons in adult songbirds. J. Neurobiol. 33, 585e601.
American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental
understanding of affective and anxiety disorders. This scrutiny is Disorders. American Psychiatric Association, Washington, DC.
critical, since if we “mistake the scaffolding for the building” we Balu, D.T., Lucki, I., 2009. Adult hippocampal neurogenesis: regulation, functional
miss an opportune time to thoughtfully craft the neurogenesis implications, and contribution to disease pathology. Neurosci. Biobehav. Rev.
33, 232e252.
hypothesis of affective and anxiety disorders, and to reveal the Belzung, C., Le Pape, G., 1994. Comparison of different behavioral test situations
potential clinical relevance behind it. used in psychopharmacology for measurement of anxiety. Physiol. Behav. 56,
In conclusion, while the neurogenesis hypothesis of depression 623e628.
Berton, O., McClung, C.A., Dileone, R.J., Krishnan, V., Renthal, W., Russo, S.J.,
offers new perspective into the etiology of MDD and anxiety disor- Graham, D., Tsankova, N.M., Bolanos, C.A., Rios, M., Monteggia, L.M., Self, D.W.,
ders, it needs to be reformulated. As scaffolding, it does not fit the Nestler, E.J., 2006. Essential role of BDNF in the mesolimbic dopamine pathway
building that is emerging from recent results. Its first postulate e in social defeat stress. Science 311, 864e868.
Bessa, J.M., Ferreira, D., Melo, I., Marques, F., Cerqueira, J.J., Palha, J.A., Almeida, O.F.,
decreased neurogenesis in the “basal” state leads to depression e
Sousa, N., 2009. The mood-improving actions of antidepressants do not depend
does not fit the evidence from literature. Rather, decreased neuro- on neurogenesis but are associated with neuronal remodeling. Mol. Psychiatry
genesis may lead to depression when animal models of depression or 14, 764e773. 739.
stress are invoked. In fact, given the historically strong connection Blows, W.T., 2000. The neurobiology of antidepressants. J. Neurosci. Nurs. 32,
177e180.
between the hippocampus, depression, anxiety, and stress and given Blundell, J., Kouser, M., Powell, C.M., 2008. Systemic inhibition of mammalian target
the more recent links between these things and adult hippocampal of rapamycin inhibits fear memory reconsolidation. Neurobiol. Learn. Mem..
neurogenesis, it is interesting to consider that this newly- Boldrini, M., Underwood, M.D., Hen, R., Rosoklija, G.B., Dwork, A.J., John Mann, J.,
Arango, V., 2009. Antidepressants increase neural progenitor cells in the human
appreciated connection between neurogenesis and stress regula- hippocampus. Neuropsychopharmacology 34, 2376e2389.
tion may have been discovered much earlier if it were not obscured Bottjer, S.W., Arnold, A.P., 1997. Developmental plasticity in neural circuits for
by the scaffolding supporting the construction of the “neurogenesis a learned behavior. Annu. Rev. Neurosci. 20, 459e481.
Bremner, J.D., Elzinga, B., Schmahl, C., Vermetten, E., 2008. Structural and functional
hypothesis of depression”. As an extension of this, the restructured plasticity of the human brain in posttraumatic stress disorder. Prog. Brain Res.
neurogenesis hypothesis should aim to clarify the relationship 167, 171e186.
between adult-generated neurons and the production or regulation Brezun, J.M., Daszuta, A., 1999. Depletion in serotonin decreases neurogenesis in the
dentate gyrus and the subventricular zone of adult rats. Neuroscience 89,
of stress and anxiety. This may have tremendous clinical relevance in 999e1002.
allowing, for example, dissection of levels of resilience to stress and Brown, E.S., Rush, A.J., McEwen, B.S., 1999. Hippocampal remodeling and damage by
to in vivo levels of neurogenesis (e.g. Manganas et al., 2007). This corticosteroids: implications for mood disorders. Neuropsychopharmacology
21, 474e484.
restructured emphasis on stress and anxiety fits well with the
Brown, E.S., Varghese, F.P., McEwen, B.S., 2004. Association of depression with
second and still somehow valid postulate e adult neurogenesis is medical illness: does cortisol play a role? Biol. Psychiatry 55, 1e9.
required for beneficial actions of antidepressants. If stress resilience Castro, J.E., Varea, E., Marquez, C., Cordero, M.I., Poirier, G., Sandi, C., 2010. Role of
or stress levels both influence adult neurogenesis and can in turn be the amygdala in antidepressant effects on hippocampal cell proliferation and
survival and on depression-like behavior in the rat. PLoS ONE 5, e8618.
regulated by levels of adult neurogenesis, these likely are dynamic Christie, B.R., Cameron, H.A., 2006. Neurogenesis in the adult hippocampus.
factors in the efficacy of antidepressants. Thus, considering Hippocampus 16, 199e207.
neurogenesis-related stress resilience may offer a new perspective e Conrad, C.D., 2008. Chronic stress-induced hippocampal vulnerability: the gluco-
corticoid vulnerability hypothesis. Rev. Neurosci. 19, 395e411.
and even more supportive scaffolding e in the search to develop and Couillard-Despres, S., Wuertinger, C., Kandasamy, M., Caioni, M., Stadler, K.,
test novel antidepressants and perhaps even prevent or at least Aigner, R., Bogdahn, U., Aigner, L., 2009. Ageing abolishes the effects of fluox-
diminish the severity of mood-related disorders. etine on neurogenesis. Mol. Psychiatry 14, 856e864.
Covington 3rd, H.E., Lobo, M.K., Maze, I., Vialou, V., Hyman, J.M., Zaman, S.,
LaPlant, Q., Mouzon, E., Ghose, S., Tamminga, C.A., Neve, R.L., Deisseroth, K.,
Nestler, E.J., 2010. Antidepressant effect of optogenetic stimulation of the
Acknowledgments medial prefrontal cortex. J. Neurosci. 30, 16082e16090.
Crabbe, J.C., Wahlsten, D., Dudek, B.C., 1999. Genetics of mouse behavior: interac-
This work was supported by grants from the National Institutes tions with laboratory environment. Science 284, 1670e1672.
Crawley, J.N., 1999. Behavioral phenotyping of transgenic and knockout mice:
of Health (R01 DA016765 and K02 DA023555 to AJE), NASA
experimental design and evaluation of general health, sensory functions, motor
(NNX07AP84G to AJE), NSERC (371716 to DCL), a Young Investigator abilities, and specific behavioral tests. Brain Res. 835, 18e26.
Award (DCL) and an Independent Investigator Award (AJE) from the Cryan, J.F., Holmes, A., 2005. The ascent of mouse: advances in modelling human
National Alliance for Research on Schizophrenia and Depression, depression and anxiety. Nat. Rev. Drug Discov. 4, 775e790.
Cryan, J.F., Slattery, D.A., 2007. Animal models of mood disorders: recent develop-
and a postdoctoral research fellowship from the Canadian Institute ments. Curr. Opin. Psychiatry 20, 1e7.
of Health Research (DCL). Special thanks to Dr. Jason Snyder for Cryan, J.F., Slattery, D.A., 2010. GABAB receptors and depression. Current status. Adv.
permission to use his blog (http://www.functionalneurogenesis. Pharmacol. 58, 427e451.
Curtis, M.A., Kam, M., Faull, R.L., 2011. Neurogenesis in humans. Eur. J. Neurosci. 33,
com/blog/) as inspiration for Tables 1 and 2 of this review. 1170e1174.
Czeh, B., Michaelis, T., Watanabe, T., Frahm, J., de Biurrun, G., van Kampen, M.,
Bartolomucci, A., Fuchs, E., 2001. Stress-induced changes in cerebral metabo-
References lites, hippocampal volume, and cell proliferation are prevented by antidepres-
sant treatment with tianeptine. Proc. Natl. Acad. Sci. U S A 98, 12796e12801.
Aasebo, I.E., Blankvoort, S., Tashiro, A., 2011. Critical maturational period of new Dagyte, G., Crescente, I., Postema, F., Seguin, L., Gabriel, C., Mocaer, E., Boer, J.A.,
neurons in adult dentate gyrus for their involvement in memory formation. Eur. Koolhaas, J.M., 2011. Agomelatine reverses the decrease in hippocampal cell
J. Neurosci. 33, 1094e1100. survival induced by chronic mild stress. Behav. Brain Res. 218, 121e128.
Abrous, D.N., Koehl, M., Le Moal, M., 2005. Adult neurogenesis: from precursors to David, D.J., Samuels, B.A., Rainer, Q., Wang, J.W., Marsteller, D., Mendez, I., Drew, M.,
network and physiology. Physiol. Rev. 85, 523e569. Craig, D.A., Guiard, B.P., Guilloux, J.P., Artymyshyn, R.P., Gardier, A.M., Gerald, C.,
Aimone, J.B., Gage, F.H., 2011. Modeling new neuron function: a history of using Antonijevic, I.A., Leonardo, E.D., Hen, R., 2009. Neurogenesis-dependent and -
computational neuroscience to study adult neurogenesis. Eur. J. Neurosci. 33, independent effects of fluoxetine in an animal model of anxiety/depression.
1160e1169. Neuron 62, 479e493.
32 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34

David, D.J., Wang, J., Samuels, B.A., Rainer, Q., David, I., Gardier, A.M., Hen, R., 2010. Hauser, T., Klaus, F., Lipp, H.P., Amrein, I., 2009. No effect of running and laboratory
Implications of the functional integration of adult-born hippocampal neurons housing on adult hippocampal neurogenesis in wild caught long-tailed wood
in anxiety-depression disorders. Neuroscientist 16, 578e591. mouse. BMC Neurosci. 10, 43.
DeCarolis, N.A., Eisch, A.J., 2010. Hippocampal neurogenesis as a target for the Heine, V.M., Maslam, S., Zareno, J., Joels, M., Lucassen, P.J., 2004. Suppressed
treatment of mental illness: a critical evaluation. Neuropharmacology 58, proliferation and apoptotic changes in the rat dentate gyrus after acute and
884e893. chronic stress are reversible. Eur. J. Neurosci. 19, 131e144.
Dere, E., Pause, B.M., Pietrowsky, R., 2010. Emotion and episodic memory in Hirschfeld, R.M., 2000. History and evolution of the monoamine hypothesis of
neuropsychiatric disorders. Behav. Brain Res. 215, 162e171. depression. J. Clin. Psychiatry 61 (Suppl. 6), 4e6.
Derrick, B.E., York, A.D., Martinez Jr., J.L., 2000. Increased granule cell neurogenesis Ho, Y.C., Wang, S., 2010. Adult neurogenesis is reduced in the dorsal hippocampus of
in the adult dentate gyrus following mossy fiber stimulation sufficient to induce rats displaying learned helplessness behavior. Neuroscience 171, 153e161.
long-term potentiation. Brain Res. 857, 300e307. Holick, K.A., Lee, D.C., Hen, R., Dulawa, S.C., 2008. Behavioral effects of chronic
Dhaliwal, J., Lagace, D.C., 2011. Visualization and genetic manipulation of adult fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or
neurogenesis using transgenic mice. Eur. J. Neurosci. 33, 1025e1036. the serotonin 1A receptor. Neuropsychopharmacology 33, 406e417.
Dobrossy, M.D., Drapeau, E., Aurousseau, C., Le Moal, M., Piazza, P.V., Abrous, D.N., Huang, G.J., Bannerman, D., Flint, J., 2008. Chronic fluoxetine treatment alters
2003. Differential effects of learning on neurogenesis: learning increases or behavior, but not adult hippocampal neurogenesis, in BALB/cJ mice. Mol.
decreases the number of newly born cells depending on their birth date. Mol. Psychiatry 13, 119e121.
Psychiatry 8, 974e982. Hwang, I.K., Yoo, K.Y., Li, H., Choi, J.H., Kwon, Y.G., Ahn, Y., Lee, I.S., Won, M.H., 2007.
Dranovsky, A., Picchini, A.M., Moadel, T., Sisti, A.C., Yamada, A., Kimura, S., Differences in doublecortin immunoreactivity and protein levels in the hippo-
Leonardo, E.D., Hen, R., 2011. Experience dictates stem cell fate in the adult campal dentate gyrus between adult and aged dogs. Neurochem. Res. 32,
hippocampus. Neuron 70, 908e923. 1604e1609.
Duman, R.S., 2009. Neuronal damage and protection in the pathophysiology and Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M.,
treatment of psychiatric illness: stress and depression. Dialogues Clin. Neurosci. Mori, K., Ikeda, T., Itohara, S., Kageyama, R., 2008. Roles of continuous neuro-
11, 239e255. genesis in the structural and functional integrity of the adult forebrain. Nat.
Duman, R.S., Malberg, J., Thome, J., 1999. Neural plasticity to stress and antide- Neurosci. 11, 1153e1161.
pressant treatment. Biol. Psychiatry 46, 1181e1191. Imayoshi, I., Sakamoto, M., Kageyama, R., 2011. Genetic methods to identify and
Eckenhoff, M.F., Rakic, P., 1988. Nature and fate of proliferative cells in the hippo- manipulate newly born neurons in the adult brain. Front. Neurosci. 5, 64.
campal dentate gyrus during the life span of the rhesus monkey. J. Neurosci. 8, Jacobs, B.L., van Praag, H., Gage, F.H., 2000. Adult brain neurogenesis and psychiatry:
2729e2747. a novel theory of depression. Mol. Psychiatry 5, 262e269.
Eisch, A.J., 2002. Adult neurogenesis: implications for psychiatry. Prog. Brain Res. Jayatissa, M.N., Bisgaard, C., Tingstrom, A., Papp, M., Wiborg, O., 2006. Hippocampal
138, 315e342. cytogenesis correlates to escitalopram-mediated recovery in a chronic mild
Encinas, J.M., Vaahtokari, A., Enikolopov, G., 2006. Fluoxetine targets early stress rat model of depression. Neuropsychopharmacology 31, 2395e2404.
progenitor cells in the adult brain. Proc. Natl. Acad. Sci. U S A 103, Jayatissa, M.N., Henningsen, K., West, M.J., Wiborg, O., 2009. Decreased cell prolif-
8233e8238. eration in the dentate gyrus does not associate with development of
Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., anhedonic-like symptoms in rats. Brain Res. 1290, 133e141.
Peterson, D.A., Gage, F.H., 1998. Neurogenesis in the adult human hippocampus. Jayatissa, M.N., Henningsen, K., Nikolajsen, G., West, M.J., Wiborg, O., 2010.
Nat. Med. 4, 1313e1317. A reduced number of hippocampal granule cells does not associate with an
Feder, A., Nestler, E.J., Charney, D.S., 2009. Psychobiology and molecular genetics of anhedonia-like phenotype in a rat chronic mild stress model of depression.
resilience. Nat. Rev. Neurosci. 10, 446e457. Stress 13, 95e105.
Feng, R., Rampon, C., Tang, Y.P., Shrom, D., Jin, J., Kyin, M., Sopher, B., Miller, M.W., Jiang, W., Zhang, Y., Xiao, L., Van Cleemput, J., Ji, S.P., Bai, G., Zhang, X., 2005.
Ware, C.B., Martin, G.M., Kim, S.H., Langdon, R.B., Sisodia, S.S., Tsien, J.Z., 2001. Cannabinoids promote embryonic and adult hippocampus neurogenesis and
Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is asso- produce anxiolytic- and antidepressant-like effects. J. Clin. Invest. 115,
ciated with reduced clearance of hippocampal memory traces. Neuron 32, 3104e3116.
911e926. Jinno, S., 2011. Decline in adult neurogenesis during aging follows a topographic
Fernando, A.B., Robbins, T.W., 2011. Animal models of neuropsychiatric disorders. pattern in the mouse hippocampus. J. Comp. Neurol. 519, 451e466.
Annu. Rev. Clin. Psychol. 7, 39e61. Joels, M., 2007. Role of corticosteroid hormones in the dentate gyrus. Prog. Brain
Finger, B.C., Dinan, T.G., Cryan, J.F., 2011a. High-fat diet selectively protects against Res. 163, 355e370.
the effects of chronic social stress in the mouse. Neuroscience. Joels, M., Pu, Z., Wiegert, O., Oitzl, M.S., Krugers, H.J., 2006. Learning under stress:
Finger, B.C., Dinan, T.G., Cryan, J.F., 2011b. The temporal impact of chronic inter- how does it work? Trends Cogn. Sci. 10, 152e158.
mittent psychosocial stress on high-fat diet-induced alterations in body weight. Joels, M., Krugers, H., Karst, H., 2008. Stress-induced changes in hippocampal
Psychoneuroendocrinology. function. Prog. Brain Res. 167, 3e15.
Fossati, P., Radtchenko, A., Boyer, P., 2004. Neuroplasticity: from MRI to depressive Kalueff, A.V., Olivier, J.D., Nonkes, L.J., Homberg, J.R., 2010. Conserved role for the
symptoms. Eur. Neuropsychopharmacol. 14 (Suppl. 5), S503eS510. serotonin transporter gene in rat and mouse neurobehavioral endophenotypes.
Frankland, P.W., Sakaguchi, M., Arruda-Carvalho, M., 2008. Starting at the endo- Neurosci. Biobehav. Rev. 34, 373e386.
phenotype: a role for alpha-CaMKII in schizophrenia? Mol. Brain 1, 5. Kaneko, N., Sawamoto, K., 2009. Adult neurogenesis and its alteration under
Fuchs, E., Czeh, B., Kole, M.H., Michaelis, T., Lucassen, P.J., 2004. Alterations of pathological conditions. Neurosci. Res. 63, 155e164.
neuroplasticity in depression: the hippocampus and beyond. Eur. Neuro- Karten, Y.J., Olariu, A., Cameron, H.A., 2005. Stress in early life inhibits neurogenesis
psychopharmacol. 14 (Suppl. 5), S481eS490. in adulthood. Trends Neurosci. 28, 171e172.
Fuss, J., Ben Abdallah, N.M., Vogt, M.A., Touma, C., Pacifici, P.G., Palme, R., Kee, N., Teixeira, C.M., Wang, A.H., Frankland, P.W., 2007. Preferential incorporation
Witzemann, V., Hellweg, R., Gass, P., 2010b. Voluntary exercise induces anxiety- of adult-generated granule cells into spatial memory networks in the dentate
like behavior in adult C57BL/6J mice correlating with hippocampal neuro- gyrus. Nat. Neurosci. 10, 355e362.
genesis. Hippocampus 20, 364e376. Kempermann, G., 2002. Why new neurons? Possible functions for adult hippo-
Fuss, J., Ben Abdallah, N.M., Hensley, F.W., Weber, K.J., Hellweg, R., Gass, P., 2010a. campal neurogenesis. J. Neurosci. 22, 635e638.
Deletion of running-induced hippocampal neurogenesis by irradiation prevents Kempermann, G., 2008. The neurogenic reserve hypothesis: what is adult hippo-
development of an anxious phenotype in mice. PLoS ONE 5. campal neurogenesis good for? Trends Neurosci..
Garner, M., Mohler, H., Stein, D.J., Mueggler, T., Baldwin, D.S., 2009. Research in Kempermann, G., 2011a. Adult Neurogenesis, vol. 2. Oxford University Press, New
anxiety disorders: from the bench to the bedside. Eur. Neuropsychopharmacol. York, NY.
19, 381e390. Kempermann, G., 2011b. Seven principles in the regulation of adult neurogenesis.
Gottesman II, , Gould, T.D., 2003. The endophenotype concept in psychiatry: Eur. J. Neurosci. 33, 1018e1024.
etymology and strategic intentions. Am. J. Psychiatry 160, 636e645. Kempermann, G., Gage, F.H., 2002. Genetic determinants of adult hippocampal
Gould, E., 2007. How widespread is adult neurogenesis in mammals? Nat. Rev. neurogenesis correlate with acquisition, but not probe trial performance, in the
Neurosci. 8, 481e488. water maze task. Eur. J. Neurosci. 16, 129e136.
Gould, E., Tanapat, P., 1999. Stress and hippocampal neurogenesis. Biol. Psychiatry Kempermann, G., Kuhn, H.G., Gage, F.H., 1997. More hippocampal neurons in adult
46, 1472e1479. mice living in an enriched environment. Nature 386, 493e495.
Gould, E., Woolley, C.S., McEwen, B.S., 1991. Adrenal steroids regulate postnatal Kempermann, G., Jessberger, S., Steiner, B., Kronenberg, G., 2004. Milestones of
development of the rat dentate gyrus: I. Effects of glucocorticoids on cell death. neuronal development in the adult hippocampus. Trends Neurosci. 27,
J. Comp. Neurol. 313, 479e485. 447e452.
Gould, E., Cameron, H.A., Daniels, D.C., Woolley, C.S., McEwen, B.S., 1992. Adrenal Kempermann, G., Krebs, J., Fabel, K., 2008. The contribution of failing adult
hormones suppress cell division in the adult rat dentate gyrus. J. Neurosci. 12, hippocampal neurogenesis to psychiatric disorders. Curr. Opin. Psychiatry 21,
3642e3650. 290e295.
Gould, E., Beylin, A., Tanapat, P., Reeves, A., Shors, T.J., 1999. Learning enhances adult Knoth, R.L., Bolge, S.C., Kim, E., Tran, Q.V., 2010. Effect of inadequate response to
neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260e265. treatment in patients with depression. Am. J. Manag. Care 16, e188ee196.
Greenwood, B.N., Fleshner, M., 2008. Exercise, learned helplessness, and the stress- Kobayashi, K., 2009. Targeting the hippocampal mossy fiber synapse for the treat-
resistant brain. Neuromolecular Med.. ment of psychiatric disorders. Mol. Neurobiol. 39, 24e36.
Hastings, N.B., Gould, E., 1999. Rapid extension of axons into the CA3 region by Koehl, M., Abrous, D.N., 2011. A new chapter in the field of memory: adult hippo-
adult-generated granule cells. J. Comp. Neurol. 413, 146e154. campal neurogenesis. Eur. J. Neurosci. 33, 1101e1114.
 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34 33

Krishnan, V., Nestler, E.J., 2011. Animal models of depression: molecular perspec- McEwen, B.S., Magarinos, A.M., Reagan, L.P., 2002. Structural plasticity and tia-
tives. Curr. Top. Behav. Neurosci 7, 121e147. neptine: cellular and molecular targets. Eur. Psychiatry 17 (Suppl. 3), 318e330.
Krishnan, V., Nestler, E.J., 2008. The molecular neurobiology of depression. Nature Meshi, D., Drew, M.R., Saxe, M., Ansorge, M.S., David, D., Santarelli, L., Malapani, C.,
455, 894e902. Moore, H., Hen, R., 2006. Hippocampal neurogenesis is not required for
Krishnan, V., Han, M.H., Graham, D.L., Berton, O., Renthal, W., Russo, S.J., Laplant, Q., behavioral effects of environmental enrichment. Nat. Neurosci. 9, 729e731.
Graham, A., Lutter, M., Lagace, D.C., Ghose, S., Reister, R., Tannous, P., Green, T.A., Ming, G.L., Song, H., 2011. Adult neurogenesis in the mammalian brain: significant
Neve, R.L., Chakravarty, S., Kumar, A., Eisch, A.J., Self, D.W., Lee, F.S., answers and significant questions. Neuron 70, 687e702.
Tamminga, C.A., Cooper, D.C., Gershenfeld, H.K., Nestler, E.J., 2007. Molecular Mizumatsu, S., Monje, M.L., Morhardt, D.R., Rola, R., Palmer, T.D., Fike, J.R., 2003.
adaptations underlying susceptibility and resistance to social defeat in brain Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer
reward regions. Cell 131, 391e404. Res. 63, 4021e4027.
Kuhn, H.G., DickinsonAnson, H., Gage, F.H., 1996. Neurogenesis in the dentate gyrus Monje, M.L., Mizumatsu, S., Fike, J.R., Palmer, T.D., 2002. Irradiation induces neural
of the adult rat: age-related decrease of neuronal progenitor proliferation. precursor-cell dysfunction. Nat. Med. 8, 955e962.
J. Neurosci. 16, 2027e2033. Nemeroff, C.B., Bremner, J.D., Foa, E.B., Mayberg, H.S., North, C.S., Stein, M.B., 2006.
Lagace, D.C., Donovan, M.H., DeCarolis, N.A., Farnbauch, L.A., Malhotra, S., Berton, O., Posttraumatic stress disorder: a state-of-the-science review. J. Psychiatr. Res.
Nestler, E.J., Krishnan, V., Eisch, A.J., 2010. Adult hippocampal neurogenesis is 40, 1e21.
functionally important for stress-induced social avoidance. Proc. Natl. Acad. Sci. Nissen, C., Holz, J., Blechert, J., Feige, B., Riemann, D., Voderholzer, U., Normann, C.,
U S A 107, 4436e4441. 2010. Learning as a model for neural plasticity in major depression. Biol.
Lavergne, F., Jay, T.M., 2010. A new strategy for antidepressant prescription. Front. Psychiatry 68, 544e552.
Neurosci. 4, 192. Noonan, M.A., Bulin, S.E., Fuller, D.C., Eisch, A.J., 2010. Reduction of adult hippo-
Leuner, B., Gould, E., 2010. Structural plasticity and hippocampal function. Annu. campal neurogenesis confers vulnerability in an animal model of cocaine
Rev. Psychol. 61, 111e140. C111e113. addiction. J. Neurosci. 30, 304e315.
Li, Y., Luikart, B.W., Birnbaum, S., Chen, J., Kwon, C.H., Kernie, S.G., Bassel-Duby, R., O’Mahony, S.M., Hyland, N.P., Dinan, T.G., Cryan, J.F., 2011. Maternal separation as
Parada, L.F., 2008. TrkB regulates hippocampal neurogenesis and governs a model of brain-gut axis dysfunction. Psychopharmacology (Berl.) 214, 71e88.
sensitivity to antidepressive treatment. Neuron 59, 399e412. Onksen, J.L., Brown, E.J., Blendy, J.A., 2011. Selective deletion of a cell cycle check-
Li, Y., Mu, Y., Gage, F.H., 2009. Development of neural circuits in the adult hippo- point kinase (ATR) reduces neurogenesis and alters responses in rodent models
campus. Curr. Top. Dev. Biol. 87, 149e174. of behavioral affect. Neuropsychopharmacology 36, 960e969.
Lopez-Munoz, F., Alamo, C., 2009. Monoaminergic neurotransmission: the history of Parent, J.M., Tada, E., Fike, J.R., Lowenstein, D.H., 1999. Inhibition of dentate granule
the discovery of antidepressants from 1950s until today. Curr. Pharm. Des 15, cell neurogenesis with brain irradiation does not prevent seizure-induced
1563e1586. mossy fiber synaptic reorganization in the rat. J. Neurosci. 19, 4508e4519.
Lucassen, P.J., Heine, V.M., Muller, M.B., van der Beek, E.M., Wiegant, V.M., De Parihar, V.K., Hattiangady, B., Kuruba, R., Shuai, B., Shetty, A.K., 2011. Predictable
Kloet, E.R., Joels, M., Fuchs, E., Swaab, D.F., Czeh, B., 2006. Stress, depression and chronic mild stress improves mood, hippocampal neurogenesis and memory.
hippocampal apoptosis. CNS Neurol. Disord. Drug Targets 5, 531e546. Mol. Psychiatry 16, 171e183.
Lucassen, P.J., Meerlo, P., Naylor, A.S., van Dam, A.M., Dayer, A.G., Fuchs, E., Peissner, W., Kocher, M., Treuer, H., Gillardon, F., 1999. Ionizing radiation-induced
Oomen, C.A., Czeh, B., 2010a. Regulation of adult neurogenesis by stress, sleep apoptosis of proliferating stem cells in the dentate gyrus of the adult rat
disruption, exercise and inflammation: implications for depression and anti- hippocampus. Brain Res. Mol. Brain Res. 71, 61e68.
depressant action. Eur. Neuropsychopharmacol. 20, 1e17. Penet, M.F., Laigle, C., Fur, Y.L., Confort-Gouny, S., Heurteaux, C., Cozzone, P.J.,
Lucassen, P.J., Stumpel, M.W., Wang, Q., Aronica, E., 2010b. Decreased numbers of Viola, A., 2006. In vivo characterization of brain morphometric and metabolic
progenitor cells but no response to antidepressant drugs in the hippocampus of endophenotypes in three inbred strains of mice using magnetic resonance
elderly depressed patients. Neuropharmacology 58, 940e949. techniques. Behav. Genet. 36, 732e744.
Luscher, B., Shen, Q., Sahir, N., 2011. The GABAergic deficit hypothesis of major Perera, T.D., Lisanby, S.H., 2000. Neurogenesis and depression. J. Psychiatr. Pract. 6,
depressive disorder. Mol. Psychiatry 16, 383e406. 322e333.
Lyons, D.M., Buckmaster, P.S., Lee, A.G., Wu, C., Mitra, R., Duffey, L.M., Perera, T.D., Park, S., Nemirovskaya, Y., 2008. Cognitive role of neurogenesis in
Buckmaster, C.L., Her, S., Patel, P.D., Schatzberg, A.F., 2010. Stress coping stim- depression and antidepressant treatment. Neuroscientist 14, 326e338.
ulates hippocampal neurogenesis in adult monkeys. Proc. Natl. Acad. Sci. U S A Perera, T.D., Dwork, A.J., Keegan, K.A., Thirumangalakudi, L., Lipira, C.M., Joyce, N.,
107, 14823e14827. Lange, C., Higley, J.D., Rosoklija, G., Hen, R., Sackeim, H.A., Coplan, J.D., 2011.
Lyons, L., Elbeltagy, M., Umka, J., Markwick, R., Startin, C., Bennett, G., Wigmore, P., Necessity of hippocampal neurogenesis for the therapeutic action of antide-
2011. Fluoxetine reverses the memory impairment and reduction in prolifera- pressants in adult nonhuman primates. PLoS ONE 6, e17600.
tion and survival of hippocampal cells caused by methotrexate chemotherapy. Pittenger, C., Duman, R.S., 2008. Stress, depression, and neuroplasticity: a conver-
Psychopharmacology (Berl.) 215, 105e115. gence of mechanisms. Neuropsychopharmacology 33, 88e109.
Madsen, T.M., Treschow, A., Bengzon, J., Bolwig, T.G., Lindvall, O., Tingstrom, A., Raber, J., Rola, R., LeFevour, A., Morhardt, D., Curley, J., Mizumatsu, S.,
2000. Increased neurogenesis in a model of electroconvulsive therapy. Biol. VandenBerg, S.R., Fike, J.R., 2004. Radiation-induced cognitive impairments are
Psychiatry 47, 1043e1049. associated with changes in indicators of hippocampal neurogenesis. Radiat. Res.
Madsen, T.M., Kristjansen, P.E., Bolwig, T.G., Wortwein, G., 2003. Arrested neuronal 162, 39e47.
proliferation and impaired hippocampal function following fractionated brain Reif, A., Fritzen, S., Finger, M., Strobel, A., Lauer, M., Schmitt, A., Lesch, K.P., 2006.
irradiation in the adult rat. Neuroscience 119, 635e642. Neural stem cell proliferation is decreased in schizophrenia, but not in
Malberg, J.E., Duman, R.S., 2003. Cell proliferation in adult hippocampus is depression. Mol. Psychiatry 11, 514e522.
decreased by inescapable stress: reversal by fluoxetine treatment. Neuro- Ressler, K.J., Rothbaum, B.O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E.,
psychopharmacology 28, 1562e1571. Hodges, L., Davis, M., 2004. Cognitive enhancers as adjuncts to psychotherapy:
Malberg, J.E., Schechter, L.E., 2005. Increasing hippocampal neurogenesis: a novel use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch.
mechanism for antidepressant drugs. Curr. Pharm. Des 11, 145e155. Gen. Psychiatry 61, 1136e1144.
Malberg, J.E., Eisch, A.J., Nestler, E.J., Duman, R.S., 2000. Chronic antidepressant treat- Revest, J.M., Dupret, D., Koehl, M., Funk-Reiter, C., Grosjean, N., Piazza, P.V.,
ment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104e9110. Abrous, D.N., 2009. Adult hippocampal neurogenesis is involved in anxiety-
Manev, H., Uz, T., Smalheiser, N.R., Manev, R., 2001. Antidepressants alter cell related behaviors. Mol. Psychiatry 14, 959e967.
proliferation in the adult brain in vivo and in neural cultures in vitro. Eur. J. Rozental, R., Mehler, M.F., Morales, M., Andrade-Rozental, A.F., Kessler, J.A.,
Pharmacol. 411, 67e70. Spray, D.C., 1995. Differentiation of hippocampal progenitor cells in vitro:
Manganas, L.N., Zhang, X., Li, Y., Hazel, R.D., Smith, S.D., Wagshul, M.E., Henn, F., temporal expression of intercellular coupling and voltage- and ligand-gated
Benveniste, H., Djuric, P.M., Enikolopov, G., Maletic-Savatic, M., 2007. Magnetic responses. Dev. Biol. 167, 350e362.
resonance spectroscopy identifies neural progenitor cells in the live human Sahay, A., Drew, M.R., Hen, R., 2007. Dentate gyrus neurogenesis and depression.
brain. Science 318, 980e985. Prog. Brain Res. 163, 697e722.
Marin-Burgin, A., Schinder, A.F., 2011. Requirement of adult-born neurons for Sahay, A., Scobie, K.N., Hill, A.S., O’Carroll, C.M., Kheirbek, M.A., Burghardt, N.S.,
hippocampus-dependent learning. Behav. Brain Res. Fenton, A.A., Dranovsky, A., Hen, R., 2011. Increasing adult hippocampal neu-
Markakis, E.A., Gage, F.H., 1999. Adult-generated neurons in the dentate gyrus send rogenesis is sufficient to improve pattern separation. Nature 472, 466e470.
axonal projections to field CA3 and are surrounded by synaptic vesicles. Samuels, B.A., Hen, R., 2011. Neurogenesis and affective disorders. Eur. J. Neurosci.
J. Comp. Neurol. 406, 449e460. 33, 1152e1159.
Massa, F., Koehl, M., Wiesner, T., Grosjean, N., Revest, J.M., Piazza, P.V., Abrous, D.N., Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N.,
Oliet, S.H., 2011. Conditional reduction of adult neurogenesis impairs bidir- Lee, J., Duman, R., Arancio, O., Belzung, C., Hen, R., 2003. Requirement of
ectionala hippocampal synaptic plasticity. Proc. Natl. Acad. Sci. U S A 108, hippocampal neurogenesis for the behavioral effects of antidepressants. Science
6644e6649. 301, 805e809.
McDonald, H.Y., Wojtowicz, J.M., 2005. Dynamics of neurogenesis in the dentate Sapolsky, R.M., 2000. Glucocorticoids and hippocampal atrophy in neuropsychiatric
gyrus of adult rats. Neurosci. Lett. 385, 70e75. disorders. Arch. Gen. Psychiatry 57, 925e935.
McEwen, B.S., 2000. The neurobiology of stress: from serendipity to clinical rele- Savignac, H.M., Hyland, N.P., Dinan, T.G., Cryan, J.F., 2011. The effects of repeated
vance. Brain Res. 886, 172e189. social interaction stress on behavioural and physiological parameters in
McEwen, B.S., Chattarji, S., 2004. Molecular mechanisms of neuroplasticity and a stress-sensitive mouse strain. Behav. Brain Res. 216, 576e584.
pharmacological implications: the example of tianeptine. Eur. Neuro- Saxe, M.D., Battaglia, F., Wang, J.W., Malleret, G., David, D.J., Monckton, J.E.,
psychopharmacol. 14 (Suppl. 5), S497eS502. Garcia, A.D., Sofroniew, M.V., Kandel, E.R., Santarelli, L., Hen, R., Drew, M.R.,
34 D. Petrik et al. / Neuropharmacology 62 (2012) 21e34

2006. Ablation of hippocampal neurogenesis impairs contextual fear condi- Tollefson, G.D., Bosomworth, J.C., Heiligenstein, J.H., Potvin, J.H., Holman, S., 1995.
tioning and synaptic plasticity in the dentate gyrus. Proc. Natl. Acad. Sci. U S A A double-blind, placebo-controlled clinical trial of fluoxetine in geriatric
103, 17501e17506. patients with major depression. The Fluoxetine Collaborative Study Group. Int.
Schatzberg, A., Roose, S., 2006. A double-blind, placebo-controlled study of ven- Psychogeriatr. 7, 89e104.
lafaxine and fluoxetine in geriatric outpatients with major depression. Am. J. Toni, N., Sultan, S., 2011. Synapse formation on adult-born hippocampal neurons.
Geriatr. Psychiatry 14, 361e370. Eur. J. Neurosci. 33, 1062e1068.
Schloesser, R.J., Manji, H.K., Martinowich, K., 2009. Suppression of adult neuro- Touma, C., 2011. Stress and affective disorders: animal models elucidating the
genesis leads to an increased hypothalamo-pituitary-adrenal axis response. molecular basis of neuroendocrine-behavior interactions. Pharmacopsychiatry
Neuroreport 20, 553e557. 44 (Suppl. 1), S15eS26.
Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., Herkenham, M., 2010. Tsigos, C., Chrousos, G.P., 2002. Hypothalamic-pituitary-adrenal axis, neuroendo-
Environmental enrichment requires adult neurogenesis to facilitate the crine factors and stress. J. Psychosom Res. 53, 865e871.
recovery from psychosocial stress. Mol. Psychiatry 15, 1152e1163. Uberti, D., Piccioni, L., Cadei, M., Grigolato, P., Rotter, V., Memo, M., 2001. p53 is
Schmidt, H.D., Duman, R.S., 2007. The role of neurotrophic factors in adult hippo- dispensable for apoptosis but controls neurogenesis of mouse dentate gyrus
campal neurogenesis, antidepressant treatments and animal models of cells following gamma-irradiation. Brain Res. Mol. Brain Res. 93, 81e89.
depressive-like behavior. Behav. Pharmacol. 18, 391e418. Uchida, S., Hara, K., Kobayashi, A., Fujimoto, M., Otsuki, K., Yamagata, H., Hobara, T.,
Schwarzer, C., 2009. 30 years of dynorphinsenew insights on their functions in Abe, N., Higuchi, F., Shibata, T., Hasegawa, S., Kida, S., Nakai, A., Watanabe, Y.,
neuropsychiatric diseases. Pharmacol. Ther. 123, 353e370. 2011. Impaired hippocampal spinogenesis and neurogenesis and altered affec-
Seminowicz, D.A., Mayberg, H.S., McIntosh, A.R., Goldapple, K., Kennedy, S., Segal, Z., tive behavior in mice lacking heat shock factor 1. Proc. Natl. Acad. Sci. U S A 108,
Rafi-Tari, S., 2004. Limbic-frontal circuitry in major depression: a path modeling 1681e1686.
metaanalysis. Neuroimage 22, 409e418. Van Bokhoven, P., Oomen, C.A., Hoogendijk, W.J., Smit, A.B., Lucassen, P.J., Spijker, S.,
Seri, B., Garcia-Verdugo, J.M., McEwen, B.S., Alvarez-Buylla, A., 2001. Astrocytes give 2011. Reduction in hippocampal neurogenesis after social defeat is long-lasting
rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, and responsive to late antidepressant treatment. Eur. J. Neurosci..
7153e7160. van Praag, H., Christie, B.R., Sejnowski, T.J., Gage, F.H., 1999a. Running enhances
Sheline, Y.I., 2000. 3D MRI studies of neuroanatomic changes in unipolar major neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad.
depression: the role of stress and medical comorbidity. Biol. Psychiatry 48, Sci. U S A 96, 13427e13431.
791e800. van Praag, H., Kempermann, G., Gage, F.H., 1999b. Running increases cell prolifer-
Sheline, Y.I., Mittler, B.L., Mintun, M.A., 2002. The hippocampus and depression. Eur. ation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2,
Psychiatry 17 (Suppl. 3), 300e305. 266e270.
Shors, T.J., Townsend, D.A., Zhao, M., Kozorovitskiy, Y., Gould, E., 2002. Neurogenesis van Praag, H., Schinder, A.F., Christie, B.R., Toni, N., Palmer, T.D., Gage, F.H., 2002.
may relate to some but not all types of hippocampal-dependent learning. Functional neurogenesis in the adult hippocampus. Nature 415, 1030e1034.
Hippocampus 12, 578e584. Veena, J., Srikumar, B.N., Mahati, K., Raju, T.R., Shankaranarayana Rao, B.S., 2011.
Sierra, A., Encinas, J.M., Maletic-Savatic, M., 2011. Adult human neurogenesis: from Oxotremorine treatment restores hippocampal neurogenesis and ameliorates
microscopy to magnetic resonance imaging. Front. Neurosci. 5, 47. depression-like behaviour in chronically stressed rats. Psychopharmacology
Singer, B.H., Jutkiewicz, E.M., Fuller, C.L., Lichtenwalner, R.J., Zhang, H., Velander, A.J., (Berl.).
Li, X., Gnegy, M.E., Burant, C.F., Parent, J.M., 2009. Conditional ablation and Vollmayr, B., Simonis, C., Weber, S., Gass, P., Henn, F., 2003. Reduced cell prolifer-
recovery of forebrain neurogenesis in the mouse. J. Comp. Neurol. 514, ation in the dentate gyrus is not correlated with the development of learned
567e582. helplessness. Biol. Psychiatry 54, 1035e1040.
Snyder, J.S., Kee, N., Wojtowicz, J.M., 2001. Effects of adult neurogenesis on synaptic Vollmayr, B., Mahlstedt, M.M., Henn, F.A., 2007. Neurogenesis and depression: what
plasticity in the rat dentate gyrus. J. Neurophysiol. 85, 2423e2431. animal models tell us about the link. Eur. Arch. Psychiatry Clin. Neurosci. 257,
Snyder, J.S., Soumier, A., Brewer, M., Pickel, J., Cameron, H.A., 2011. Adult hippocampal 300e303.
neurogenesis buffers stress responses and depressive behaviour. Nature 5. Wahlsten, D., Metten, P., Phillips, T.J., Boehm 2nd, S.L., Burkhart-Kasch, S., Dorow, J.,
Stam, R., 2007. PTSD and stress sensitisation: a tale of brain and body Part 2: animal Doerksen, S., Downing, C., Fogarty, J., Rodd-Henricks, K., Hen, R., McKinnon, C.S.,
models. Neurosci. Biobehav. Rev. 31, 558e584. Merrill, C.M., Nolte, C., Schalomon, M., Schlumbohm, J.P., Sibert, J.R., Wenger, C.D.,
Stanfield, B.B., Trice, J.E., 1988. Evidence that granule cells generated in the dentate Dudek, B.C., Crabbe, J.C., 2003. Different data from different labs: lessons from
gyrus of adult rats extend axonal projections. Exp. Brain Res. 72, 399e406. studies of gene-environment interaction. J. Neurobiol. 54, 283e311.
Suh, H., Deng, W., Gage, F.H., 2009. Signaling in adult neurogenesis. Annu. Rev. Cell Wang, J.W., David, D.J., Monckton, J.E., Battaglia, F., Hen, R., 2008. Chronic fluoxetine
Dev. Biol.. stimulates maturation and synaptic plasticity of adult-born hippocampal
Surget, A., Saxe, M., Leman, S., Ibarguen-Vargas, Y., Chalon, S., Griebel, G., Hen, R., granule cells. J. Neurosci. 28, 1374e1384.
Belzung, C., 2008. Drug-dependent requirement of hippocampal neurogenesis Warner-Schmidt, J.L., Duman, R.S., 2006. Hippocampal neurogenesis: opposing
in a model of depression and of antidepressant reversal. Biol. Psychiatry 64, effects of stress and antidepressant treatment. Hippocampus 16, 239e249.
293e301. Yamasaki, N., Maekawa, M., Kobayashi, K., Kajii, Y., Maeda, J., Soma, M., Takao, K.,
Surget, A., Wang, Y., Leman, S., Ibarguen-Vargas, Y., Edgar, N., Griebel, G., Belzung, C., Tanda, K., Ohira, K., Toyama, K., Kanzaki, K., Fukunaga, K., Sudo, Y., Ichinose, H.,
Sibille, E., 2009. Corticolimbic transcriptome changes are state-dependent and Ikeda, M., Iwata, N., Ozaki, N., Suzuki, H., Higuchi, M., Suhara, T., Yuasa, S.,
region-specific in a rodent model of depression and of antidepressant reversal. Miyakawa, T., 2008. Alpha-CaMKII deficiency causes immature dentate gyrus,
Neuropsychopharmacology 34, 1363e1380. a novel candidate endophenotype of psychiatric disorders. Mol. Brain 1, 6.
Surget, A., Tanti, A., Leonardo, E.D., Laugeray, A., Rainer, Q., Touma, C., Palme, R., Yap, J.J., Takase, L.F., Kochman, L.J., Fornal, C.A., Miczek, K.A., Jacobs, B.L., 2006.
Griebel, G., Ibarguen-Vargas, Y., Hen, R., Belzung, C., 2011. Antidepressants Repeated brief social defeat episodes in mice: effects on cell proliferation in the
recruit new neurons to improve stress response regulation. Mol. Psychiatry. dentate gyrus. Behav. Brain Res. 172, 344e350.
Takemura, N.U., Kato, N., 2008. Adult neurogenesis and systemic adaptation: animal Zhao, C., Deng, W., Gage, F.H., 2008a. Mechanisms and functional implications of
experiments and clinical perspectives for PTSD. Prog. Brain Res. 167, 99e109. adult neurogenesis. Cell 132, 645e660.
Tamminga, C.A., Stan, A.D., Wagner, A.D., 2010. The hippocampal formation in Zhao, Z., Taylor, W.D., Styner, M., Steffens, D.C., Krishnan, K.R., MacFall, J.R., 2008b.
schizophrenia. Am. J. Psychiatry 167, 1178e1193. Hippocampus shape analysis and late-life depression. PLoS ONE 3, e1837.
Tanti, A., Belzung, C., 2010. Open questions in current models of antidepressant Zhu, X.H., Yan, H.C., Zhang, J., Qu, H.D., Qiu, X.S., Chen, L., Li, S.J., Cao, X., Bean, J.C.,
action. Br. J. Pharmacol. 159, 1187e1200. Chen, L.H., Qin, X.H., Liu, J.H., Bai, X.C., Mei, L., Gao, T.M., 2010. Intermittent
Taylor, P.J., Gooding, P., Wood, A.M., Tarrier, N., 2011. The role of defeat and hypoxia promotes hippocampal neurogenesis and produces antidepressant-like
entrapment in depression, anxiety, and suicide. Psychol. Bull. 137, 391e420. effects in adult rats. J. Neurosci. 30, 12653e12663.