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Physiol Rev 85: 523–569, 2005;
doi:10.1152/physrev.00055.2003.
Adult Neurogenesis: From Precursors
to Network and Physiology
DJOHER NORA ABROUS, MURIEL KOEHL, AND MICHEL LE MOAL
Laboratoire de Physiopathologie des Comportements, Institut National de la Santé
et de la Recherche Médicale, U588, Université de Bordeaux 2, Bordeaux, France
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I. Neurogenesis in the Adult Brain: a New Paradigm for Structure-Function Relationships
II. From Newly Born Cells to Network
A. Definitions
B. In vivo evaluation of adult neurogenesis: methodological issues
C. Integration of the newly born cells into neurogenic site networks
D. Factors regulating adult neurogenesis
III. The Anatomo-Functional Approach
A. Environmental and physiological influences on neurogenesis
B. Activation of the stress axis: acute and long-term effects on neurogenesis
C. Aging and longitudinal observations
D. Involvement of neurogenesis in pathologies
IV. Conclusion
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Abrous, Djoher Nora, Muriel Koehl, and Michel Le Moal. Adult Neurogenesis: From Precursors to Network and
Physiology. Physiol Rev 85: 523–569, 2005; doi:10.1152/physrev.00055.2003.—The discovery that the adult mammalian brain creates new neurons from pools of stemlike cells was a breakthrough in neuroscience. Interestingly, this
particular new form of structural brain plasticity seems specific to discrete brain regions, and most investigations
concern the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampal formation (HF). Overall, two
main lines of research have emerged over the last two decades: the first aims to understand the fundamental
biological properties of neural stemlike cells (and their progeny) and the integration of the newly born neurons into
preexisting networks, while the second focuses on understanding its relevance in brain functioning, which has been
more extensively approached in the DG. Here, we propose an overview of the current knowledge on adult
neurogenesis and its functional relevance for the adult brain. We first present an analysis of the methodological
issues that have hampered progress in this field and describe the main neurogenic sites with their specificities. We
will see that despite considerable progress, the levels of anatomic and functional integration of the newly born
neurons within the host circuitry have yet to be elucidated. Then the intracellular mechanisms controlling neuronal
fate are presented briefly, along with the extrinsic factors that regulate adult neurogenesis. We will see that a
growing list of epigenetic factors that display a specificity of action depending on the neurogenic site under
consideration has been identified. Finally, we review the progress accomplished in implicating neurogenesis in
hippocampal functioning under physiological conditions and in the development of hippocampal-related pathologies
such as epilepsy, mood disorders, and addiction. This constitutes a necessary step in promoting the development of
therapeutic strategies.
I. NEUROGENESIS IN THE ADULT BRAIN: A
NEW PARADIGM FOR STRUCTUREFUNCTION RELATIONSHIPS
Developmental biology teaches us that brain functioning requires neurons of appropriate types to be generated in appropriate places and numbers, and then to
migrate to their final positions and refine their synaptic
contacts to a high degree of precision and avoid aberrant
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connections. Finally, the brain must accommodate
growth of the organism and new behavioral or cognitive
capacities. For decades, neurobiologists have known that
neuronal network organization as well as individual performances are altered by environmental events, experience, or internal signals such as hormones, aging, and
various injuries (322).
The adult brain faces two seemingly contradictory
challenges. On the one hand it must maintain behavior
0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society
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first observations of adult neurogenesis (11), followed by
the studies of Kaplan and Hinds (for a historical view, see
Ref. 249), were followed by negative reactions and critical
publications that did not confirm the existence of newborn neurons in adults (452). Ironically, at about the same
period, data were published on neurogenesis in birds
related to the appearance of seasonal song, a discovery
that gave rise to new thoughts on brain plasticity and
adaptation (for review, see Ref, 410).
Overall, two main lines of research have emerged
since the discovery that neurogenesis persists in discrete
regions of the adult brain. The first aims to isolate neural
stem cells and understand their fundamental biological
properties, the ultimate objective being to manipulate
them and enhance repair and regeneration. The second
focuses on understanding its functional relevance, especially in the DG. We will thus approach these two lines of
research in the following chapters. As we will see, it has
now been unambiguously demonstrated that persistent
neurogenesis occurs in the SVZ and DG of adult rodents.
Most of our knowledge on the birth, proliferation, migration, and death of adult-born cells results from studies
performed in the SVZ paradigm that easily allow the dissection of the properties of the stem cells (and their
progeny) and the integration of the newly born neurons
into preexisting networks. Once the existence of the phenomenon had been established, the important step was to
understand what triggers and inhibits it, and how it is
regulated. Identifying the functional roles of these adultborn neurons in the context of structure-function relationships will be the main focus of the review. The considerable evidence supporting the participation of these
new neurons in brain functioning has been collected in
the DG, and their role in information storage and hippocampal-related pathology will be examined. On the
assumption that the DG transforms entorhinal inputs to
facilitate storage in CA3, adult neurogenesis may allow
the DG to adapt to new flows of relevant information
while at the same time preserving it for the processing of
old memories. In more general terms, we will ask whether
neurogenesis acts on memory consolidation in a specific
and functional manner or whether it prepares the HF for
general experiences and challenges.
II. FROM NEWLY BORN CELLS TO NETWORK
A. Definitions
The recent interest in adult neurogenesis studies has
led to a promiscuous use of the term stem cell and a
broadening of its definition. However, based on their
functional properties, one can distinguish “stem” cells
from “progenitor or precursor” cells. Thus a stem cell is
currently defined as an undifferentiated cell that exhibits
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and thus preserve the underlying circuitry, and on the
other hand, it must allow circuits to adapt to environmental challenges. This dilemma between stability and plasticity is a subject of debate. It has been suggested that the
structural changes underlying plasticity exist at the levels
of dendritic spines, dendrites, and axons (28, 287, 297,
383, 408). However, direct observation of dendrites and
spines in the adult brain supports two divergent view
points, i.e., both long-term dendrite stability (192, 368)
and experience-dependent synaptic plasticity (541). Data
suggest that dendritic spines are heterogeneous in shape
and structure and can be roughly divided in two groups:
large spines that survive for months and even years and
small spines that are motile, change form rapidly, and
either disappear or transform into large spines (for review, see Refs. 132, 216, 255). During long-term potentiation (LTP) of synaptic transmission, which is known to
involve modifications in dendritic spine morphology (297,
337, 586), small spines are both generated and eliminated
(143, 338). Given the structure-stability-function relationships, it has been suggested that the small spines are
generated during activity-dependent processes and acquisition of memories, providing an inexhaustible source of
new synapses, and that the large spines are the structural
basis of memories in the long-term (255). For many authors, all these local and cellular phenomena have been
labeled as neuroplasticity, a concept used to account for
the functional observations.
In the search for structure-function relationships,
great enthusiasm followed the discovery that embryonic
neurons, for instance, dopaminergic neurons, could be
transplanted into adult brains, survive and alleviate some
postlesion behavioral alterations. Although it generated a
considerable amount of data, this approach has not
proven very successful so far in living up to functional and
therapeutic hopes (157, 217). However, it has generated a
considerable amount of data on the growth and the migration of these neurons, and on their ability to make
synapse with the surrounding neurons of the host and to
influence the activity of their target neurons. However,
the turning point has been the demonstration that the
adult mammalian brain is also capable of mitosis and that
the generated cells differentiate into neurons that migrate
to integrate circuitries. Interestingly, this particular new
form of structural brain plasticity seems specific to discrete brain regions and most investigations concern the
subventricular zone (SVZ) and the dentate gyrus (DG)
of the hippocampal formation (HF), although an interesting debate developed in the wake of the proposition
that neurogenesis occurs in the neocortex of the adult
primate.
In brief, the discovery of neurogenesis in the adult
brain confronted the persistent assumption that adult
neurons did not undergo proliferation and that structure
could not be changed in this way. In the 1960s, Altman’s
NEUROGENESIS IN THE ADULT BRAIN
B. In Vivo Evaluation of Adult Neurogenesis:
Methodological Issues
1. Original studies: DNA synthesis staining and
BrdU utilization
The original studies on in vivo cell proliferation relied on the use of [3H]thymidine ([3H]dT), which is incorporated into the cell during DNA synthesis, i.e., the S
phase of the cell cycle. Mitotically active cells are subsequently revealed by autoradiography. More recently,
BrdU, an analog of thymidine, has been used in lieu of
[3H]dT (412). These markers have comparable availability
times and labeling efficiencies (411). Although [3H]dT
presents the advantage of good stoichiometry (allowing
determination of the number of mitotic events after labeling), BrdU revealed by immunohistochemistry is more
frequently used as the cost is lower, section processing is
faster, and stereological analysis is possible. In addition,
BrdU is easier to combine with other cellular markers,
which makes it possible to phenotype the newly born
cells by double or triple immunohistochemistry.
The original protocols used for BrdU labeling, established by Gage and colleagues (268, 267), consisted of a
dozen BrdU injections (50 mg · kg⫺1 · day⫺1 ip). Since this
pioneering work, with the flurry of data, protocols have
diversified. As we will see in section III, the number and
the doses of BrdU injections as well as the frequency of
administration vary considerably from one experiment to
another depending on the area of interest (fewer injections are required for studying the SVZ compared with the
DG), the species, the phenomena being examined (a decrease or an increase in neurogenesis), and the subject
type (young intact subjects, impaired or old individuals).
To make the picture more complex, BrdU is sometimes
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administered in mice via drinking water (1–1.5 mg/ml for
2– 4 wk) to minimize animal pain and distress (80, 332),
with the disadvantage that individual daily intake is unknown.
Following BrdU injections, the killing of the animal is
adjusted depending on the step of neurogenesis that is
being investigated: cell proliferation, cell determination
toward a given phenotype, cell migration and differentiation, or cell death. In this way, to study proliferation,
animals are killed following the last BrdU injection within
a short time lapse ranging from a few hours to a few days.
As early as 2 h after a single injection, mitotic figures can
be seen, and this time point has been proposed as a true
measure of proliferation. However, in the case of senescent rats, multiple injections are required as cell proliferation and the frequency of labeled clusters are too low.
Furthermore, when animals are killed within a short time
after the last BrdU injection, newly born cells are small,
irregular, and clustered (the clusters being more numerous with multiple BrdU injections), which renders quantitative analysis challenging. For this reason, a washout
protocol of a few days allowing cells to migrate is applied
in many experiments. Cell migration is followed by killing
the animals at different days (1–10 days) after BrdU injection, in which case it is necessary to limit the number
of BrdU injections (208). Survival of the newborn cells is
usually studied by killing the animals after a long delay
(several weeks) following BrdU administration, when the
phenotype of the cells has been determined. Less frequently, retroviral tracing has also been used for “developmental” studies (81, 123, 439, 501). However, because
retroviral infection is not controlled, labeling is quite
variable and is thus unsuitable for quantitative analysis
between different experimental groups (556). Finally, in
most pharmacological and behavioral studies, the treatment under investigation is interrupted after BrdU pulses,
and animals are killed after a “chase” period of several
weeks. It is important to be aware that in this case, the
influence of the treatment on cell determination and cell
survival is not addressed. To do so, the “treatment” should
be prolonged over the “chase” period time (for example,
see Refs. 267, 335).
2. Phenotyping cells
One of the most important tasks is to phenotype
cells, and markers specific to the dividing cells or the
state of maturation of newly born cells are available for in
vivo studies.
A) PRECURSOR CELLS. So far, no marker that is exclusive to
stemlike cells has been identified, which certainly reflects
the divergence in opinion on the identity of the stemlike
cell population. However, markers of stem-cell candidates or simply dividing cells are now available and can
be divided into two categories depending on the purpose
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the ability to proliferate, to self-renew, and to differentiate
into multiple yet distinct lineages (356, 570). In the adult
brain, most stemlike cells are in a quiescent stage, except
in the two neurogenic zones considered here, the SVZ and
the DG of the HF, where they have a very slow dividing
turnover (a few weeks). In contrast, progenitor cells are
mitotic cells with a faster dividing cell cycle that retain
the ability to proliferate and to give rise to terminally
differentiated cells but are not capable of indefinite selfrenewal; they are more committed than stemlike cells,
and their multipotentiality is still a matter of debate.
Finally, when the cell type being studied is not clear, as is
the case in vivo, both stem and progenitor cells are referred to as precursor cells. For an overview of the characteristics that can be used to differentiate neural stem
from progenitor cells, and of the controversies that still
persist around definitions, we refer the reader to reviews
by Gage (160), Geuna et al. (167), and Seaberg and van der
Kooy (494).
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nal markers is the basic helix-loop-helix (bHLH) transcription factor NeuroD, which seems to be expressed
from a very early stage to the stage where new neurons
develop dendrites (496, 497). Some of these markers stain
nonneuronal cells, and some of them (TOAD 64, PSANCAM, DCX) are present in the brain, for example, in the
piriform cortex, independently of neurogenesis (113, 389,
392, 423, 498, 560), which makes the interpretation of
results more difficult.
C) MATURE NEURONS. The most frequently used specific
markers for mature neurons are neuron specific enolase
(NSE), neuronal specific nuclear protein (NeuN) (386),
and microtubule-associated protein (MAP-2). However,
the identification of the neuronal phenotype of newly
generated cells using these markers is considered ambiguous as they also label other types of cells (189, 411, 453,
454). An alternative approach consists in demonstrating
that adult-born cells do not express any marker for glial
cells such as 2⬘,3⬘-cyclic nucleotide (CNP) for oligodendrocytes, and calcium binding proteins (S100, S100␤) or
glial fibrillary acidic protein (GFAP) for astrocytes.
3. Current identified pitfalls
In addition to the problem of neuronal identification,
several methodological pitfalls have been identified. First,
embryonic and postnatal injections of BrdU have been
reported to induce physical, morphological, and behavioral abnormalities (282, 495). Although only a few studies
have addressed the deleterious effects of BrdU injections
in adulthood, a neurotoxic effect has been reported in
aged rats, loss of body weight, and deterioration in the
state of the coat being induced by repeated administrations of 150 mg · kg⫺1 · day⫺1 of BrdU for 5 days (130).
Together with its early teratogenic effects, this suggests
that incorporation of BrdU into mitotically active cells
may inhibit cell formation and affect stemlike cell population. This raises the as yet unresolved problem that
BrdU may alter the functioning of the labeled cells. Second, changes in neurogenesis detected by variations in
BrdU staining may be related to a modification in BrdU
availability through an alteration in blood flow or in
blood-brain barrier permeability. To rule out such confounding parameters, using endogenous markers of the
cell cycle (Ki67, PCNA, HH3, and P34cdc2) and evaluating
changes in different brain regions may be helpful. For
behavioral studies, adequate control groups should be
used to measure the involvement of a potential modification of blood flow by exercise. Third, pharmacological
treatments or behavioral and environment-induced
changes in neurogenesis may exert their effects by modifying the length of the cell cycle, the number of proliferating cells, or both. However, in most “functional” studies,
evaluating the cell cycle parameters is difficult if not
impossible, and one might question the relevance of this
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of the studies. The first category covers “universal” or
general molecular markers that are used to define the
biological characteristics of stemlike cells (for an extensive review, see Ref. 440). Among these markers, the most
widely used is nestin, which defines classes of intermediate filament proteins; it was first described as the product
of a gene whose expression distinguishes precursors from
more differentiated cells in the neural tube (156) and was
found to be specifically expressed in neural progenitor
cells (307). More recently, a family of molecular markers has been identified, which includes mouse-Musashi1
(m-Msi1), a neural RNA-binding protein expressed predominantly in proliferating neuronal and/or glial precursor cells but not in newly generated postmitotic neurons
and oligodendrocytes (246, 479).
The second category of markers is more specifically
used in research aimed at uncovering the functional role
of adult neurogenesis and consists of antigens present in
cycling cells that are used as proliferative markers. They
are often used in combination with BrdU, since incorporation of BrdU alone identifies cells undergoing DNA
replication but does not formally provide evidence that
these cells are actually capable of division. They include
Ki-67, a nuclear protein expressed in dividing cells for the
entire duration of their mitotic activity, the expression of
which is neither linked to DNA repair nor to apoptotic
processes (142, 259). Although less frequently used, proliferating cell nuclear antigen (PCNA) allows assessment
of cell proliferation as well. It is an auxiliary protein of
DNA polymerase ␦ which is increasingly expressed
through G1, peaks at the G1/S interface, and decreases
through G2 (146, 162, 294). This marker has been used
successfully to study cell proliferation and cell cycle
length in conjunction with BrdU cumulative labeling (39).
Finally and much less used are P34cdc2, a key player in
the initiation of mitosis (415), and phosphorylated Histone H3 (HH3) expression, which is confined to cells in
the G2 and M phases of the cell cycle. In general, cells in
the G2 phase exhibit punctuate HH3 nuclear staining that
changes to a more condensed pattern once they enter the
M phase (214).
B) IMMATURE NEURONS. The mammalian RNA-binding protein Hu, the homolog of the Drosophila neuron-specific
RNA-binding protein Elav, is exclusively expressed in
postmitotic neurons (7, 479) and thus is frequently used
as an early neuronal marker (31, 414). Other markers
include neuron-specific class III ␤-tubulin (TuJ1), a cytoskeletal protein expressed in all postmitotic neurons
(360, 361), doublecortin (DCX), which encodes a microtubule-associated protein expressed in migrating neuroblasts (155, 168, 389), TOAD 64 (turned on after division,
also called TUC-4, CRMP4, PUlip1), a cytoplasmic protein
expressed transiently by postmitotic neurons (366), and
the polysialylated-neuronal cell adhesion molecule PSANCAM (277, 498). Another candidate for immature neuro-
NEUROGENESIS IN THE ADULT BRAIN
4. Summary
This last decade has been marked by tremendous
advances including the development of BrdU labeling
methods, the discovery of selective markers that differentiate neurons from glial cells, and the use of new molecular and genetic tools to follow the “development” of
the newly born cells. As we will see in the following
sections, this technical progress has led to a lot of research and data that have confirmed observations made in
the early 1960s and considered at that time by many
specialists as nonconclusive. However, researchers are
now aware of problems and agree that proper interpretations depend on accepted rules: 1) [3H]dT and BrdU
labeling are not sufficient to unambiguously differentiate
old neurons from newborn cells, 2) the neuron-specific
markers presently used must be complemented by appropriate controls to detect false positives and by electrophysiological recordings to assert real neuronal phenotypes, and 3) the maturation and the integration of the
adult-born neurons must be followed up.
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C. Integration of the Newly Born Cells
Into Neurogenic Site Networks
1. The SVZ
A) IDENTIFICATION OF THE STEMLIKE CELLS. The SVZ, located
throughout the lateral wall of the lateral ventricle, harbors
the largest population of proliferating cells in the adult
brain of rodents (12, 448, 511), monkeys (178, 179, 182,
248, 286, 434), and humans (47, 144), and it has been
estimated that 30,000 cells are generated bilaterally daily
in the mouse SVZ (317). This region exhibits a rostrocaudal gradient of proliferative activity: proliferation is
higher in the dorsolateral corner of the rostral ventricle
and falls caudally, moving from the striatum towards the
HF (511). This gradient has been correlated with the
capability of the constitutively proliferative cells to divide
and to form neurospheres (381, 493) and certainly reflects
the existence of two populations of dividing cells, one of
quiescent stemlike cells and one of rapidly proliferating
progenitor cells (381, 382). Four cell types have been
described in the SVZ: 1) ependymal ciliated cells (type E)
facing the lumen of the ventricle, whose function is to
circulate the cerebrospinal fluid; 2) proliferating type A
neuroblasts, expressing PSA-NCAM, Tuj1, and Hu, and
migrating in “chains” toward the olfactory bulb (OB); 3)
slowly proliferating type B cells expressing nestin and
GFAP, and unsheathing migrating type A neuroblasts; and
4) actively proliferating type C cells or “transit amplifying
progenitors” expressing nestin, and forming clusters interspaced among chains throughout the SVZ (15, 55, 122,
124, 166, 220, 474).
Although it has been proposed that the stemlike cells
may be ependymal type E cells, which were shown to
divide in vivo and to differentiate into neurons in the OB
(242), this view has been challenged by van der Kooy and
colleagues (85) who have found that ependymal cells
generating spheres do not have the ability to self-renew or
to produce neurons, and by Capela and Temple (79) who
have shown that ependymal cells do not form neurospheres. It is more likely that the type B cells represent a
stemlike cell type (123, 124). Indeed, after 1 wk of intracerebroventricular (icv) infusion of the antimitotic drug
cytosine-␤-D-arabinofuranoside (AraC), type C and type A
cells are eliminated, whereas type B cells continue to
divide. Between 1 and 2 days after treatment cessation,
type C cells reappear, followed 2 days later by type A
cells, suggesting that type B cells give rise to type C cells,
which in turn generate neuroblasts (125). Furthermore,
following the targeted introduction of a retrovirus into
GFAP-positive cells, which include type B cells, labeled
cells migrate towards the OB where they give rise to new
neurons (123). Thus the lineage progression B 3 C 3 A
has been proposed (123, 124). However, Doetsch et al.
(126) have also shown that after exposure to high concentrations of EGF, the type C cells retain stemlike cell
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“exercise.” Finally, BrdU or [3H]dT labeling might produce false negatives and positives. The most commonly
used dose of BrdU (50 mg/kg) labels only a fraction of the
proliferating cells (75), which may result in an apparent
absence of effects of a given experimental setting on cell
proliferation. However, multiple injections of this low
dose may overcome this problem. Furthermore, because
the precursor cell population most certainly does not
divide synchronically, labeling all dividing cells with a
single injection of BrdU, whatever the dose, appears utopist. On the other hand, higher doses of BrdU associated
with an enhanced sensitivity of immunohistochemical
methods might lead to labeling apoptotic cells or nonproliferating cells that synthesize DNA for repair (594), and
thus to false positives. This problem is particularly relevant for studies on lesions, epilepsy, or ischemia, where a
high rate of cell death is observed. There are several
possible ways to rule out BrdU labeling of nonproliferative cells: 1) observing mitotic figures a few hours after
BrdU or [3H]dT application; 2) using other endogenous
cell cycle markers; 3) using electronic microscopy; 4)
analyzing a time course of BrdU labeling (95); 5) combining BrdU with markers of cell death, although in this case
false negative results due to the downregulation of markers by dying cells cannot be ruled out; 6) using retroviral
labeling (81, 123, 439, 501, 556), which is not devoid of
disadvantages (the type of cells incorporating the virus
may not be fully controlled, and stereotaxic injection,
known to cause injury, is required); and 7) visualizing
neurogenic sites in nestin-promoter-GFP transgenic mice
(577).
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properties (126). In fact, there are opposing views on
whether neurospheres are derived from GFAP-positive
cells (type B cells) or from fast proliferating type C cells
(225, 380) (see Fig. 1).
B) MIGRATION OF THE NEWLY BORN CELLS THROUGH THE ROSTRAL
D) DIFFERENTIATION OF THE NEWLY BORN CELLS IN THE OLFACTORY
The newly born cells differentiate mainly into neurons that grow dendritic trees and differentiate into two
types of intrabulbar interneurons. Most of the cells (75–
99%) differentiate into GABA granule cells (GCs),
whereas a smaller number (1–25%) differentiate into periglomerular cells expressing GABA and/or tyrosine hydroxylase (38, 81, 256, 326, 439, 475, 572). Several months
after their birth, 10,000 GABAergic granule neurons, 100
periglomerular GABAergic neurons, and ⬎60 new dopa-
BULB.
FIG. 1. Neurogenesis in the subventricular
zone (SVZ)/olfactory bulb (OB) system. Top panel:
a sagittal view of a rodent brain showing the sites of
neurogenesis in the SVZ/OB system is given. Cells
proliferate mainly in the SVZ, migrate along the
rostral migratory stream (RMS) to reach the OB,
where they migrate radially and undergo terminal
differentiation. Bottom panel: a sequence of cell
types involved in neuronal lineage and specific
markers allowing cell identification are presented.
Markers appearing in bold are specific to each stage
(see text for further details).
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The newly generated cells originating
from different levels of the SVZ migrate in chains rostrally, up to 5 mm in rodents and to 20 mm in monkeys, to
reach the OB (122, 286, 317). This migration, which follows the rostral migration stream (RMS) and requires 2– 6
days in rodents (220, 317, 325), involves PSA-NCAM (100,
220, 418, 474, 540) and a chemorepulsion mechanism
through Slit-Robo signaling (574). Although a role of the
OB as a chemoattractant structure has been suggested, its
involvement in proliferation and guidance of the newly
born cells still remains unclear. Indeed, whereas OB removal (275), transection of the olfactory peduncle (231),
or unilateral nostril occlusion (96) does not prevent SVZ
precursors from proliferating and migrating towards the
OB, a transection through the RMS (9) or a removal of the
rostral OB (314) impedes neuroblast migration. It has thus
been proposed that a diffusible attractant is secreted in
specific layers in the OB, including the glomerular layer
(314).
After reaching the middle of the OB, the newborn
cells detach from chains, migrate radially, and progress
into one of the overlying cell layers whereupon they undergo terminal differentiation. Neuroblast detachment
from chains is initiated by Reelin and tenascin, whereas
radial migration depends on tenascin-R (198, 478).
C) LIFE AND DEATH OF THE NEWLY BORN CELLS. Massive cell
death has been observed during the first 2 mo after a BrdU
MIGRATORY STREAM.
pulse (572). This elimination mechanism is prominent in
the OB compared with the RMS and the SVZ (39, 50, 439)
and may maintain constant OB cell number by a continuous cell turnover, as was suggested during earlier development (419). The number of newly born cells that survive 1 mo after a BrdU pulse (50 mg · kg⫺1 · day⫺1 of BrdU
for 4 consecutive days in 2-mo-old female wistar rats) has
been estimated to be 60,000 per granule cell layer in one
study (50) and 120,000 in another (572). In the latter case,
it was shown that 50% of the newly generated neurons
(⬃80,000 per granule cell layer and ⬃800 per periglomerular layer) that survived the initial period of cell death
survived for at least 19 mo (572), confirming earlier work
(253). With the use of retroviral labeling of precursors in
the SVZ, it was confirmed that one-half of the labeled cells
died shortly after their arrival in the OB (between 15 and
45 days after neuronal birth) and that most dying cells
were mature, harboring dendritic arborization, and receiving connections (439). It was further shown in this
study that survival of the newly generated granule cells
depends on sensory input.
NEUROGENESIS IN THE ADULT BRAIN
2. The DG
A) IDENTIFICATION OF THE STEMLIKE CELLS. Cell proliferation
was first demonstrated in the DG of rodents 40 years ago
by autoradiography in a germinal zone which is not, in
contrast to the SVZ, located close to the walls of the
ventricle. This subgranular zone (SGZ) is located at the
interface between the granule cell layer (GCL) and the
hilus of the DG, deep within the parenchyma (12, 13). This
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cell proliferation is also a feature of monkeys (178, 182,
284) and humans (144). The nature of the proliferating
cells is still a matter of debate. According to work carried
out in Alvarez-Buylla’s laboratory (501), the stemlike cells
may correspond to a subpopulation of GFAP-positive
cells, equivalent to the type B cells described in the SVZ,
since 2 h after their birth a large majority of newly born
cells express GFAP (501). While the number of these cells
decreases in the following days, the proportion of dividing
GFAP-negative cells increases. These small dark cells,
originally described by Kaplan and Bell (251), are called D
cells. Chronic treatment with the antimitotic AraC eliminates most dividing cells, D cells, and astrocytes, but soon
after treatment cessation, some surviving B cells begin to
divide, whereas D cells reappear only at 4 days. Type B
cells, specifically labeled with an avian retrovirus, give
rise to granule neurons with mossy fibers reaching the
CA3 subfield. These results indicate that B cells act as
stemlike cells, regenerate D cells, which function as transient precursors, and give rise to new granule neurons.
This hypothesis is reinforced by the observation that astrocytes retain expression of m-Msi1 (480). On the basis
of the analysis of nestin-promoter GFP transgenic mice,
two classes of cells have been identified: type 1 cells
(GFAP⫹, S100␤⫺, DCX⫺, PSA-NCAM⫺), which correspond to type B cells, and are the putative stem cell, and
type 2 cells (GFAP⫺, S100␤⫺, DCX⫹, PSA-NCAM⫹) supposed to be the type D cells (154, 159, 289, 521). Because
there is no overlap between glial and neural markers in
type 2 cells, an observation inconsistent with Seri et al.
lineage (501), it has been proposed that either type 1 cells
divide asymmetrically and thus generate a neuronal lineage-restricted progenitor cell (type 2) and a glial lineagerestricted progenitor cell, or alternatively that a transient
stage (lacking glial and neuronal markers) exists between
the type 1 and type 2 cells (521). On the other hand,
Palmer et al. (424) reported that very few proliferating
cells in the adult DG are GFAP-positive (424), a discrepancy as yet unexplained. Finally, the assumption that the
DG harbors stemlike cells has been challenged by showing that this region contains progenitor cells with restricted properties rather than stemlike cells with selfrenewing properties (475, 493) (see Fig. 2).
B) LIFE AND DEATH OF THE NEWLY BORN CELLS. Following a
single pulse with [3H]dT or BrdU, the number of labeled
cells doubles within 24 h and then roughly doubles again
over the next 2 days in rats (204, 416) and tree shrews
(177), indicating that cells continue to divide during this
time lapse (416). These data are in agreement with the
measured length of the cell cycle estimated to be ⬃24 h in
3-mo-old rats (75). It has been proposed that the progeny
continue to divide further during the first week after their
birth as the number of labeled cells continues to rise
(204). Recently, it has been confirmed that the cells are
still in the cell cycle 3 days after their initial division (521).
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minergic periglomerular neurons have survived and are
added per bulb daily (572).
The different maturation stages of adult-born granule
cells have been observed using retroviral labeling of precursors in the SVZ (439). Five different classes of adultborn cells were distinguished according to their morphology and location: 1) migrating neuroblasts in the rostral
extension of the RMS (days 2–7), 2) neuroblasts migrating radially (days 5–7), 3) GCs with dendritic processes
that do not extend beyond the mitral cell layer (days
9 –13), 4) GCs with a nonspiny dendritic arborization in
the external plexiform layer (days 11–22), and 5) mature
GCs with extensive dendritic arborization (days 15–30).
The newly born GCs and periglomerular neurons
appear to be synaptically integrated into the existing circuitry as they are labeled following an injection (within
the piriform cortex) of a green fluorescent protein (GFP)
expressing pseudorabies virus (PVR GS518) known to be
transported along the neurons and to cross synapses (80).
E) FUNCTIONAL PROPERTIES OF THE NEWLY BORN CELLS. The temporal sequence of electrophysiological changes in the
adult born neurons has been observed by coupling live
imaging (the newly born cells being labeled with a replication-defective retrovirus expressing eGFP) and patchclamp recordings (81). Migrating neuroblasts [class 1 and
2 according to the description of Petreanu and AlvarezBuylla (439)] were found to be silent, action potentials
appearing later. Class 1 cells expressed functional GABAA
receptors and AMPA receptors, and when they started
migrating radially (class 2), they expressed functional
N-methyl-D-aspartate (NMDA) receptors. Synaptic
(GABAergic then glutamatergic) inputs were present in
nonspiking neurons (class 3 and 4) while they were growing their dendrites. Spiking activity was the last property
acquired by class 5 neurons, their electrophysiological
characteristics being indistinguishable from those of
older GCs.
The functionality of adult-born neurons was further
examined using the induction of the immediate early gene
product c-Fos, a marker for mapping activated neurons
(222). With this approach, it has been shown that 1) in
mice, 3- to 7-wk-old adult-born periglomerular neurons
respond to physiological (odors) stimuli (80); and 2) in
hamsters, sociosexual cues are able to activate the adultborn neurons localized in both the accessory and the main
OB (221).
529
530
ABROUS, KOEHL, AND LE MOAL
The clusters of dividing cells have been shown to
include several cell types: neural precursors, committed
neuroblasts, glial precursors, and endothelial precursors
(angioblasts representing 37% of proliferative cells) that
are proximal to vessels (256, 363, 424). This suggests that
neurogenesis most probably occurs within the context of
vascular recruitment. Within this niche, endothelial cells
may constitute a critical regulator for self-renewal of
stemlike cells (505) through the release of trophic factors
(see sect. IID2C and Table 1).
In the rodent DG, the vast majority of newly born
cells are postmitotic and at least partially differentiated
between 3 and 7 days (111, 416), since during this period
BrdU-labeled cells express NeuroD (417). The cells that
do not terminally differentiate die within 1 wk of their
generation, a process affecting 60% of the newborn cells
(111, 204). In the macaque, a similar time course has been
demonstrated with an initial rise in BrdU-labeled cells
followed by a fall after 5 wk (182). Interestingly, the GCL
harbors a much lower number of proliferating cells compared with the SVZ. Thus, in a study performed in 9- to
10-wk-old rats, ⬃9,000 newborn cells were found to be
generated per day (75). In a more recent study, only
⬃4,000 new cells, out of which 3,000 were found to be
new neurons, were shown to be added daily in the DG of
4-mo-old rats (456); this discrepancy in the number of
newborn cells is certainly linked to the difference in the
age of the animals used in the studies, as the production
of new neurons in the DG diminishes with age (see sect.
IIIC1A). In the macaque, the number of newborn cells per
day (⬃200) represents 0.004% of one GCL (284).
C) FATE OF THE NEWLY BORN CELLS. The newborn cells differentiate mainly into neurons in the GCL. In his original
Physiol Rev • VOL
study using electron microscopy, Kaplan and co-workers
(249 –252) reported that the newborn cells exhibit the
ultrastructural characteristics of neurons. Then, they
were shown to express neuronal markers. During the first
2 days after their birth, most BrdU-labeled cells express
nestin (95), then TuJ1 (75) or TOAD-64 (75, 536) in the
following 3 days, and DCX between 1 and 14 days after
their generation (65). DCX-BrdU-colabeled cells show features of progenitor cells as some of them coexpress Ki-67
and are thus still able to divide (58, 154, 521). This rapid
postmitotic status of new cells has been confirmed with
calretinin, a calcium binding protein that is transiently
expressed by postmitotic cells, the expression of which is
observed as early as 1 day after labeling dividing cells, a
peak being reached after 1 wk (58). Although newly born
cells express NeuN as early as 72 h after their generation
(58, 193), only half of the BrdU-IR cells expressed NeuN
over 3 wk (65). Using NSE, half of the newly born cells
were found to be neurons 2 wk after their birth (78).
Calbindin is expressed later, by 3 wk after birth (180, 290,
536, 537). A low percentage of adult-born cells differentiates into astrocytes (GFAP/S100␤), and rare are those
that adopt a microglial or oligodendrocyte phenotype
(521). It should be emphasized that even 4 mo after their
labeling a nonnegligible proportion of BrdU-IR cells have
an unknown phenotype. In monkeys, most newly generated cells are claimed to be neurons as well since they
express TuJ1, TOAD-64, NeuN, NSE, and calbindin, and
rarely markers of astrocytes (GFAP) or oligodendrocytes
(CNP) (178, 182, 284). It was first thought that the newly
born cells did not survive, thereby constituting a continuously refreshed pool of neurons (189). However, it was
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FIG. 2. Neurogenesis in the hippocampal system. Top panel: a frontal
view of a rodent brain showing the sites
of neurogenesis in the dentate gyrus
(DG) of the hippocampal formation (HF)
is given. The HF forms a trisynaptic network: multimodal inputs are transferred
from neocortical regions to the DG via
the entorhinal cortex; information is then
transferred from the DG to CA3 through
the mossy fibers, onward through the
Schaffer collaterals to CA1 (and the subiculum) and then via the entorhinal cortex back out to the cortical associative
areas (16). Cells proliferate in the subgranular layer (SGL) located at the interface between the hilus and the granular
layer (GL), where they migrate and differentiate into mature neurons. Bottom
panel: a sequence of cell types involved
in neuronal development, along with specific markers allowing cell identification,
is proposed [see text and recent review
from Kempermann et al. (265) for further
details].
531
NEUROGENESIS IN THE ADULT BRAIN
1. Extrinsic factors regulating in vivo cell proliferation and neurogenesis in the subventricular
zone/olfactory bulb system and the dentate gyrus of the hippocampal formation under physiological conditions
TABLE
Subventricular Zone/Olfactory Bulb
Factors
Dentate Gyrus
Cell
Neuronal
Long-term
Cell
Neuronal
Long-term
proliferation Neurogenesis differentiation survival proliferation Neurogenesis differentiation survival
Reference Nos.
Hormones and peptides
0
m
n
m
n
0
0
m
mproE
n
m then n
0
m (4h)
0
m
0
m
m
m
0
0
0
0
71, 74, 176, 465
17, 71, 76, 212
n
536
29, 536
29, 422, 536
435
421
506
362
0
254
349
349
0
0
Neurosteroids
DHEA
PregS
Allopreg
m
m
n
m
m
m
0
Neurotransmitters
Glutamate
Ent. Cx. lesion
NMDA activation
NMDA blockade
AMPA potentiation
mGluR II blockade
Serotonin
5-HT depletion
Lesion ⫹ graft
Reuptake inhibition
5-HT1A blockade
5-HT1A activation
5-HT1B blockade
5-HT1B activation
5-HT2A/2c blockade
5-HT2A/2c activation
5-HT2c blockade
5-HT2c activation
Norepinephrine
Depletion
Reuptake inhibition
No donor
m
n
m
m
m
n
m
m
m
0
m
0
m
m
0
m
0
m
n
m
m
n
m
0
0
n
0
0
0
0
m
m
0
m
0
0
29, 61
63
10, 335, 483
451
30, 483
30
0
n
m
m
0
73
73, 76
46, 73, 76, 177, 390
27
581
n
0
0
m
292
335
587
Growth or trophic factors
bFGF
EGF
HB-EGF
TGF-␣
IGF-I
BDNF
CNTF
VEGF
m
m
m
m
m
n
m
m
n
0
m
m
m
m
0
0
0
m
0
n
m
0
n
m
m (ovx)
0 or m (hpx)
m
m
m
m
m
m
0
0
295
311
311
m
n
n
m
n
n
n
m
n
86, 87
83, 102
99
0
238, 240, 291
291
236, 238, 240
98
1, 310, 435, 542
593
141
241
Morphogenic factors
Shh
BMP
Noggin
n
m
n
m
n
m
Vitamins and retinoids
Vitamin E
Deficiency
Supplementation (tocopherol)
Retinoic acid (chronic
treatment)
n
Adx, adrenalectomy; Cort, corticosterone; OVX, ovariectomy; 17␤-E, 17␤-estradiol; proE, proestrus; PregS, pregnenolone sulfate; Allopreg,
allopregnanolone; Ent. Cx., entorhinal cortex; Hpx, hypophysiectomy; 0, no change; blank case, not determined; m, increase; n, decrease.
Physiol Rev • VOL
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Corticosterone
Suppression (adx)
Cort. treatment
Estradiol
Estrus cycle
OVX
OVX ⫹ acute 17␤-E
OVX ⫹ chronic 17␤-E
17␤-E
Prolactin
PACAP
532
ABROUS, KOEHL, AND LE MOAL
Physiol Rev • VOL
showing, using c-fos, that 40% of 1-mo-old newborn granule neurons were able to respond to various chemoconvulsants (232, 234). In contrast, following a more physiological form of hippocampal stimulation consisting in a
hippocampal-dependent learning task, only 3% of cells are
activated (232). Finally, besides these functional excitatory adult-born granule cells, it has been shown that
GABAergic newborn basket cells form functional inhibitory synapses with the granule cells (316). This discovery
raises the question of the mechanisms and factors involved in the production of excitatory granule neurons
versus inhibitory interneurons.
3. The cortex
Although very controversial, the existence of adult
neurogenesis in the cortex deserves attention. Indeed,
Altman and co-workers in the 1960s (11, 12, 14) and
Kaplan in the early 1980s (247–249) reported evidence for
neurogenesis in the cortex of rats and cats. More recently,
neurogenesis has been described in the rat anterior neocortex (182) and in the prefrontal, inferior temporal, and
posterior parietal cortex of macaques (179, 182). Within 2
wk after BrdU injection(s), the number of BrdU-labeled
cells increased and then fell after 5 wk, indicating that a
large number of newly born cells died. The surviving cells
were assumed to be neurons since they extended axons
locally and expressed markers of immature (TOAD 64,
TuJ1) and mature (38 –52% of BrdU-NeuN cells) neurons
but did not express GFAP or CNP. Although the site of
origin of the newly born neurons remains unclear, it has
been proposed that they may be generated into the SVZ
and migrate to neocortical areas through the white matter
or may be recruited from local quiescent stemlike cells
(179, 182, 284).
In contrast to these data, other groups have reported
a complete absence of neurogenesis in the mouse (134,
332) and monkey cortex (281, 453). Neurogenesis was
observed in the neocortex of mice only following a targeted apoptotic degeneration of corticothalamic neurons
(332), and in this case, endogenous neural precursors
migrated and differentiated into neocortical neurons in a
layer- and region-specific manner and reformed appropriate long-distance corticothalamic connections; thus they
appeared to reconstruct the lesioned circuits. In the primate neocortex, although cell proliferation occurs, the
newly born cells do not seem to differentiate into neurons
(285). These discrepancies may be due to differences in
housing conditions, the animals’ histories, and genetic
background, and other technical considerations (survival
times, BrdU dosage and administration mode, immunohistochemistry. . .), but generally, the existence of this
cortical neurogenesis is still a matter of debate (411).
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more recently found that they do not have an ephemeral
existence and survive for at least 11 mo (263).
Recently, it has been shown that beside glutamatergic granule neurons, a small percentage of newly born
cells (14%) differentiate into GABAergic basket cells
(316). Furthermore, under specific circumstances (ischemia or neonatal kainate administration), pyramidal cells
in Ammon’s horn are also generated (see also sect. IIID1B;
Refs. 128, 399, 489). However, the progenitors responsible
for the regenerating pyramidal neurons originate from the
periventricular region rather than from the SGZ (399).
D) INTEGRATION OF THE NEWLY BORN CELLS. The newborn cells
integrate the GCL 4 –10 days after their generation. As
they form dendrites, they receive synaptic contacts and
extend axons into the CA3 region, suggesting that they
make synapses long before being fully mature (75, 204,
252, 344, 517). Indeed, using virus-based transynaptic activity neuronal tracing (PVR GS518), the neurons generated in the DG have been shown to be synaptically integrated into the preexisting circuitry 4 – 8 wk after their
birth (80), whereas they reach a mature morphology
(soma size, total dendritic length, dendritic branching,
and spine density) only 4 mo after their birth (513).
E) FUNCTIONAL PROPERTIES OF THE NEWLY BORN CELLS. When still
located at the interface of the hilus, the newly born cells
exhibit electrophysiological properties characteristic of
immature neurons: they are completely unaffected by
GABAA receptor inhibition, and they exhibit paired-pulse
facilitation, have a lower threshold for induction of longterm potentiation (LTP), and display robust LTP (564).
With the use of nestin-promoter GFP transgenic mice,
type I cells (putative B cells) were found to have low input
resistance values, whereas the type II cells (type D cells,
expressing PSA-NCAM) exhibited higher input resistance
and voltage-dependent sodium currents (159). Recently,
PSA-NCAM expressing cells have been shown to differ
from mature neurons in their passive (input resistance)
and active membrane properties (such as calcium spikes
that boost fast sodium action potentials) and in their
enhanced ability to develop LTP (490). One month after
their birth, the “newborn” neurons, labeled by a retroviral
vector expressing GFP, exhibit some electrophysiological
properties (input resistance, threshold potential for spiking and firing) similar to those of mature granule neurons
(556). The stimulation of the perforant pathway, the main
excitatory afference to the DG, elicits responses in “newborn” GFP-labeled cells, indicating that they receive functional synaptic inputs and are therefore functionally integrated into the preexisting network. However, a depression of synaptic currents is evoked in these cells following
the paired-pulse stimulation of the perforant pathway,
whereas a facilitation response is observed in mature
cells, a discrepancy attributed to differences in presynaptic release properties (556). The functionality of the adultborn granule cells has been further demonstrated by
NEUROGENESIS IN THE ADULT BRAIN
4. Summary
D. Factors Regulating Adult Neurogenesis
Although various factors that affect the division, migration, and differentiation of neural precursor cells have
been isolated, the precise mechanisms that control neuronal fate in the adult nervous system remain largely
unknown. Both cell intrinsic programs and extracellular/
environmental factors, which we will review below, are at
play.
1. Intrinsic programs controlling neurogenesis
Two fundamental decisions are involved in order for
a precursor cell to generate a neural cell. The first one is
to decide whether to self-renew or to undergo mitotic
arrest, and the second is to interpret mitotic arrest, using
cell autonomous cues that direct toward a particular fate.
Much of our current understanding of these cell intrinsic
programs comes from work performed when neurogenesis is at its best, i.e., during development. However, it is
important to emphasize that the rules that govern neuronal specification during development may not be the same
in the adult brain. Furthermore, since a description of the
Physiol Rev • VOL
detailed molecular mechanisms involved in cell proliferation and determination is beyond the scope of this review, we here propose only a brief overview of the intrinsic factors involved, with a special mention whenever
their involvement has been extended to the adult neurogenic zones.
A) CONTROL OF CELL PROLIFERATION. Among the cell cycle
factors regulating cellular proliferation, Rb (retinoblastoma) and its related proteins (p107, p130), necdin, and
the E2F protein families are key players (for a review, see
Ref. 580). Thus, during the G1 phase, Rb predominates in
a hypophosphorylated form that can bind to E2F, a positive regulator of the cell cycle (403), thereby repressing
its transcriptional activity and preventing the cells from
entering the S phase. In cycling cells, phosphorylated Rb
accumulated during the late G1 phase releases E2F, thus
allowing S phase entry. This phosphorylation depends on
the activation of cyclin-dependent kinases (CDK) acting
sequentially. Early to mid-G1, cyclins of the D class (D1,
D2, and D3) activate CDK4/CDK6, and in late G1, cyclin E
activates CDK2, leading to hyperphosphorylation of the
Rb protein. Two families of CDK inhibitors (CDKIs) that
can suppress cell proliferation by inhibiting Rb phosphorylation have been identified (566): members of the inhibitors
of CDK4 family (INK4 family), including p15Ink4b, p16Ink4a,
p18Ink4c, and p19Ink4d, and members of the kinase inhibitory
protein family (Cip/Kip family) such as p21Waf1/Cip1, p27Kip1
or p57Kip2 (see Fig. 3).
It is now clear that the Rb and E2F protein families
are differentially expressed in proliferative and postmitotic cells of the adult brain. Thus, in the two neurogenic
sites, the DG and the SVZ, Rb immunoreactivity is high in
proliferating neuronal precursors and reduced during terminal differentiation (415), which implies that the transient increase in the level of Rb is an important step in the
initiation of terminal mitosis in neuronal progenitors.
Moreover, the Rb protein family was found to be essential
for the development of a neural lineage and the exit from
the cell cycle, whereas it does not seem to be involved in
the maintenance of postmitotic neurons (69, 89, 228, 299).
The role of E2F1 as a key factor in regulating adult
neurogenesis has been further emphasized in a recent
study performed in mice lacking E2F1. These mice, when
adult, exhibit a lower level of cell proliferation and a
reduction in the number of neurons generated in adult
neurogenic areas (94).
The role of cell cycle regulators in the control of
neuron production has been studied as well. Transgenic
mice that lack p27Kip1 expression display a higher rate of
cell proliferation versus differentiation in the SVZ, leading
to an increased number of type C cells, a reduced number
of type A neuroblasts, and no change in the number of
type B cells (127). Finally, distinct functions for CDK
inhibitors, either in the control of cell cycle exit and
differentiation during neurogenesis (respectively, p27Kip1
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Following a century of doubt and controversies,
there is now a consensus that neurogenesis occurs in the
adult brain in at least two regions, the SVZ and the DG. In
both structures, stemlike cells proliferate, migrate, and
differentiate mainly into granule neurons that will synthesize GABA in the OB and glutamate in the DG. Although
less studied, a small proportion of adult-born cells differentiate into other types of interneurons (the periglomerular in the OB and the basket cells in the DG). Altogether
this adult neurogenesis leads to the birth of ⬃30,000 new
neurons per day in the SVZ and between 3,000 and 9,000
in the DG of young adult rats, depending on their age. The
reasons for which, 1) the SVZ and the DG harbor adult
neurogenesis, 2) neurogenesis is curtailed in the DG compared with the OB, and 3) genesis rates are much lower in
primates, are currently unknown. Furthermore, because
these structures do not grow in size, a homeostatic compensatory equilibrium must be attained through an increase in cell death that must be equivalent to the initial
addition of neurons. This poorly understood phenomenon, in particular in the DG, deserves more attention for
it is an important partner of neurogenesis. Finally, recent
evidence indicates that the adult-born neurons of the OB
and the DG are functional and thus play a physiological
role. Although these findings suggest a relevant contribution of these newly generated neurons to the bulbar or
hippocampal function, further studies are needed to confirm these reports and fully unravel their fundamental
consequences on the animals’ behavior (see sect. III).
533
534
ABROUS, KOEHL, AND LE MOAL
and p19Ink4d) or in the maintenance of a quiescent state in
neural progenitors (p18Ink4c) or neurons (p21Cip1) in
adults have been underlined (303).
B) CONTROL OF CELL FATE. Data from developmental biology have clearly indicated that a core genetic program
involving multiple bHLH transcription factors is required
for both neuronal differentiation and determination.
These factors, deriving from proneural and neurogenic
genes, antagonistically control the switch from cell proliferation to neural differentiation: cascades of neuronal
bHLH genes promote differentiation, whereas antineuronal bHLH genes repress them under the control of Notch
and keep cells at a precursor stage (for recent general
reviews, see Refs. 358, 473).
Two classes of proneural genes can be distinguished:
the determination factors, such as Mash1 (mammalian
achaete-scute homolog), Math1 (mammalian atonal homolog), and Ngns (Neurogenins) including Ngn2, expressed early in mitotic neural precursor cells, and the
differentiation factors, including NeuroD, NeuroD2, and
Math2, expressed later in postmitotic cells (for reviews,
see Refs. 49, 379). It was recently determined that these
proneural genes are downstream effectors of Pax6 (for a
review, see Ref. 174), a transcription factor that promotes
neurogenesis (210).
These proneural genes are components of a cell-cell
signaling mechanism whereby a cell that becomes committed to a neural fate inhibits its neighbor from doing
likewise. This process of lateral inhibition, which restricts
the domains of the proneural gene activity and involves
neurogenic genes, is mediated by the Notch pathway (for
reviews, see Refs. 23, 32, 161, 244, 491, 567). Among the
effectors of Notch, three families of negative regulators of
Physiol Rev • VOL
the bHLH transcription factors are known: the HES, Id,
and HES-related (HESR or HERP) families (226, 413,
481, 545). These effectors repress neuronal determination and differentiation in those cells not destined to
become neuroblasts. Paralleling this regulation of neuronal proliferation by inhibiting neuronal fate, Notch
was also found to be involved in determining glial fate
(186, 398, 467).
Recent studies have highlighted that some of these
factors, which are at play during development, may be
involved in neuronal cell fate during adulthood. Thus
Notch1 and Hes5 were found to be expressed at high
levels and with a similar pattern in both the adult SVZ
and DG, whereas numb and numblike, which negatively
regulate the Notch signal transduction, were not, suggesting an active Notch signal in the adult neurogenic
zones (523). Similarly, the mRNA expression of several
bHLH factors was found to be present at various degrees in the adult HF, ranging from the restricted expression of Mash1 within the proliferative SGZ, which is consistent with its role in maintaining a precursor cell phenotype, to the widespread profile of Hes5 throughout the
HF (140).
In conclusion, despite the considerable advances
achieved recently with the development of molecular
tools, the complex intrinsic machinery that controls and
coordinates proliferation and differentiation is still poorly
understood. As is the case for hematopoiesis, for which
much progress has been achieved, understanding the
gene expression patterns of progenitor cells and their
progeny will be a critical step in elucidating the mechanisms underlying cell fate.
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FIG. 3. Schematic representation of
the mammalian cell cycle. The cyclin
D/cdk4 – 6 complex phosphorylates the Rb
protein leading to sequential phosphorylation by cyclinE/cdk2 and the release of free
E2F. Phosphorylation of Rb relieves transcriptional repression of genes involved in
the induction of S-phase entry. The ability
of the cyclin/cdk enzymes to phosphorylate Rb is inhibited by cyclin-dependent
kinase inhibitors (cdkis), the activation of
which thus suppresses cell proliferation.
The basic helix-loop-helix (bHLH) proneural genes NeuroD, Mash1, and Ngn1 control the switch from cell proliferation to
neural differentiation by activation of the
Kip/Cip Cdki family, thus preventing progression through the G1-S phases. The HLH
proteins Id1 and Id3 (inhibitor of differentiation) repress neuronal determination by
direct binding with proneural bHLH proteins, but also favor progression through
the cell cycle via inhibition of the INK4 and
Kip/Cip Cdki families. Activating and inhibiting influences are represented by blue arrows and red lines, respectively.
NEUROGENESIS IN THE ADULT BRAIN
Physiol Rev • VOL
tors (77), corticosterone may not act directly on proliferating precursors, although it cannot be excluded that
immature forms of receptors that are not recognized by
current antibodies are involved. Corticosterone could act
on neighboring glial or neuronal cells expressing corticosteroid receptors, which could control the cell cycle by
releasing growth factors (515). Alternatively, corticosterone could regulate proliferation indirectly by increasing
glutamate release in the DG (520) (see sect. IID2B) as the
effects of adx or high levels of corticosterone can be
blocked by NMDA receptor activation or inactivation,
respectively (76). Corticosterone may also inhibit cell
proliferation by dowregulating the production of insulinlike growth factor I (IGF-I) (585, 592).
II) Gonadal hormones. The influence of female gonadal hormones has been investigated in the DG since
estrogen replacement therapy seems to reduce the risk of
age-related cognitive impairments (213). Although cell
proliferation in the GCL (and not the hilus) is higher in
female than in male rats, the newly born cells do not
survive, which explains the lack of sex differences in the
number of BrdU-IR cells 2 wk after labeling (536). Sexdependent proliferative activity involves the stimulatory
influence of estrogens, since the number of BrdU-labeled
cells is highest during the proestrus phase of the estrus
cycle, when circulating levels of estrogens are highest
(536), and acute administration of 17␤-estradiol reverses
the ovariectomy-induced decrease in cell birth (29, 536).
In contrast, using TOAD-64 and calbindin as early and late
neuronal markers, it has been shown that estradiol does
not alter neuronal differentiation (536).
However, discrepant results have been reported following chronic administration of estradiol to ovariectomized adult female rats (435), spontaneous hypertensive
rats (436), or adult wild meadow voles (163). Cell proliferation in the GCL (measured 24 h after a single intraperitoneal injection of [3H]dT) is lower in female meadow
voles captured during the breeding season, when estradiol levels are high, compared with reproductively inactive females. A similar relationship has been confirmed in
laboratory-reared female meadow voles (421).
These apparently contradictory results might be explained by a complex regulatory mechanism. In fact, a
single administration of estradiol initially enhances
(within 4 h) and subsequently suppresses (within 48 h)
cell proliferation in the DG of ovariectomized female rats
or meadow voles (420, 421). The increase in cell proliferation is mediated by serotonin (29), whereas the decrease
is prevented by adx (422), suggesting an involvement of
corticosterone. However, although corticosterone-induced regulation of cell birth certainly involves NMDA
receptors, estradiol influences on cell proliferation are
not mediated by these receptors (420). Finally, estrogen
may act directly on estrogen receptors subtype ␣ (ER ␣)
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2. Extrinsic factors regulating neurogenesis
A) HORMONES AND NEUROSTEROIDS. I) Adrenal corticosteroids. Historically, corticosteroids were the first factors
to be studied for their influence on adult neurogenesis
(354). Corticosteroids are released into the blood circulation following the activation of the hypothalamo-pituitary-adrenal (HPA) axis, primarily by stress (351). Corticosterone, the main corticosteroid in rodents, regulates
its own secretion through negative feedback, by interacting with two receptors (the mineralocorticoid MR, the
glucocorticoid GR), present in the DG. Suppression of
corticosterone secretion after bilateral adrenalectomy
(adx) increases glial and neuronal births in the DG (71,
176), whereas mitotic activity in the SVZ remains unchanged (465), suggesting a site-specific inhibitory influence of corticosteroids. It was further shown that proliferation increases within 24 h after adx and remains constant over the 6 subsequent days; the newly generated
cells survive for at least 4 wk in the absence of corticosterone, indicating that their survival is corticosterone
independent (465). Cell death is also enhanced, but the
populations of cells undergoing mitosis or apoptosis are
distinct: immature cells divide at the interface of the hilus,
whereas more mature neurons, located at the interface of
the molecular layer, die (72). These alterations are prevented by corticosterone replacement (176, 465). The respective roles of MR and GR on adrenalectomy-induced
structural modifications have recently been examined
(374). Treatment with a low dose of the MR agonist,
aldosterone, prevents adrenalectomy-induced increase in
cell death, whereas a higher dose is necessary to normalize cell proliferation. Furthermore, treatment with a GR
agonist, RU 28362, at doses that should fully occupy this
receptor prevents both adrenalectomy-induced cell death
and birth. Thus the stimulation of both MR and GR mediates the effects of corticosterone on cell proliferation
and protects mature cells from cell death.
This inhibitory action of corticosterone on neurogenesis has also been found in other models: 1) acute corticosterone administration {2 ⫻ 40 mg/kg administered 1 h
before a single [H3]dT injection (71, 76); implantation of a
200-mg corticosterone pellet followed by 1 ⫻ 200 mg/kg
BrdU (17)}, 2) chronic corticosterone treatment [1 ⫻ 40
mg/kg for 21 days; BrdU 10 ⫻ 50 mg/kg every 12 h on days
17–21 (212)], 3) stress (see sect. IIIB1), and 4) interindividual differences in the activity of the HPA axis (305; see
sect. IIIB2).
The mechanisms by which corticosterone hampers
cell proliferation remain unknown. In vitro, glucocorticoids block the G1 phase of the cell cycle, notably through
repression of cyclin D1, cyclin D2, Cdk4 and Cdk6, and
induction of the CDKIs p21Cip1 and p27Kip1 (438, 585, 592).
However, it remains to be determined which of these
mechanisms is involved in vivo. Because only a small
minority of precursor cells express corticosteroid recep-
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cell proliferation in several species within hours (73, 76,
420), which is congruent with the antiproliferative properties of glutamate on in vitro cortical cell proliferation
(318). However, it should be mentioned that an inhibitory
influence of glutamate receptor blockade on neurogenesis
has been reported in stroke-damaged brains (see sect.
IIID1B). The newly born cells induced by the inactivation
of NMDA receptors differentiate into neurons, expressing
DCX, TOAD-64, NSE, or NeuN markers (73, 177, 390, 417).
Furthermore, the MK-801-induced neurons are functional
as they respond to NMDA stimulation, measured by the
phosphorylation of extracellular signal-regulated kinase
(ERK), 29 days after their birth date (417). This indicates
that newly born neurons acquire components for the intracellular signal transduction cascade linking NMDA receptors to phosphorylation of ERK (114).
The mechanisms by which precursor proliferation is
inhibited by glutamate in vivo through NMDA receptors
remain unknown, but they most probably do not involve
collateral deleterious effects as treatment with CGP 43487
upregulates cell birth without inducing cell death or astrogliosis (390).
Because glutamate also acts onto AMPA receptors,
detected in neural progenitors (165), the influence of
potentiators of AMPA receptors such as LY451646 has
been evaluated on hippocampal mitotic activity. Acute
administration of LY451646 (0.025, 0.05, 0.125 mg/kg)
does not influence the number of newly born cells observed 24 h after BrdU pulse (4 ⫻ 75 mg/kg every 2 h).
However, the median dose increases the number of cells
per cluster (64%) and the number of clusters (45%) (27).
Furthermore, chronic treatment (21 days) with LY451646
(0.05, 0.125, 0.500 mg/kg) enhances the number of proliferating cells, of cells per cluster, and of clusters in a
dose-dependent manner (27).
Altogether, these results suggest that glutamate exerts a complex influence on hippocampal cell proliferation, increasing it through activation of AMPA receptors,
and inhibiting it through activation of NMDA receptors.
Finally, the recent discovery that GABA and glutamate are
cotransmitted at the mossy fibers synapses adds further
complexity to the respective role of each neurotransmitter in neurogenesis regulation (196).
II) Serotonin. In the 1970s, it was proposed that early
forming serotonin (5-HT) neurons act as humoral signals
governing neuronal development and neurogenesis in particular (26, 298). Since then, several approaches have
shown that serotonin upregulates cell proliferation in the
adult DG and SVZ (see also sect. IIID2A). Inhibition of 5-HT
synthesis (by subchronic injections of PCPA for 6 days)
and selective lesions of 5-HT neurons of the raphe decrease the number of BrdU- and PSA-NCAM-IR cells in the
DG and the SVZ (BrdU 50 mg/kg ip injected on the last 3
days of PCPA treatment at 1–2h intervals and animals
killed 6 h after the last injection; Ref. 61). This upregula-
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present on hippocampal precursors (435) or through
IGF-I receptors (see sect. IID2C).
III) Neurosteroids. Neurosteroids represent a subclass of steroids synthesized de novo in many regions of
the brain, independently of peripheral sources (36). They
are synthesized in the HF, by glial cells mainly, and influence hippocampal-mediated functions (349). Two principal families can be distinguished according to their pharmacological properties (333). In particular, dehydroxyepiandrosterone (DHEA) and pregnenolone sulfate
(Preg-S) act as allosteric antagonists of the GABAA receptors while allopregnanolone (AlloP) is a positive modulator of these receptors.
Chronic treatment of young adult male rats with
subcutaneous pellets of DHEA (200 mg/pellet for 12 days)
has been shown to stimulate hippocampal cell proliferation measured 24 h after BrdU injections (50 mg · kg⫺1 ·
day⫺1) given on the last 4 days of the steroid treatment
(254). After an additional 16 days of treatment, the newly
born cells survive and express the neuronal marker NeuN.
Interestingly, DHEA treatment is also able to reverse the
suppressive effect of corticosterone on neurogenesis, suggesting that it may act as an antistress neurohormone.
Recently, we have shown that icv infusion of Preg-S
(2 ⫻ 12 nmol/7 ␮l) increases cell proliferation in the DG
of young adult rats within 24 h, whereas treatment with
AlloP (2 ⫻ 6.3 nmol/7 ␮l) decreases it (348). The newly
generated cells survive for at least 1 mo and differentiate
mainly into neurons (expressing NeuN). These actions of
Preg-S are mediated by GABAA receptors present on hippocampal precursors, since icv administration of muscimol, a GABAA agonist, blocks Preg-S-induced cell proliferation. Furthermore, a direct action of Preg-S was suggested as this compound stimulates in vitro the
proliferation of spheres derived from the adult SVZ (348).
Altogether, the reported effects of DHEA and Preg-S
are congruent with the observations that in vitro activation of GABAA receptors inhibits cortical cell proliferation, whereas GABAA receptors antagonists stimulate it
(21, 318, 327).
B) NEUROTRANSMITTERS AND NEUROREGULATORS. I) Glutamate.
Destruction of the perforant pathway, the main glutamatergic afference to the DG arising from the entorhinal
cortex, increases cell proliferation, thus indicating that
under these experimental conditions glutamate exerts an
inhibitory influence (73). As expected, blockade of NMDA
subtypes of glutamate receptors by injection of a noncompetitive antagonist (MK801) increases cell genesis within
a few hours in rats (1 mg/kg; Refs. 73, 76), tree shrews (1
mg/kg; Ref. 177), gerbils (3 ⫻ 3 mg/kg; Ref. 46), and
ovariectomized adult female meadow voles (30 mg/kg;
Ref. 420), and treatment with the competitive NMDA receptor antagonist CGP 37849 (5 mg/kg) increases both
cell proliferation and granule neurons density (73). Conversely, administration of NMDA (30 mg/kg) decreases
NEUROGENESIS IN THE ADULT BRAIN
Physiol Rev • VOL
concurrent with 2 ⫻ 50 mg · kg⫺1 · day⫺1 of BrdU at 8-h
intervals; Refs. 236, 238) stimulate cell birth in the SVZ (1
and 7 days after growth factor infusion, respectively)
certainly via EGF receptors (381, 416, 502). However,
these two factors probably have distinct actions, since
HB-EGF increases the number of BrdU-IR cells expressing DCX or NeuroD in the SVZ as well as the number of
newly generated cells reaching the OB (236, 240), whereas
EGF reduces the number of newly born neurons reaching
the OB (291). In the DG, HB-EGF (236, 238) but not EGF
(291) increases cell proliferation by interacting most
probably with EGF receptors expressed by the dividing
cells (416). The adult-born cells express the neuronal
marker NeuroD (236).
Transforming growth factor (TGF)-␣ is required for
SVZ precursor proliferation. Indeed, icv administration of
TGF-␣ (400 ng/day for 6 days) induces a dramatic increase
in precursor proliferation (98), whereas TGF-␣ null mice
show a decrease in proliferating cells in the SVZ, and in
the total number of newly born cells within their target,
the OB (543). No data on the influence of TGF-␣ on
hippocampal precursors are yet available.
IGF-I is a growth-promoting peptide hormone that is
produced in the CNS by neurons and glial cells (20) and
exhibits neurotrophic properties in adulthood (405). Its
influence on neurogenesis has been examined in hypophysiectomized rats presenting low levels of circulating IGF-I (1). Thus peripheral administration of IGF-I
(1.25 mg · kg⫺1 · day⫺1) induces an increase of cell proliferation in the dentate GCL and the hilus after 6 days.
Long-term treatment (0.39 mg · kg⫺1 · day⫺1 for 20 days)
increases both BrdU-labeled cell number and their differentiation into neurons as measured by the percentage of
BrdU-IR cells expressing calbindin. In contrast, an IGF-Iinduced increase in cell proliferation in nonhypophysiectomized rats is not associated with an enhancement of
their differentiation potential toward a neuronal fate
(542). In vitro experiments (2) strongly suggest that IGF-I
regulates cell proliferation in vivo by acting directly on
IGF-I receptors expressed by newly born cells (542), but
a recent study has also shown that estrogen receptors are
necessary for the induction of in vivo hippocampal cell
proliferation by IGF-I (435).
Brain-derived neurotrophic factor (BDNF) is a member of a family of related neurotrophic proteins, the function of which is to prevent neurons from dying during
development. Chronic icv infusion of BDNF (0.012 ␮l/day
for 12 days) increased BrdU-labeled cells in the SVZ and
in the GCL of the OB (593). The newly born cells expressed TuJ1 or MAP2. Survival (169, 276) and/or differentiation (6, 22) of the neuronal precursors and their
progeny rather than proliferation seem to be influenced
by BDNF. Concerning the DG, it has been shown that
heterozygous BDNF knockout mice exhibit reduced proliferation and survival of BrdU-labeled cells (301), sug-
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tion of hippocampal cell proliferation depends on serotonin as it is reversed by intrahippocampal grafts of embryonic 5-HT neurons (63). Partial lesions of 5-HT raphe
neurons lead, after an initial deprivation of hippocampal
5-HT fibers, to a spontaneous reinnervation of this structure by 5-HT fibers. At this time, the fall of mitotic activity
(and PSA-NCAM expression) is reversed (62). These actions of serotonin are mediated by 5-HT1A receptors in
both the DG and the SVZ (30, 451) while 5-HT2A and
5-HT2C receptors are selectively involved in the regulation
of cell proliferation in the DG and SVZ, respectively (30).
Finally, 4 wk after chronic treatment with 5-HT1A or
5-HT2A agonists (daily injection of 8-OH-DPAT or RO
600175 for 15 days, 75 mg/kg of BrdU injected twice on
the last 8 days of the treatment), the newly born cells in the
DG and/or the OB express NeuN (30).
III) Nitric oxide. Nitric oxide (NO), a free radical
molecule synthesized from L-arginine by NO synthase,
serves as a neurotransmitter in the brain (8). In the SVZ of
adult mice, neuronal precursors have been found to be
within the sphere of influence of a NO source and to
express NO synthase at the sites of terminal differentiation (377). Administration of DETA/NONOate, a NO donor, to young adult rats significantly increases both cell
proliferation and migration in the SVZ and the DG (587).
C) TROPHIC FACTORS. Many trophic factors have been
shown to have mitogenic actions in the adult brain neurogenic regions. Thus the proliferative effects of basic
fibroblast growth factor (bFGF or FGF-2) have been
clearly demonstrated for the SVZ. Chronic administration
of bFGF intracerebroventrically (360 ng/day for 14 days,
50 mg · kg⫺1 · day⫺1 of BrdU being injected during the last
12 days of the treatment; Ref. 291) or intranasally (5 ⫻ 0.2
␮g/day at 5-min intervals for 1 wk concurrent with 2 ⫻ 50
mg · kg⫺1 · day⫺1 of BrdU at 8-h intervals; Ref. 240)
increases the number of mitotic nuclei in the SVZ within
24 h. This leads to an increased number of newly born
neurons (expressing DCX in the SVZ; Ref. 240) that reach
the OB where they express NeuN (4 wk after their birth;
Ref. 291). In contrast, in the DG, a lack of effect (291) or
a small but nonsignificant increase in cell birth (25%,
following 3 days icv infusion of 10 ␮g/ml) was reported
(238). Consistently, in mice lacking bFGF, basal hippocampal neurogenesis is “normal,” suggesting that other
factors may maintain low levels of precursor proliferation
under resting conditions (582). However, overexpression
of bFGF by gene transfer in wild-type and bFGF-deficient
mice upregulates DG cell proliferation, which indicates
that a robust and constant bFGF expression is a necessary condition for increasing cell birth in this structure
(582).
Epidermal growth factor (EGF; 350 ng/day for 14
days, 50 mg · kg⫺1 · day⫺1 of BrdU being injected during
the last 12 days of the treatment; Ref. 291) and heparinbinding EGF (HB-EGF; 3 days icv infusion of 10 ␮g/ml
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tives named growth/differentiating factors (GDF). These
glycoproteins play a crucial role in bone remodeling and
in the regulation of dorsoventral patterning of the neural
tube and cell fate during embryonic development. Furthermore, several BMPs, including BMP4, are involved in
repression of the oligodendroglial lineage and generation
of the astroglial lineage during brain maturation (190).
Similarly, in the adult SVZ, BMPs (BMP2, BMP4, BMP7)
inhibit neurogenesis and direct astroglial differentiation,
whereas their antagonist Noggin promotes neurogenesis
(311). It has been proposed that Noggin produced by the
type E cells antagonizes the type B cells expressing BMP
(311). Furthermore, BMP2, BMP4, and BMP7 have been
found to activate a promoter of the gene for the HLH
factor Id1, which is known to inhibit the function of
neurogenic transcription factors such as Mash1 and neurogenin. Thus the switch from neuronal to astrocyte fate
realized by BMPs certainly involves HLH proteins (578).
These findings were extended to the HF. Indeed, a novel
secretory factor, neurogenesin-1 (Ng1), released by hippocampal astrocytes and dentate granule cells adjacent to
progenitor cells, was found to promote neuronal fate in
the adult HF through antagonism of BMPs, which alter the
fate of neural stemlike cells from neurogenesis to astrogliogenesis by upregulating the expression of the negative
HLH factors Id1, Id3, and Hes5 (548).
E) REGULATION BY GLIAL CELLS. Regulation of adult neurogenesis by glial cells has been emphasized (500). Astrocytes, which play an important role as sensors of changes
in their extracellular microenvironment, could regulate
neurogenesis by secreting local signals (514). These signals, unknown so far, may be ionic fluxes, neurosteroids,
cytokines, growth factors, and glutamate metabolites (48,
243, 245, 296, 486, 516, 579, 595). The observation that
some proliferating cells in the DG express a receptor for
S100␤, a small acidic calcium binding neurotrophic protein released by astrocytes, reinforces the putative contribution of glial cells in the regulation of adult neurogenesis (339).
F) REGULATION BY CELL DEATH. An equilibrium between neurogenesis and cell death probably ensures a homeostatic
balance in the adult brain. This hypothesis, based on the
observation that the neurogenic structures do not grow in
size, implies that cell death provides a stimulus for increased neurogenesis, a hypothesis reinforced by several
lines of argument: 1) during development, there is a balance between the birth and death of granule cells (183); 2)
mechanical lesions, aspiration, and transection stimulate
neuronal precursor proliferation in the GCL and/or the
SVZ (180, 242, 531, 546, 568); 3) proliferation in the SVZ is
upregulated under inflammatory conditions (70); 4) adrenalectomy, limbic seizures, and ischemia enhance both
cell death and cell birth; and 5) the apoptotic degeneration of corticothalamic neurons (by means of targeted
photolysis) induces endogenous neural precursors to dif-
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gesting a role for BDNF as a positive regulator of both
proliferation and survival. However, repeated, but not
single, administration of a compound that stimulates endogenous BDNF, riluzole, increases cell birth (3-fold) but
not cell survival. Most of the newly generated cells (90%)
differentiate into granule neurons (expressing NeuN)
(257). This effect is blocked by icv administration of
BDNF-specific antibodies, suggesting that an increase in
BDNF is necessary for the promoting effect of riluzole on
precursor proliferation. Altogether these data show that
BDNF plays an important role in the maintenance of basal
neurogenesis, a conclusion similar to that obtained following a developmental loss of function of this gene
(312).
Vascular endothelial growth factor (VEGF) is a
hypoxia-induced angiogenic protein that exhibits neurotrophic and neuroprotective properties (359). Given that
neurogenesis occurs in close proximity to blood vessels
and that clusters of dividing cells contain endothelial
precursors (see sect. IIC2B), VEGF may constitute the link
between neurogenesis and angiogenesis. This is supported by the observation that icv administration of VEGF
(0.24 ␮g/day for 3 days concurrent with 2 ⫻ 50 mg · kg⫺1
· day⫺1 BrdU) stimulates cell proliferation in the rodent
SVZ and SGZ by 7 days after treatment onset (241). At that
time, the newly born cells express DCX and NeuN markers. The neuroproliferative effect of VEGF is associated
with an upregulation of cyclin D1, Cyclin E and cdc25, and
an increase in the nuclear expression of E2F1, E2F2, and
E2F3 (591), which is consistent with a regulation of the
G1/S phase transition of the cell cycle.
D) MORPHOGENIC FACTORS. Sonic hedgehog (Shh), an important morphogen in development, is a signaling glycoprotein that acts through Patched 1-Smoothened (Ptc1Smo) receptor complex to trigger various events during
CNS development, including determination of ventral
neural phenotypes, induction of oligodendrocyte precursors, proliferation of specific neuron progenitor populations, and modulation of growth cone movements (for a
review, see Ref. 346). In a comprehensive study, Lai and
co-workers (295) investigated the role of Shh in the adult
brain and showed that it increased proliferation of cultured adult rat hippocampal progenitors in a dose- and
time-dependent fashion. In vivo, the exogenous administration of Shh and the inhibition of its signaling increased
and reduced cell proliferation, respectively. Finally, the
presence of the Shh receptor Patched in the DG and
Ammon’s horn in the HF, and the high levels of expression of Shh in structures that project towards the DG
support the assumption that Shh could be an endogenous
positive regulator of cell proliferation in the adult DG
(295).
Another group of early neural morphogens, the bone
morphogenic proteins (BMPs), belongs to the TGF-␤ superfamily, which includes TGF-␤, activins, and the rela-
NEUROGENESIS IN THE ADULT BRAIN
A. Environmental and Physiological Influences
on Neurogenesis
1. Experience in enriched environments,
neurogenesis, and learning
III. THE ANATOMO-FUNCTIONAL APPROACH
Complementary to the neuroanatomic studies that
revealed some key biological properties of adult neural
stemlike cells, the integration of the adult newborn neurons into preexisting networks has prompted the fundamental question of their functional relevance. So far, most
studies have focused on the role of adult neurogenesis in
hippocampal functioning. Parsimoniously, this region, included in the limbic-cognitive system, is part of an integrated network involved in learning and memory, attentional processes, motivational states, and emotion (68,
135, 136, 227, 352, 484). As pointed out by Hampton et al.
(201), current theories of hippocampal function wrestle
with two major conceptual issues: whether the structure
encodes spatial, nonspatial, or both types of information
(139) and whether the information encoded is episodic or
semantic. Recent evidence infers that hippocampal neuronal networks could support the cognitive mechanisms
of declarative memory by encoding features of experiPhysiol Rev • VOL
ences. Indeed, declarative memory involves a record of
everyday experiences, which includes information about
the content of that experience and the spatial and temporal context in which it occurred (episodic memory), woven together into the framework of the individual’s knowledge (semantic memory) (135). According to the memory
space model of declarative memory, the HF plays a critical role in 1) representing experiences as a series of
events and places and 2) linking memories together by
identifying common features into a network that supports
inferential expression. This said, the role of the HF in
long-term memory is in dispute as the “standard theory”
assumes that the HF becomes dispensable after the conversion of short-term memory into long-lasting memory,
whereas the “multiple trace theory” makes the assertion
that the HF is involved in the storage and retrieval of
episodic memory regardless of the age of memory (394).
Although current advances do not yet allow the attribution of a specific role for newborn neurons in this
conceptual framework, in the following sections we will
review the progress achieved in implicating neurogenesis
in both hippocampal functioning under physiological conditions and the apparition of hippocampal-related pathologies, which are mainly studied in preclinical animal models. Operationally, two approaches have been considered:
the first consists of relating changes in hippocampal neurogenesis to changes in the ability to perform hippocampal-related tasks, and the second consists of studying the
influence of hippocampal-related tasks on neurogenesis.
A) OLD PROBLEM, NEW DATA. Rosenzweig and co-workers
(470 – 472) were the first to introduce the concept of an
enriched situation, i.e., a complex environment enriched
in sensorial stimulations, social experiences, and physical
and cognitive exercises (555). This concept has given rise
to a wealth of studies showing that exposure to such
environments, which are considered as enriched for standard laboratory conditions, modifies brain functioning,
learning, problem-solving ability, brain chemistry, and
several structural aspects of brain organization. The consequence of environment enrichment on hippocampal
neurogenesis was originally studied in “juvenile” female
C57Bl/6J mice. Exposure to an enriched environment between 3 and 13 wk of age was found to increase survival
of newly born cells (measured 4 wk after daily injections
of 50 mg BrdU for 12 consecutive days from days 28 to 40
of enrichment), whereas cell proliferation (measured 1
day after the BrdU pulses) remained unchanged in the
GCL and in the hilus (267). Similar results have been
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ferentiate into mature neurons in regions of the cortex
undergoing targeted neuronal death (332). The induction
of neurogenesis in these regions of the adult neocortex
that do not normally undergo any neurogenesis (332) may
result from the removal of a normal inhibitory influence
or the loss of a secreted stimulatory factor produced by
the dying cells.
G) SUMMARY. Adult neurogenesis within each neurogenic site is regulated differently by a growing list of
“epigenetic factors” [to which should be added prolactin
(506), norepinephrine (35, 292), the pituitary adenylate
cyclase-activating polypeptide (PACAP) (362), ciliary neurotrophic factor (141), retinoic acid (99), and vitamin E
(83, 86, 87); see Table 1 for a complete summary]. Although most of these factors modulate cell proliferation
through unknown mechanisms, a regulation of Cyclin D1
and p27Kip1 expressions may constitute a common pathway (438).
The specificities of each neurogenic site may be related to differences in the intrinsic properties of the dividing cells (for example, their intrinsic ability to sense
neural activity; Ref. 114) and/or in their microenvironment, which corresponds to the summation of local neurogenic signals expressed or synthesized “locally” by
healthy neighboring cells or by dying cells. These signals
may also be synthesized “peripherally” and released in
neurogenic sites by neuronal afferences or by blood vessels. In this context, the role of the cerebral vasculature
has gained importance as adult neurogenesis occurs
within an “angiogenic niche,” and an alteration in the
vascular microenvironment, or its ability to respond to
changes in metabolic demands, may be responsible for a
disruption in neurogenesis (371, 372, 460).
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ABROUS, KOEHL, AND LE MOAL
B) MECHANISMS INVOLVED IN ENRICHMENT-INDUCED NEUROGENESIS.
Exposure to an enriched environment is known to influence brain chemistry, in particular neurotransmitters and
trophic factors, which may underlie its action on neurogenesis (151, 370, 442, 471, 555, 584). In addition to these
factors, several components of this environment may be
involved in the regulation of neurogenesis.
Thus the effects of an enriched environment on neurogenesis and spatial memory may be related to an enhancement of motor exercise rather than learning. To
examine this hypothesis, female mice were housed with a
running wheel, injected with BrdU (50 mg · kg⫺1 · day⫺1
for the first 12 days) and killed 1 or 30 days after the last
BrdU injection. In these conditions, cell proliferation and
cell survival in the GCL, and performances in spatial
learning tasks were enhanced, suggesting that “physical
activity” is an important mediator of enrichment-induced
neurogenesis (553, 554). Further studies proposed that
the stimulatory effects of running are mediated by VEGF
(148), blood-borne IGF-I (542), NMDA receptor ⑀1-subunit, and BDNF production (278).
In their early studies, Rosenzweig and Bennett (471)
suggested that environmental changes or novelty were a
major factor in the effects of enrichment on brain and
behavior (471), which suggests that it could be a relevant
factor involved in enrichment-induced neurogenesis as
well. The observation that exposure to enriched conditions for an extended period of 6 mo does not add further
benefit certainly lends weight to this hypothesis (262).
Physiol Rev • VOL
The social environment may also contribute to enrichment-induced neurogenesis. This hypothesis has been
tested in rats reared for 4 wk in isolation and injected with
BrdU (2 ⫻ 50 mg · kg⫺1 · day⫺1) on the last 3 days of the
rearing treatment. Compared with grouped-reared rats,
isolation decreases hippocampal cell proliferation within
24 h, the number of newly born cells surviving over an
additional period of 4 wk of isolation, and the percentage
of newly born cells expressing TOAD-64. Interestingly,
the isolation-induced decrease in cell proliferation is reversed by a subsequent 4 wk of group housing (BrdU
being injected on the last 3 days of the rearing period; Ref.
320). Together, these results indicate that social environment is a highly relevant factor underlying the anatomical
effects of an enriched environment.
2. Reciprocal relation between learning
and neurogenesis
A) LEARNING INFLUENCES SEVERAL ASPECTS OF NEUROGENESIS. The
effect of learning on survival of newly born cells has been
examined in the water maze and in eyeblink conditioning
using a trace protocol (175). In this latter test, which
requires an intact HF (385, 512), animals have to associate
an auditory tone (conditioned stimulus) with a corneal
airpuff or electrical stimulation (unconditioned stimulus)
that is temporally separated by a trace interval (350). In
both learning tasks, rats are tested 1 wk after a single
BrdU injection (200 mg/kg). The number of BrdU-labeled
cells is enhanced by learning immediately or 1 wk after
the end of training, an effect accompanied by a decrease
in cell death. In associative learning, the performance of
individual rats positively predicts the life span of 1-wk-old
BrdU-labeled cells, i.e., rats exhibiting the best behavioral
scores possessed more newborn cells; this also suggests
that learning (and not training) is a sufficient condition to
increase the survival of adult-born cells (309). This learning-induced increase in cell survival was maintained 2 mo
after acquisition of associative learning (309). The observed enhancement of cell survival is specific to learning
because neurogenesis remains unchanged in rats exposed
to unpaired conditions in eyeblink conditioning or in rats
producing the same amount of motor responses in the
water maze. Furthermore, learning-induced upregulation
of neurogenesis may be specifically attributed to hippocampal functioning as delay-eyeblink conditioning,
classically attributed to the cerebellum, and training on a
cued test in the water maze, a hippocampal-independent
type of learning, do not modify neurogenesis (508).
Although these experiments indicate an enhancing
effect of learning in the water maze on cell survival,
contradictions exist concerning cell proliferation. When
animals are injected daily for the entire testing period (50
mg · kg⫺1 · day⫺1 for 12 days; Ref. 554) or the very last day
of testing (200 mg/kg; Ref. 175), the number of BrdU-
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obtained with adult female rats (after injecting BrdU 50
mg · kg⫺1 · day⫺1 on days 26 –30 of enrichment) (407).
These first reports led Kempermann and Gage (262) to
further investigate the impact of environmental enrichment on mice, and it was later shown that cell proliferation in the GCL was increased only when mice were killed
3 mo after their removal from the enriched environment
(262). In addition, a comparison of different strains of
mice showed that enriched experience affects hippocampal neurogenesis differently according to genetic background: as reported above, it increases cell survival but
not cell proliferation in C57BL/6 mice (267) which have a
high baseline level of neurogenesis (268), whereas it increases cell proliferation in 129/SvJ mice (261) which
have low levels of neurogenesis (268). This interesting
finding indicates that environment has a differential impact depending on inheritable traits, an effect still unexplained. Finally, in most experiments, enrichment led to
an improvement in spatial memory in the water maze, a
learning task that requires the subjects to learn multiple
extra-maze visual cues, allowing them to build a dynamic
spatial representation of their surroundings to navigate to
a platform hidden underneath the water surface (378).
However, whether these genetic variations of neurogenesis have a functional significance in spatial memory remains unknown (266).
NEUROGENESIS IN THE ADULT BRAIN
labeled cells remains unchanged. However, when animals
are injected at the end of the learning phase (50 mg ·
kg⫺1 · day⫺1 for 3 days), when an asymptotic level of
performance is reached, then the number of newly born
neurons in the GCL of the DG increases (306). To reconcile these data, we hypothesized that different phases of
the learning process have distinct actions on cell proliferation. To test this hypothesis rats were injected with
BrdU (50 mg · kg⫺1 · day⫺1) either during the initial phase
(4 days, Fig. 4, A and E), characterized by a fast and large
improvement in performance, or during the late phase (4
days, Fig. 4C), when an asymptotic level of performance
Physiol Rev • VOL
was reached. We found that the early phase of learning
does not modify proliferation (Fig. 4A), whereas the late
one does (121). Indeed, the number of newly born cells
increased contingently with the late phase of learning
(Fig. 4B), and these new cells differentiated into neurons
that persisted in the DG for at least 5 wk after the animals
had acquired the task. In contrast, the late phase of learning induced a decrease in the number of newly born cells
produced during the early phase (Fig. 4C).
Most importantly, the extent of BrdU cell loss was
inversely related to learning performances: rats with the
highest and lowest cell loss have the best and worst
performances, respectively. This decline in adult-born
cells most probably mirrors cell death, since learning
induces an increase in numbers of pyknotic cells (129)
and tunnel-positive cells (18). The observations that learning in the water maze increases the expression of proteins
involved in apoptosis (82) and that intrahippocampal administration of anticaspases, which blocks cell death,
impairs long-term but not short-term spatial memory
(106), strengthen the hypothesis that cell death is an
important component of hippocampal learning.
The mechanisms by which cell survival and proliferation are regulated during learning are so far unknown. A
nonspecific effect of training or exercise on blood flow to
the brain that may increase BrdU availability is unlikely,
since neurogenesis is unchanged in control “swimmers”
(121, 175). Trophic factors known to support the viability
and function of many types of neurons are likely mediators of learning-dependent changes in the HF. Indeed,
hippocampal bFGF and BDNF are increased during task
learning and decreased once an asymptotic performance
is reached (171, 271).
B) A BLOCKADE OF NEUROGENESIS DISTURBS LEARNING. The participation of neurogenesis in memory formation has been
more directly tested by using the DNA methylating agent
methylazoxymethanol (MAM; 5 mg/kg for 14 days concurrent with 75 mg · kg⫺1 · day⫺1 of BrdU on days 10 –12-14).
This treatment decreases the number of adult-born cells
by 80% and alters trace conditioning, whereas delay conditioning, neuronal responsiveness (presynaptic neurotransmitter release and excitability), and synaptic plasticity are not disrupted (509). Three weeks after treatment
cessation, the replenishment of immature neurons is associated with a recovery to acquire the trace conditioned
response. Altogether, these results suggest that newly
born cells are necessary for the formation of trace memories. Because MAM treatment for 6 days only is unable to
affect trace conditioning, adult-born cells may not be
“functional” until 1–2 wk after birth. Although it has been
shown that newborn cells extend their axons in the CA3
subfield within 4 –10 days after birth (204), a basic temporal study following their functional maturation (by
means of electrophysiological properties or c-fos expression) is still lacking.
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FIG. 4. Learning can increase or decrease the production of newborn cells. The aim of these experiments was to distinguish the effects
of the early phase (␪) of learning (characterized by a rapid and large
improvement in performance) and of the late phase of learning (when
asymptotic levels of performance are reached) on neurogenesis. To this
end, bromodeoxyuridine (BrdU; solid bars) was injected during the early
␪ (A, E) or the late ␪ (C) of learning and animals were killed (arrows)
after partial learning (A, at the end of the early ␪) or when the task had
been mastered (C and E, at the end of the late ␪). The early ␪ of learning
did not modify the number of cells generated during this period (B). The
late ␪ of learning increased the number of newly born cells generated
during this period (D), whereas it decreased the number of newly born
cells produced during the early ␪ (F). C, control group; L, learning group.
**P ⬍ 0.001 compared with control group. [Modified from Döbrössy et
al. (121).]
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ABROUS, KOEHL, AND LE MOAL
tainly as a consequence of an altered neurogenic microenvironment (369, 372). The reduction in hippocampal
mitotic activity is accompanied 1 wk postirradiation by
behavioral deficits in a hippocampal-dependent task of
spatial short-term memory (place-recognition). In contrast, performances in the water maze remain unaffected
2 wk postirradiation, a time by which proliferative activity
has resumed, albeit at a low level (⬃75 nascent cells daily
in the dorsal DG; Ref. 330).
3. Discussion
Data accumulated in the past decade suggest that the
birth of new cells is a necessary condition for the acquisition of memory traces (see also data on prenatal stress
and aging). However, a higher reduction in cell genesis
seems to be required for the appearance of deficits in
learning spatial cues than in trace conditioning, a difference which may be related to task difficulty (508). Furthermore, hippocampal-dependent behaviors influence
cell proliferation, cell survival, and cell death. The question of how adult neurogenesis participates in memory
processing (i.e., encoding, consolidation, retrieval) is as
FIG. 5. Influence of the different phases of
learning on neurogenesis. The early phase (␪) of
learning increases the survival of cells that predate
exposure to the task (175). These cells could be
involved in the encoding of memory traces, allowing task acquisition (see sect. IIIA3A). Since the
learning-induced increase in cell survival is longlasting (309), the surviving adult-born neurons
could participate in the long-term storage of information and to recall remote memories. Two distinct
processes take place after completion of the late
phase of learning (121; see Fig. 4 and sect. IIIA3, B
and C): 1) death of the cells born during the early
phase of learning, which may be involved in memory trace consolidation. This cell death phenomenon could constitute a trimming mechanism that
suppresses old unnecessary neurons and/or the immature neurons that are too old or have not established learning-related synaptic connections. 2)
There is an increase in the number of cells generated contingently with the late phase training.
Given that the learning-induced increase in cell proliferation is long-lasting, these newly born cells
could be involved in a resetting process rendering
the DG available for the acquisition of new memories (forgetting and flexibility).
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Recently, it has been reported that the formation of
spatial memories may not be associated with neurogenesis. Indeed, the blockade of cell proliferation by the same
14-day MAM treatment as described above does not alter
spatial learning in the water maze or contextual conditioning in fear conditioning (510). In our opinion, this lack
of effect is due to the residual newly born cells that
continue to be generated under MAM (⬍700/day for 3
BrdU injections), indicating that learning can occur with a
very small percentage of new neurons. This assumption is
based on the observation that some aged rats are able to
acquire spatial navigation learning despite a very low
number of newly born cells [⬃200/day for 5 BrdU injections; see sect. IIIC2, Fig. 6 (130)].
An emerging strategy to clarify the role of neurogenesis in learning consists of using ionizing-irradiation
known to induce cognitive impairments in animals (37, 66,
119, 184) and in humans (372). X-irradiations (0 –15 Gy)
decrease the number of BrdU-labeled cells in a dosedependent manner (following a 60 mg/kg injection of
BrdU 1 h before death) and the number of cells expressing p34cdc2 or Ki-67 in the adult DG (369, 433, 532). Two
months after irradiation, the production of adult-born
neurons (expressing NeuN) is significantly reduced cer-
NEUROGENESIS IN THE ADULT BRAIN
yet unresolved. Although speculative, the following
framework is proposed (Fig. 5).
A) DO ADULT-BORN NEURONS PRODUCED BEFORE LEARNING HAVE A
Physiol Rev • VOL
ory traces themselves but may play a critical role in
linking representations of distinct experience, and longterm storage of spatial representations could be achieved
by synaptogenesis occurring within this CA3 (455). Alternatively, adult-born neurons could store the contextual
information regarding the episode (the so-called contextual trace; Ref. 394).
B) A ROLE OF CELL DEATH IN STABILIZATION? A surprising phenomenon is that the death of old and/or newly born
neurons also plays an important role in enabling hippocampal learning. This may constitute a trimming mechanism replacing the unnecessary old neurons and/or the
immature neurons that have not established learning-related synaptic connections with freshly minted ones. This
may serve the function of increasing the signal-to-noise
ratio, thus consolidating the memory trace. This phenomenon, which on one hand is consistent with the “use it or
lose it” principle and on the other hand goes against the
classic assumption in learning-induced structural plasticity that “more is better,” recalls the regressive events
observed during development (450).
C) IS LEARNING-INDUCED CELL PROLIFERATION INVOLVED IN MEMORY
Learning-induced cell proliferation
is not correlated with learning performances, suggesting
that these newly born cells do not directly sustain ongoing
learning and may rather be involved in future behaviors.
This phenomenon may represent a resetting process ensuring that the hippocampal system is available to process
new memories. This hypothesis is strengthened by the
observation that presenilin-1 knockout mice that present
normal basal neurogenesis exhibit a reduction in enrichment-induced cell proliferation and better retrieval of
contextual fear memory traces compared with control
mice (153). Thus a deficiency in the upregulation of cell
proliferation induced by the late phase of learning may
prevent memory clearance, thereby impairing forgetting
processes and disabling hippocampal functions. It is also
possible that this alteration in cell proliferation alters the
inferential use of past memories in a novel situation (flexibility) and thus leads to rigidity and perseverance.
CLEARANCE OR FLEXIBILITY?
B. Activation of the Stress Axis: Acute
and Long-Term Effects on Neurogenesis
Exposure to stressful events prepares animals to engage in fight or flight responses, and a role of the HF in
these defensive behaviors has been proposed (52, 205).
Moreover, as stressful events have deleterious effects on
hippocampal integrity (351, 352, 484), the influence of
different types of stress on hippocampal neurogenesis has
been studied.
1. Effects of stress on neurogenesis
In most studies, a decrease in cell proliferation has
been observed after stressful events, but this effect ap-
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Since survival of the newly born
cells whose birth predates the beginning of learning is
increased during the learning task (175), the encoding of
memory traces may be processed in these adult-born
neurons. According to the “use it or lose it” principle, the
cells that survived and integrated into the granule cells/
mossy fiber system could function as postsynaptic detectors of correlated afferent activity and thereby update the
bearing map, which is constructed in the DG from directional cues (229). After processing, which relies on pattern separation properties (270), episodic memories are
stored temporally by virtue of the CA3 auto-associative
system (468). The adult-born neurons could also be involved in temporal pattern completion: if a degraded version of a stimulus is presented after learning, the represented feature can be recalled from this incomplete input
information.
The role of adult-born neurons in long-term storage
and retrieval of remote memories is still elusive as the
role of the HF and the DG is still a matter of debate. One
view stipulates that the HF has a limited storage capacity
as 1-mo-old memories do not require the HF, memory
traces being transferred within cortical areas where they
are consolidated and permanently stored (19, 56, 273, 274,
342, 573). In relation to this apparent time-limited role of
the HF, it was originally thought that after encoding and
conversion of short-term memory into long-lasting memory, the adult-born neurons were eliminated (189). However, adult-born neurons that have been recruited by
learning survive for several weeks (121, 309) and thus
outlive the time required for cortical transfer. This timewindow is, in our opinion, hardly reconcilable with the
“consolidation transfer hypothesis.” Furthermore, if one
considers that adult-born neurons are integrated into the
DG, which is no longer necessary for maintaining the
memory traces, they may have adopted another, as yet
undetermined, role (508).
However, the view that the HF becomes dispensable
after the conversion of short-term memory into longlasting memory is disputed, as it is supposed to be involved, together with neocortical areas, in the storage and
the retrieval of remote memories (387, 388, 393–395). In
particular, the HF seems important in the recall of old,
detailed, episodic memories that are context dependent
(469, 527). This scenario is consistent with the long-term
survival of adult-born neurons (121, 309), which could act
as binding detector cells capable of memorizing bindings
between items (503) or could store a memory index, i.e.,
an index of neocortical areas that are activated by experiential events and contain no intrinsic meaning in terms
of representation of external events (538). In these cases,
adult-born neurons most probably do not store the mem-
ROLE IN MEMORY PROCESSING?
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ABROUS, KOEHL, AND LE MOAL
Physiol Rev • VOL
induced cell proliferation and defensive behaviors (149).
The activity of the HPA axis is known to be regulated by
corticotrophin-releasing hormone and vasopressin, the
roles of which have recently been evaluated. Thus the
chronic blockade of CRF1 and V1B receptors (by
SSR125543A and SSR149415, respectively, 30 mg · kg⫺1 ·
day⫺1 for 28 days) starting 3 wk after the beginning of
chronic mild stress (CMS for 21 days) reverses the stressinduced reduction of cell proliferation (measured 24 h
following 1 ⫻ 75 mg/kg of BrdU injected at the end of the
drug treatment period) (10). These antagonists are also
able to prevent the stress-induced reduction of neurogenesis (by means of NeuN labeling) estimated 30 days after
the cessation of the drug treatment and BrdU pulse (3.75
mg/kg every 2 h on the last 3 days of the CMS). The
normalization of neurogenesis is furthermore associated
with a prevention of the stress-induced hippocampal atrophy.
2. Interindividual differences in stress reactivity
Interindividual differences in behavioral reactivity to
stress or to novelty and coping abilities have been evidenced in our laboratory in an outbred population of rats.
Animals are split into two groups according to the median
score of behavioral response, the behaviorally high-reactive (HR) rats, and the low-reactive (LR) rats (443, 446).
Compared with the LR phenotype, the HR phenotype is
characterized by a series of adaptive defects of a cognitive
and motivational nature corresponding to a deficit in inhibition and control processes (115, 304, 443, 447). These
interindividual differences have been related to differences in corticosterone secretion, HR rats displaying a
hyperactive HPA axis (305, 443, 444, 446).
The behavioral trait of reactivity to stress has been
shown to predict the level of neurogenesis in the GCL of
the DG (305). Two weeks after their behavioral characterization, rats were injected with BrdU (3 ⫻ 50 mg/kg
spaced by 4-h intervals) and killed the next day or 14 days
later. Cell proliferation was found to be negatively correlated with locomotor reactivity to novelty, and when the
group was split according to the median behavioral score
into LRs and HRs, cell proliferation in LRs was twice that
observed in HRs. Survival of nascent neurons was not
influenced by this behavioral trait. A difference in the
HPA axis reactivity most probably underlies the differences in neurogenesis, primarily due to differences in cell
genesis. The functional significance of this difference in
DG plasticity remains unclear but may reflect a disruption
of behavioral inhibition in the HRs (187).
3. Perinatal manipulations
Studies on stress during the perinatal period have
also led to intriguing observations. It is well documented
from animal and human studies that during the perinatal
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pears highly dependent on the nature and the timing of
stress.
In male but not female rats, exposure to the odor of
a predator [trimethyl thiazoline (TMT), the major component of fox feces] downregulates the number of proliferating cells estimated 2 h, 24 h, and 1 wk after a single
BrdU injection (100 –200 mg/kg) (149, 537). However, this
effect is transient as TMT-induced downregulation of
BrdU cell numbers disappears 3 wk after labeling when
dividing cells express NeuN or NSE (149). Likewise, in
male tree shrews (Tupaia belangeri), a single exposure to
an unknown congener, which results in the establishment
of a dominant/subordinate relationship, brings down the
number of dividing cells (labeled by one injection of
BrdU, 75 mg/kg) in the DG of the subordinate within 2 h
(177). In the marmoset (Callithrix jacchus) however, a
single exposure to a resident-intruder model of stress
reduces the number of newly born cells (2 h after 1 ⫻ 75
mg/kg BrdU) in the DG of the intruder (181). Repeated (3
or 6 wk) but not acute (2 or 6 h) restrain stress decreases
cell proliferation duration-dependently in the SGZ of rats
(2 h after 1 ⫻ 200 mg BrdU/kg; Ref. 441). In contrast, the
acute stress of cold immobilization and a forced swim
reduce cell proliferation (1 day after a 1 ⫻ 200 mg/kg
BrdU injection before the stress) in the DG and not the
SGZ, an effect that is normalized within 1 day (209).
Chronic, unpredictable stress exerted over 3 wk reduces
mitotic activity in the SGZ (and not the DG) as estimated
by KI-67 staining. At this time point, another batch of
animals was injected with BrdU (1 ⫻ 200 mg/kg), and 3
wk later, the effect of chronic stress on the survival of
BrdU-labeled cells was examined. Because the BrdU cell
number was unchanged, it was concluded that cell survival is not influenced by stress. Finally, male tree shrews
subjected to a 7-day period of psychosocial stress exhibit
reduced cell birth (evaluated 1 day after 1 ⫻ 100 mg/kg
BrdU; Ref. 104). This stress-induced reduction in adultborn cells leads to a decline in neurogenesis, the neuronal
phenotype being inferred by the expression of NeuN (441)
or NSE (177, 181) 1 mo after labeling.
Because stressful events are known to activate the
HPA axis, leading to a rise in plasma levels of corticosterone, and to activate the release of endogenous opioids,
which are involved in defensive behaviors, the role of
these two factors has been evaluated. To confirm the
involvement of corticosterone, male rats were adrenalectomized, and low levels of hormone were restored. In
these conditions, the prevention of the TMT-induced rise
in corticosterone blocks the downregulation of cell proliferation (537). In contrast, administration of naltrexone,
an opioid antagonist (5 mg/kg, 30 min before TMT exposure), does not attenuate the effect of TMT on cell proliferation, whereas the expression of defensive behaviors
(defensive burying, stretch approach) is partially attenuated (219), which indicates a dissociation between TMT-
NEUROGENESIS IN THE ADULT BRAIN
Physiol Rev • VOL
because maternal separation is known to decrease corticosteroid-binding globulin (559), and thus enhance the
free, and active, fraction of corticosterone reaching the
brain, a higher level of “efficient” hormone could be responsible for the effects of maternal separation on hippocampal cell proliferation.
Given the involvement of the HF in learning and
memory, we hypothesized that prenatal stress would lead
to cognitive deficits via an inhibition of neurogenesis in
the DG. Thus we have shown that prenatal stress is associated with an alteration in learning and memory performances, and more importantly, that the learning-induced
increase in cell proliferation observed in control animals
is blocked in prenatally stressed rats (306). This result is
in accordance with our previous observation that cell
proliferation is increased only when the animals reach an
asymptotic level of performance, i.e., when the task has
been mastered (see sect. IIIA2A and Fig. 4). Furthermore,
the behavioral deficits induced by prenatal stress, similar
to those observed in animals exposed to X-irradiations
(37), confirm an enabling role for hippocampal neurogenesis in cognition.
C. Aging and Longitudinal Observations
1. Neurobiology of the age-related decline
in neurogenesis
A) INFLUENCE OF AGING ON NEUROGENESIS. Aging is a life-long
process beginning with conception and ending with
death. Within this developmental continuum, sexual
maturity (2–3 mo in rodents) is used to define the start
of adulthood. Although the definition of “how old is
old” varies depending on species, genetic background,
and experimental conditions, studies addressing the
effects of age on biobehavioral parameters in rodents
have identified at least three ages: adult (up to 10 mo),
middle-aged, and “old” or “aged” or senescent (from 20
mo) (91, 92).
The persistence of neurogenesis in the DG of senescent rats was first reported by Kaplan and Bell (248,
250, 251). An age-related decline in DG neurogenesis
has been confirmed in mice and rats using several BrdU
labeling protocols (54, 208, 290, 306, 310, 499), whereas
conflicting results have been reported for the SVZ (238,
253, 290, 543).
The decline in DG neurogenesis, which mainly occurs between 2 and 12 mo of age, does not seem to be
related to 1) an alteration in adult-born cell survival as
the percentage of surviving BrdU-labeled cells 1 mo
after their birth is independent of the age of the animals
(54, 208, 269, 310) or 2) a general change in metabolic
conditions, as neuronal precursors respond to BDNF’s
influence to the same extent throughout life (169).
Rather, it may be a decline in proliferative activity that
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period the development of an organism is subjected to
complex environmental influences and that deleterious
life events during development induce neurobiological
and behavioral defects (207, 557, 569). Indeed, environmental changes and stimulations have the greatest impact
when produced in the early stages of life and during
developmental periods, leading to phenotypical orientations lasting throughout life. These environmental influences, which have been evidenced for decades, have been
explored at structural and mechanistic levels only recently, revealing profound structural changes in the HF
(see, for instance, Ref. 353). Stressful events during the
prenatal period, such as prenatal stress which consists in
stressing pregnant dams, or during the postnatal period in
the rat, as for example maternal deprivation, i.e., longlasting separations of the mum-pup dyad, alter brain
chemistry, enhance emotional reactivity, produce cognitive impairments, and increase vulnerability to drugs of
abuse (185, 482, 569). We and others have shown that
stressful events during the prenatal (306) and the postnatal (300, 367, 431) periods downregulate hippocampal
neurogenesis. In prenatally stressed rats, we found that
cell proliferation (4 ⫻ 50 mg/kg of BrdU over 3 days) is
reduced from adolescence to senescence, indicating an
acceleration in the age-related decline of cell proliferation
in the GCL. Survival of the newly born cells and neuronal
differentiation (measured with NeuN) are not modified,
and thus the net reduction in the number of adult-born
neurons is associated with a decrease in the number of
granule cells from adulthood to senescence. Given that
corticosterone has been implicated in long-term behavioral changes induced by prenatal stress (280), this downregulation of neurogenesis may result from heightened
corticosterone secretion (see sect. IID2A). Similarly, maternally deprived rats are characterized by reduced cell
proliferation in the GCL both when infants (proliferation
measured on postnatal day 21 following 7 days of maternal separation and 7 ⫻ 50 mg/kg BrdU) (300, 431) and
when adults [proliferation measured at 2–3 mo of age
following daily 3-h maternal separation bouts from postnatal day 1 to 14 and 1 ⫻ 200 mg/kg BrdU 2 h or 1 wk
before death (367)]. In this recent study, the authors
found that maternal deprivation reduced the number of
immature, but not mature, neurons that are added to the
DG in adulthood (367). Because maternal separation is
reported to alter the activity of the HPA axis (482), it has
been hypothesized that corticosterone mediates the effect
of maternal separation on neurogenesis. In fact, it has
been shown that the maternal separation-induced decrease in cell proliferation is abrogated by adrenalectomy
plus corticosterone treatment aimed at restoring basal
diurnal levels of the hormone. The authors proposed that
hippocampal precursors might be hypersensitive to corticosterone, the diurnal basal and stress-induced levels of
which are not modified in their paradigm (367). However,
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ABROUS, KOEHL, AND LE MOAL
underlies the age-related decline in neurogenesis, since
the number of newly born cells a few hours after labeling (54, 290) and the number of nestin-positive cells
(391) are lower in aged rats. However, it remains to be
determined whether the reduction in proliferative activity is a consequence of a developmental lengthening
of the cell cycle time and/or of a shrinking of the
proliferative cell population. Finally, neuronal differentiation seems to be delayed with advancing age as
suggested by the high percentage of cells that do not
express a neuronal or an astrocytic phenotype 1 mo
after their birth (54, 208, 264, 310, 391).
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B) FACTORS REGULATING NEUROGENESIS IN THE SENESCENT BRAIN.
The progressive decline in cell proliferation could derive from inadequate local environmental cues; the
aged DG may be under the influence of inhibitory factors and/or may lack stimulatory factors that sustain
division, differentiation, and/or survival of the newly
born cells.
I) Inhibitory factors. Corticosterone has received
particular attention since basal levels of this hormone,
known to inhibit cell proliferation in young rats (see sect.
IID2A), increase during aging (324, 484). Thus, 1 wk after
adrenalectomy in old rats, cell proliferation is upregulated
in the GCL (373) and in the DG (GCL and hilus, Ref. 74).
On the other hand, survival of the newly born cells is
unrelated to corticosterone levels (373), and most of them
differentiate into neurons expressing TOAD-64 or NeuN
(74, 373).
Glutamate is also known to inhibit DG neurogenesis in young rats (see sect. IID2B). Similarly, in middleaged and aged rats, a single injection of a NMDA receptor antagonist (CGP-43487, 5 mg/kg 2 h after an injection of BrdU, 200 mg/kg) increases hippocampal cell
proliferation 5 days later. By 3 wk, despite a decline in
the number of newly born cells, more cells survived in
the treated aged rats compared with saline aged counterparts (391).
II) Activating factors. The involvement of the neurosteroid Preg-S in the hippocampal neurogenesis of old
rats has been examined. Indeed, 1) hippocampal levels of
Preg-S in the HF of senescent rats correlate with spatial
memory abilities, 2) intrahippocampal infusion of Preg-S
in cognitively impaired aged rats reverses memory disturbances (551), and 3) Preg-S stimulates neurogenesis in
the adult DG (see sect. IID2A). We have shown that icv
Preg-S infusion increases cell proliferation in the senescent DG (348). This suggests that the age-related decrease
in Preg-S levels could lead to a loss of stimulation of
hippocampal neurogenesis and to subsequent cognitive
deficits. Finally, because Preg-S acts as a negative allosteric modulator of GABAA receptors, our results support
the inhibitory hypothesis of neurodegenerative disorders
such as Alzheimer’s disease and age-related brain impairments, which postulates the involvement of abnormally
strong inhibitory GABAergic transmission (341).
Because adult neurogenesis can be enhanced by the
administration of growth factors (see sect. IID2C), the
responsiveness of the aged brain has been the subject of
investigation. In particular, a stimulatory effect of IGF-I
has been examined since 1) IGF-I brain levels decrease
with age (90), 2) IGF-I receptor mRNA is upregulated as a
function of aging and cognitive decline (522), and 3) IGF-I
infusion improves cognitive function in aged rats (345).
The chronic icv administration of IGF-I (1.2 ␮g/day for 14
days) in senescent rats elicits an approximately threefold
increase in BrdU-labeled cells (BrdU, 2 ⫻ 50 mg · kg⫺1 ·
day⫺1 on days 7–11) in the SGZ and the hilus (310). In a
4-wk survival study, IGF-I and saline-treated animals displayed a similar number of newly born cells (BrdU-labeled on days 7–11) compared with animals killed after a
short survival delay, indicating that IGF-I acts on cell
proliferation rather than on cell survival. Finally, in contrast to what was observed in adult rats (1), IGF-I did not
modify cell fate in old animals, with 20% of newly born
cells differentiating into neurons (inferred from NeuN
expression). Thus the threefold increase in BrdU-positive
cells elicited by IGF-I translated into a threefold increase
in adult-born neurons.
The influences of FGF-2 and HB-EGF were also examined in 20-mo-old mice (icv infusion of 10 ␮g/ml for 3
days concurrent with 50 mg · kg⫺1 · day⫺1 BrdU). One
week after the cessation of the treatments, the number of
newly born cells was higher in both the SGZ and the SVZ;
these cells expressed DCX and occasionally GFAP (238).
More speculatively, it may be hypothesized that
proinflammatory cytokines such as interleukin 6 (IL-6)
also play an important role in age-related decline in neurogenesis. Indeed, 1) it is involved in the appearance of
age-related cognitive disorders in humans (59, 120, 328,
355, 466, 565), 2) chronic stress increases its production
in aged patients (272), 3) IL-6 expression is increased in
the HF of senescence-accelerated mice (539), and 4) hippocampal neurogenesis is reduced in adult transgenic
mice with chronic IL-6 production (552) or after administration of bacterial lipopolysaccharide, a potent activator
of IL-6 (138, 372).
In summary, precursors that are able to enter the cell
cycle are still present in the aged brain, and low levels of
neurogenesis are linked to the accumulation of inhibitory
substances and/or the decrement of stimulatory factors.
The mechanisms of action of these modulators are still
unknown and, in particular, it remains to be determined
whether they act on the length of the cell cycle or on the
number of dividing cells. Whatever the underlying mechanism, these results point to possible pharmacological
actions for preventing or treating age-related cognitive
impairments.
NEUROGENESIS IN THE ADULT BRAIN
2. Functional implications of age-related modulation
of neurogenesis in memory
tion of the cognitive abilities of aged rats in the water
maze, we have shown (Fig. 6) that neurogenesis (i.e., cell
proliferation, cell determination, and cell survival) is
higher in cognitively unimpaired rats than in impaired
ones (130).
Because age-impaired and -unimpaired rats did not
differ in granule cell number, as previously described
(458), it seems that the rejuvenation of granule cells
rather than a change in their absolute number is the main
factor sustaining memory formation. In other words, successful aging, i.e., preserved cognitive functions, is associated with the maintenance of a relatively high neurogenesis level, whereas pathological aging, i.e., memory
deficits, is linked to exhaustion of neurogenesis. These
differences in hippocampal neurogenesis may be due to
differences in stimulatory and/or inhibitory substances,
which may respectively prevent or accelerate pathological aging. We propose that the age-related increase in
corticosterone levels, resulting from repeated stressful
events, may lead, through life-span inhibition of neurogenesis, to defects in hippocampal networks that would
be responsible for cognitive dysfunctions. The observation that lowering corticosterone levels in middle-aged
animals significantly increases hippocampal neurogenesis
and postpones the onset of spatial memory deficits supports this hypothesis (M. F. Montaron, E. Drapeau, C.
Aurousseau, M. Le Moal, P. V. Piazza, and D. N. Abrous,
unpublished data).
During pathological aging, alterations in hippocampal neurogenesis most probably mirror a more general
failure in the mechanisms underlying neuronal plasticity
(364). Similarly, it has been shown that lipofuscin deposits, an index of cell suffering, are higher in aged rats with
impaired cognitive function (64) and are decreased in
aged mice housed in an enriched environment (264). According to the hypothesis of the “Red Queen Theory” (5),
during aging there is competition for the available plasticity to compensate for neuronal degeneration or to store
new information. Thus, in pathological aging, hippocampal plasticity is exhausted, and the capacity of the old
FIG. 6. Hippocampal neurogenesis depends on
the cognitive status of the aged rats. To demonstrate
a quantitative correlation between neurogenesis and
performance in a hippocampal-dependent test, we
took advantage of the well-established presence of
individual differences in spatial memory abilities
within a population of old rats. Indeed, in the water
maze, some old individuals show clear impairment in
spatial reference memory while others are not impaired and exhibit cognitive capacities similar to
those of younger individuals. We found that cell proliferation (A), the survival of adult-born cells (B), and
the number of adult-born neurons (C) are higher in
the dentate gyrus of aged unimpaired (AU) than aged
impaired rats (AI). *P ⬍ 0.05, **P ⬍ 0.01 compared
with AU. [Modified from Drapeau et al. (130).]
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The hypothesis that the decline in neurogenesis may
be responsible for age-related alteration in cognitive function has been tested by examining the influence of an
enriched environment, and by taking advantage of the
existence of interindividual differences in age-related cognitive functions. The influence of enriched environments
on spatial memory and on neurogenesis (cell proliferation, cell survival, and neuronal differentiation) has been
studied in 18-mo-old mice (269). Although the effects are
not as strong as those observed in young animals, after 68
days of enrichment, neuronal differentiation is enhanced
whereas cell proliferation and cell survival remain unchanged compared with nonenriched aged animals; performances in spatial memory are slightly improved. A
similar conclusion was reached when middle-aged female
mice were raised for 10 mo in an enriched environment
(264), which indicates that as was found in younger subjects (see sect. IIIA1A), long-term exposure to an enriched
environment in old subjects does not afford any further
beneficial effect compared with short-term exposure as
neither cell proliferation nor cell survival are increased. In
this study, the improvement in learning parameters observed after enrichment was suggested to be aspecific,
resulting from better adaptive skills in exploration,
greater locomotor aptitude, and endurance following enrichment, leading the authors to suggest that the contribution of adult hippocampal neurogenesis to hippocampal plasticity might require a physically active pursuit as
opposed to a passive sensory stimulation (264).
Large individual differences exist in cognitive abilities, and all aged rats do not exhibit cognitive disorders;
some rats perform as well as young controls, whereas
others present spatial memory impairments (457). The
existence of such individual differences has been used as
a naturalistic strategy to study the neurobiological correlates of cognitive aging, and it has been shown that the
extent of memory dysfunction is related to the magnitude
of changes occurring in the HF. Following a characteriza-
547
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ABROUS, KOEHL, AND LE MOAL
brain to acquire new information and to compensate for
ongoing degenerating processes is impeded.
D. Involvement of Neurogenesis in Pathologies
1. Pathological conditions associated with an
upregulation of neurogenesis
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A) EPILEPSY. Human temporal lobe epilepsy (TLE) is
associated with atrophy of the HF, an effect known since
the beginning of the 19th century, and a loss of hippocampal and DG neurons (57, 384). In this pathology, the
dentate granule cells give rise to abnormal axonal projection into the supragranular inner molecular layer of the
DG and to an aberrant reorganization of the mossy fibers
(MF) in the CA3 subfield of Ammon’s horn (529). It has
been suggested that the sprouting of MF is relevant in the
hyperexcitability of the TLE (426). This has led to investigation into whether newly born cells are important in
the genesis of dentate MF sprouting (MFS) and participate in the reorganization of the network.
Kindling, an animal model of TLE, is characterized by
a permanent epileptic state produced by a series of seizures induced by electrical stimulations made in various
brain areas such as the hippocampus (42), the perforant
path (396), and the amygdala (425, 492). Single and repeated kindling stimulations in the ventral CA1 region
induce a facilitation of mitotic activity 2 wk later (42).
Stimulation in the perforant pathway leads to a marked
increase in the number of BrdU-labeled cells as early as 3
days after the last stimulation, whereas repeated kindling
does not evoke further stimulation of cell proliferation
(396). Cell division is in fact suppressed, suggesting a
diminished efficiency of repeated or prolonged stimulation to elicit a neurogenic response. In the amygdala
kindling model, it has been reported that during the early
phases of kindling, when focal seizures are present, DG
cell proliferation remains unchanged, whereas it is upregulated during the later phase of kindling, when motor
seizures are present (425, 492).
In various chemoconvulsant (pilocarpine or kainate)
models of human TLE, the induction of seizures is accompanied by a dramatic increase in neurogenesis in the SGZ
of the DG (430). This increase is observed after a latent
period of a few days following the status epilepticus (SE)
and persists during the first week, before levels of neurogenesis return to baseline over the following weeks (396,
430). The recruitment of proliferative cells after kainate
treatment occurs preferentially in GFAP cells, suggesting
an increase in proliferative glial-like astrocytes (type B)
(223). The expression patterns of multiple bHLH transcription factors have been studied following epileptogenesis; some were found to be increased (Mash1, Id2), some
decreased (Hes5), and others unchanged (NeuroD, NeuroD2, Id3, and Math2), suggesting that molecules control-
ling cell-fate decisions in the developing dentate gyrus are
also operative during seizure-induced neurogenesis (140).
The newly born cells induced by seizures, which survive
for up to 4 wk and differentiate into neurons (430), migrate to abnormal locations such as the CA3 cell layer, the
dentate hilus and inner molecular layer (108, 430, 487).
These ectopic granulelike neurons retain many, but not
all, of their granule cell intrinsic properties (487). Incidentally, ectopic locations of SVZ-derived neuroblasts have
also been observed in the striatum and the cortex following pilocarpine treatment (428).
Seizure-induced neurogenesis appears to precede
MFS, suggesting that newly born cells could be important
in the genesis of the ectopic innervation of Ammon’s horn
by dentate fibers. This hypothesis has been tested by
coadministrating kainate or pilocarpine with cycloheximide (CHX), a protein synthesis inhibitor known to abolish MFS (40). Contrary to what was expected, CHX did
not influence chemoconvulsant-induced neurogenesis, indicating that its effect on MFS is independent of cell
proliferation (97). Similarly, a single session of X-ray
treatment, which attenuates pilocarpine-induced neurogenesis, fails to prevent MFS (427), indicating that neurogenesis upregulation is not sufficient to generate MFS.
Thus the participation of the newly born cells in network
reorganization and in the recurrence of epileptic seizure is
still open to debate.
The mechanisms by which seizure activity stimulates
neurogenesis are unknown. They may involve electrical
activation since 1) physiological activity such as LTPelicited mossy fiber stimulation is sufficient to increase
neurogenesis in the DG (118), and 2) pure electrical activation, consisting in a continuous stimulation of the perforant path, elicits focal hippocampal seizure discharges
and increases BrdU cell number 6 days later (430). Seizure-induced upregulation of neurogenesis may also involve 1) an alteration in excitatory amino acid transmission due to degeneration of the entorhinal afferences to
the granule neurons of the DG (430); 2) activation by the
dying cells (42, 50); 3) a change in bFGF, as kainateinduced upregulation of neurogenesis is blocked in mice
lacking bFGF, an effect reversed by gene transfer (582);
4) changes in other neurotrophic factors (145, 164, 172,
583); and 5) activation of the 5-HT1A receptor as infusions
of a 5-HT1A receptor antagonist (WAY-100,635) impede
the increase in pilocarpine-induced neurogenesis whereas
cell death, MF sprouting, and the onset of spontaneously
recurring seizure are not prevented (451).
In summary, neurogenesis is altered by epileptiform
status, and surprisingly maintenance of the newly born
cells (in homotypic and ectopic locations) is systematically observed in the different models of epilepsy. The
abnormal circuits may contribute to the unstable hippocampal circuitry and the development of chronic TLE.
As proposed by Gray and Sundstrom (188), the DG could
NEUROGENESIS IN THE ADULT BRAIN
Physiol Rev • VOL
ischemia involves the release of glutamate and overstimulation of glutamate receptors, which in turn upregulates
neurogenesis. Indeed, the blockade of NMDA or AMPA/
kainate glutamate receptors by specific antagonists
(MK801; NBQX) inhibits the stroke-induced increase in
neurogenesis (25, 46); however, these effects are surprising in light of the stimulatory influence of glutamate receptor blockade on neurogenesis in control brains (see
sect. IID2B).
Mitotic factors such as bFGF are certainly involved
as ischemia-induced upregulation of neurogenesis is
blocked in mice genetically deficient in bFGF (582) and is
increased following adenovirally mediated transfer of
bFGF (347). Chronic icv infusions of bFGF and EGF
greatly enhance the potential of endogenous progenitors
to proliferate in response to ischemia and the cells then
regenerate CA1 pyramidal neurons. The regenerated neurons are integrated into the neural circuitry as they receive afferences, project onto their normal target, the
subiculum, and reverse the ischemia-induced deficits in
cognitive functions (399). This constitutes the most impressive example of network reconstruction leading to
behavioral recovery that takes advantage of adult endogenous neurogenesis. Infusion of VEGF (0.54 ␮g/day on
days 1–3 of reperfusion concurrent with 2 ⫻ 50 mg ·
kg⫺1 · day⫺1 BrdU) increases the number of adult-born
cells 1 mo (and not 3 days) after labeling, beyond the
increase caused by ischemia (526). Ischemia-induced cell
proliferation, measured within 3 wk post-BrdU pulse (2 ⫻ 50
mg · kg⫺1 · day⫺1 BrdU injected for 6 days starting 1 day
after MCAO), is also increased by icv infusion of IGF-I and
glial-derived neurotrophic factor (117).
Modulation of cell birth by ischemia also involves the
production of several classes of inflammatory molecule
metabolites. Administration of inhibitors of cyclooxygenase (Cox; i.e., acetylsalicylic acid, indomethacin, NS398),
the rate-limiting enzyme for prostaglandin synthesis, curtails ischemia-induced proliferation after transient global
ischemia in adult gerbils or rats (293, 485, 547). Mutation
of one of the Cox isoenzymes, Cox-2, suppresses the
ischemia-induced increase in hippocampal cell proliferation (485). Cox-2 may affect neurogenesis through the
production of prostaglandin E2 (547), which may act directly via prostaglandin EP3 receptors expressed in the
GCL (397) or indirectly through bFGF (477). Alternatively, the production of NO, a key factor in inflammation,
may be at play as administration of a NO donor (DETA/
NONOate) to rats subjected to MCAO significantly increases cell proliferation in the SVZ and the DG, and
significantly improves neurological recovery (587). This
enhanced neurogenesis is certainly associated with the
activation of inducible NOS since its inhibition (by aminoguanidine) prevents ischemia-induced neurogenesis.
Furthermore, stroke-induced neurogenesis is abolished in
mice lacking the iNOS gene (590). The participation of
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“regulate as a gate with respect to controlling the propagation of seizure with granule cells controlling the
throughput of epileptiform activity transition through the
HF by virtue of a feed forward inhibitory pathway.” These
alterations in neurogenesis may participate in the memory dysfunction associated with epilepsy (530). Although
unverified, this latter finding suggests that the presence of
more new neurons is not necessarily associated with a
good memory and that neurogenesis and memory function may follow an inverted U-shaped curve.
B) ISCHEMIA. Until recently it was thought that the functional recovery that occurs in some cases following brain
damage (such as stroke and trauma, see sect. IIID1D) was
related to the remodeling of neuronal pathways in nondamaged areas. The discovery of adult neurogenesis
prompted researchers to investigate the role played by
new neurons in recovery of lost functions.
Transient global ischemia, induced in gerbils and rats
by bilateral common carotid artery occlusions, increases
cell proliferation in the DG in a dose-dependent manner
(260, 315, 575, 576). A peak in cell proliferation occurs 1–2
wk after ischemia, and a quarter of the newly generated
cells die during the first month (315). During the first 2 wk
after their birth, the newly born cells transiently express
NeuroD and DCX (258). Those cells that survive differentiate into granule neurons expressing NeuN or MAP2 at 1
mo of age (258, 315). They acquire functional features of
mature neurons as NMDA stimulation induces the phosphorylation of ERK in 34 and 61% of BrdU-NeuN labeled
cells of 1 and 2 mo of age, respectively (258).
After focal cerebral ischemia, induced by unilateral
middle cerebral artery occlusion (MCAO) (24, 237, 589,
590), cell genesis is increased to various degrees in the
ipsilateral DG (as well as in the SVZ, OB, and cortex) over
a period of several weeks. Increased BrdU incorporation
in the DG (as in the others structures) contralateral to the
infarct, occurring following a lapse of a few days, suggests
a role for diffusible or humoral factors (237, 534). The
newly born cells differentiate into granule neurons without any apparent degeneration (590). The enhancement of
BrdU-labeled cells in the OB and the cortex has been
attributed to the migration of neuronal precursors from
the SVZ towards their normal target or towards the infarct, respectively (588). The presence of cell clusters in
cortical areas, in the vicinity of blood vessels, also suggests the recruitment of resident quiescent stemlike cells
or the infiltration of blood-borne cells (589). New cells
arising from the SVZ also colonize the striatum after
ischemia, 20% of which survive (representing 0.2% of the
cell loss) and assume the phenotype of cells lost due to
the lesion (24, 239, 429).
Neurogenesis upregulation in the DG has been attributed to cell death in the entorhinal cortex or the CA1
region (46), a hypothesis not always verified (25, 315). It
has been proposed that the neuronal damage that follows
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ABROUS, KOEHL, AND LE MOAL
2. Pathologies associated with a downregulation
of neurogenesis
A) AFFECTIVE DISORDERS. In unipolar major depression,
bipolar mood disorders, and other chronic diseases associated with affective disorders [posttraumatic stress disorder (PTSD), Cushing’s disease], brain imaging studies
have consistently described hippocampal atrophy (60,
195, 329, 504, 518, 519, 550). Although a role for neuro-
Physiol Rev • VOL
genesis in mood disorders is speculative, it has been
suggested that a fall in neurogenesis in the DG contributes, together with atrophy and death of hippocampal
neurons, to hippocampal attrition.
I) Antidepressants. It has been suggested that biogenic amine deficiency underlies mood disorders, and
indeed, treatments increasing extracellular levels of serotonin or norepinephrine are effective in the remediation
of depressive symptoms. Because serotonin and norepinephrine stimulate cell genesis (see sect. IID2B and Table
1), and given that it takes weeks for antidepressants to
take effect, it has been proposed that they may exert their
action via a remodeling of neuronal networks by promoting either neurogenesis or the survival of hippocampal
neurons believed to be endangered (131). Chronic (and
not acute) treatments with different classes of antidepressants such as a selective serotonin reuptake inhibitor
(fluoxetine, 5 or 10 mg · kg⫺1 · day⫺1 for 11–28 days), a
selective norepinephrine reuptake inhibitor (reboxetine,
mg · kg⫺1 · day⫺1 for 21 days), a monoamine oxidase
inhibitor (tranylcypromine, 7.5 mg · kg⫺1 · day⫺1 the first
week and 10 mg · kg⫺1 · day⫺1 the second week), and
tricyclic antidepressants (TCAs, imipramine and desipramine: 20 mg · kg⫺1 · day⫺1 for 28 days) increase hippocampal cell proliferation evaluated 2 or 24 h after the
last BrdU pulse (1 ⫻ 75 mg/kg or 4 ⫻ 75 mg/kg every 2 h)
performed on the final day or 4 days after the treatment
(335, 483). Three weeks after labeling, most of the newly
born cells express NeuN (70%), independently of the
classes of antidepressants (335, 483). It was further
shown that a fluoxetine- but not an imipramine-induced
increase in cell proliferation is mediated by 5HT1A receptors, since it is abolished in mice lacking 5HT1A receptors
(483).
To determine effects of fluoxetine on cell survival,
BrdU (4 ⫻ 75 mg/kg spaced by 2 h) was administered
before intitiation of the chronic treatment (5 mg/kg for 14
days). Neither survival nor maturation of the cells, evaluated 28 days after the last BrdU injection, was influenced
by fluoxetine treatment (335). The preclinical contribution of hippocampal neurogenesis has been examined in
the learned helplessness paradigm, a classical animal
model for depression, and it was reported that inescapable stress induced a decrease in cell proliferation that
was reversed, together with behavioral despair, by a 7-day
course of fluoxetine (10 mg/kg) (334). A strongest link
between “depression” and neurogenesis was evidenced
following X-irradiation that blocked the effects of fluoxetine and imipramine on both novelty-suppressed feeding
(another test used to assess chronic antidepressant effects) and neurogenesis (483).
Although the etiologies of mood disorders are numerous, ranging from various environmental factors to genetic vulnerability, several lines of evidence suggest that
stress-induced cellular changes in the adult HF, mediated
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leukotrienes, another key class of inflammatory molecules, has been postulated in cell proliferation induced by
stroke (340). Finally, factors produced as part of the
ischemia-hypoxic response such as the cytokine erythropoietin (507) and the recently discovered “stem cell factor” (SCF) acting through the c-kit receptor tyrosine kinase (235), may also modulate neurogenesis after
ischemia.
In summary, enhancement of neurogenesis in the DG
and other brain regions may compensate for disconnected circuits that occur after ischemia and contribute to
the improvement of functional outcome. Exploiting this
plasticity potential of the ischemic brain may provide a
possible strategy for enhancing recovery in patients suffering from this injury.
C) HUNTINGTON’S DISEASE. Huntington’s disease (HD) is a
neurodegenerative disease that leads to neuronal loss in
the caudate-putamen. The discovery of progenitor cells in
the human brain (144) has raised the possibility that
progenitors from the SVZ may provide a source of replacement. Postmortem analysis of control and HD human brains has revealed that cell proliferation, evaluated
with PCNA, is increased in the subependymal layer in HD
brains as a function of the severity of the illness (103).
The newly generated cells expressed neuronal and glial
markers (Tuj1 and GFAP, respectively).
These pioneer data indicate that the diseased adult
brain is still capable of neuronal regeneration, which
opens new avenues in the treatment of neurodegenerative
diseases.
D) OTHER TYPES OF CEREBRAL INJURY. Traumatic brain injury
(TBI), the most common cause of death in developed
countries, increases cell proliferation in the SGZ (as well
as in the SVZ and the cortex; Refs. 107, 319, 459). The
number of newly born cells increases as early as 24 h
post-TBI; the cells accumulate over time and express
TOAD-64 and NeuN (65%) 9 and 21 days, respectively,
after the last BrdU injection (200 mg/kg for 9 days; Ref.
107). Similarly to what can be observed after ischemia,
DETA/NONOate administration (for 7 days starting 1 day
after TBI) to rats subjected to TBI significantly increases
proliferation, survival, migration, and differentiation of
neural progenitors in the DG (as well as other brain
structures) and significantly improves neurological functional outcome (319).
NEUROGENESIS IN THE ADULT BRAIN
Physiol Rev • VOL
IV) Summary. These results suggest that antidepressants, ECT, and mood stabilizers may exert some of their
therapeutic effects on mood disorders by stimulating neurogenesis. They also suggest that alternative strategies for
stimulating neurogenesis may provide new avenues for
the treatment of mood disorders. Since a fall in neurogenesis has been associated with an alteration in cognitive
functions, further studies are needed to clarify the involvement of neurogenesis, and hippocampal function, in
the development of cognitive deficits observed in depression in young and elderly patients.
B) SCHIZOPHRENIA AND NEUROLEPTICS. Developmental dysfunction of the HF is thought to play a major role in the
pathogenesis of schizophrenia (206, 488), and defects
such as a reduction in hippocampal volume (53, 400, 558),
hippocampal shape deformations (101), abnormalities in
the GCL (357), the MF pathway (170), the hippocampal
cell density (41, 150, 233) and orientation (93, 288), and in
several cellular markers (203, 313) have been reported.
These changes are believed to underlie the progressive
deficit in cognition that is a hallmark of schizophrenia.
Interestingly, models of aberrant neurogenesis (prenatal
stress, X-rays, or MAM manipulations) are thought to
reproduce some of the behavioral characteristics associated with schizophrenia (313).
The influence on neurogenesis of chronic treatment
with the typical neuroleptic haloperidol, a mainstay in the
treatment of schizophrenia, has been evaluated, leading
to controversial results. Indeed, haloperidol has been
shown to increase (110) or to have no effect (199, 335,
483, 562) on neurogenesis in the rodent DG. Differences in
dosage, time course of drug treatment, species and age of
the animals, and BrdU labeling protocol could account for
the observed discrepancy. On the other hand, chronic
treatment with atypical neuroleptics such as risperidone
(0.5 mg · kg⫺1 · day⫺1 for 21 days) or olanzapine (2 mg ·
kg⫺1 · day⫺1 for 21 days) increases cell proliferation (24 h
after 1 ⫻ 100 mg/kg BrdU on the 20th day of neuroleptic
treatment) in the SVZ but not in the DG (562). A low dose
of clozapine (0.5 mg · kg⫺1 · day⫺1 for 4 wk before a single
injection of BrdU at 200 mg/kg) enhances the number of
BrdU-IR cells in the DG; however, this effect is transient
as the newly born cells do not survive 3 wk after labeling.
Although these data clearly show that further work is
required to sort out discrepancies in results, they also
suggest that schizophrenia may be associated with reduced neurogenesis in the DG, where normal levels could
be reestablished by neuroleptic treatment, a hypothesis
that awaits confirmation.
C) ADDICTION TO DRUGS OF ABUSE. Long-term neuroadaptive
changes in the mesolimbic dopaminergic system have
classically been observed in drug abuse (283, 402). A
potential role of the HF in addiction has been suggested
based on the observation that both a reduction in hippocampal volume and structural abnormalities are ob-
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by an upregulation of the HPA axis, contribute to the
pathophysiology of these disorders, at least in animal
models. The impact of antidepressants on neurogenesis
was therefore tested in various stress models. In adult
male tree shrews exposed to chronic psychosocial stress
(see sect. IIIB1), chronic treatment with tianeptine (50
mg · kg⫺1 · day⫺1 for 28 days), a modified TCA, reversed
the stress-induced decline in hippocampal volume, hippocampal activity, and hippocampal neurogenesis (104).
In rat pups, fluoxetine treatment (5 mg/kg for 7 days
concurrent with 50 mg/kg BrdU) counteracted the downregulation of cell proliferation observed in the DG of
2-wk-old maternally separated pups (300). In a chronic
mild stress model (CMS; see sect. IIIB1), chronic treatment with the antidepressant fluoxetine (10 mg/kg for 28
days starting 3 wk after the beginning of the CMS) reversed the stress-induced reduction of cell proliferation
and prevented the stress-induced reduction of neurogenesis and hippocampal atrophy (10).
II) Electroconvulsive therapy. Electroconvulsive
therapy (ECT) is one of the most effective treatments for
major depression, especially in subjects who do not respond to antidepressants, but its mechanisms of action
remain largely unknown. Electroconvulsive seizure (ECS)
differs from kindling and chemoconvulsant treatments in
that it does not lead to an epileptiform state and does not
cause cell death. ECS (one daily for 10 days) enhances (2
or 24 h after a BrdU pulse) cell proliferation in the DG,
and the newly born cells survive for at least 3 mo, a time
point when most of them express NeuN (75%) and few
GFAP (13%) (331, 335). This proliferative effect is dosedependent as a series of seizures further increases neurogenesis (331). The neurogenic efficacy of ECS has been
investigated in conditions mimicking stress-induced depression, i.e., in animals with high corticosterone levels.
The downregulation of neurogenesis (75%) in the GCL of
rats chronically treated with corticosterone was eliminated by ECS performed at the end of the treatment (212).
Because ECS upregulates several factors described as
stimulating neurogenesis, such as bFGF, neuropeptide Y,
VEGF, BDNF, and Cox-2 (404, 406), these factors are
likely mediators of the proliferative effect of ECS. Among
them, BDNF deserves special mention as ECS-induced
MFS is diminished in BDNF knockout mice (549).
III) Mood stabilizers. Chronic treatment with lithium
can reverse the hippocampal attrition in sufferers of manicdepressive illness (MDI) and enhance the levels of Nacetylaspartate, a putative marker of neuronal viability
(375, 376, 544). Chronic treatment of mice with lithium
(2.4 g/kg during 3– 4 wk) increases the number of BrdUlabeled cells by 25% 1 day after BrdU treatment (1 ⫻ 50
mg/kg over 12 days), two-thirds of which coexpress
NeuN. Interestingly, the expression of bcl-2, an antiapoptotic regulator, is also increased suggesting that survival
of the newly born neurons might be enhanced (84).
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of nicotine abuse on hippocampal neurogenesis, rats were
trained to self-administer nicotine (0.02, 0.04, and 0.08
mg · kg⫺1 · infusion⫺1) for 42 days. A profound decrease
in hippocampal cell proliferation was observed for the
two highest doses of nicotine 1 day after BrdU pulse (4 ⫻
50 mg/kg on days 39 – 41). This effect is not simply due to
a difference in blood flow leading to a decrease in BrdU
availability, since nicotine intake does not affect cell proliferation in the SVZ. Half of the newly born cells in the
DG were found to express NeuN. In parallel with the
decrease in cell proliferation, cell death, measured by the
number of pyknotic cells, was increased by the two highest nicotine doses (3). Similar results were obtained following imposed administration of nicotine (1 mg · kg⫺1 ·
day⫺1 for 3 days concurrent with 50 mg/kg BrdU) to
adolescent rats (230). Although the mechanisms involved
in the effects of nicotine have not yet been investigated,
nicotine could act directly on nicotinic acetylcholine receptors that are present on immortalized hippocampal
progenitor cells (44), or indirectly through an upregulation of the HPA axis (67) and/or a downregulation of the
serotoninergic system (43).
III) Alcohol. The possibility that alcohol brings about
damage in the adult brain by disrupting neurogenesis has
been examined. Thus both acute (gavage with 5 g/kg
ethanol) and chronic (ethanol infusion 3 times/day over 4
days for a mean dose of 9.3 g · kg⫺1 · day⫺1) binge alcohol
treatments halve cell proliferation in the SGZ of the DG
within 5 h (409). Furthermore, after 28 days, chronic
binge treatment decreases the survival rate of the newly
born cells (409). In contrast, in animals fed for 6 wk with
a moderate dose of ethanol (6.4% vol/vol), the number of
newly born cells (labeled by 7 BrdU injections at 2-h
intervals) is not reduced when animals are killed 1 h after
the last BrdU injection (218). In fact, the number of
nascent cells decreases only after 2 wk suggesting that, in
this experimental model, cell survival, rather than cell
proliferation, is affected by ethanol exposure, a hypothesis that was confirmed by showing that cell death was
dramatically increased in the DG. Finally, these effects
are specific to the DG as bulbar neurogenesis is not
influenced by chronic alcoholism. Similar results were
obtained with imposed injections of alcohol to adolescent
rats (1 mg · kg⫺1 · day⫺1 for 3 days concurrent with 50
mg · kg⫺1 · day⫺1 BrdU), which led to a downregulation of
hippocampal cell proliferation and increased cell death
(230). Furthermore, coadministration of alcohol with nicotine reduces cell proliferation and cell death more potently than treatment with either one of the agents (230).
Although these effects of ethanol could be mediated by
NMDA or GABAA receptors (224), oxidative stress might
also play a role since the antioxidant ebselen, used in the
treatment of cognitive disorders of alcoholic patients,
prevents ethanol effects on hippocampal neurogenesis
(218).
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served in patients with chronic alcoholism (4, 112, 357,
524) and in psychostimulant addicts (33). In animals,
chronic treatment with different drugs of abuse leads to
structural changes in the HF (308, 432, 461, 463), to cell
loss (563), and to LTP alterations (109, 158, 191, 200, 202,
449). The possible involvement of the HF in addiction is
supported by the observation that 1) inhibiting the activity of the calcium/calmodulin-dependent protein kinase II
impairs drug conditioning (321, 535) and attenuates the
dependence on morphine and relapse (321), 2) dorsal
hippocampal lesions disrupt acquisition of cocaine conditioning (365), 3) electrical stimulation of the glutamatergic efferent pathway of the HF to the nucleus accumbens reinstates cocaine-seeking behavior (561) and Damphetamine self-administration behavior (533), and 4)
inactivation of the ventral subiculum decreases reinstatement of cocaine-seeking behavior (525). These results
suggest that memory traces of the association between a
specific context and the availability of the drug could be
stored in the HF, and the hypothesis that drug addiction is
an aberrant form of learning mediated by maladaptive
recruitments of hippocampal-dependent memory system
has recently gained interest (45, 147, 401, 462, 571). In this
context, the involvement of neurogenesis in addiction has
been studied by examining the influence of several drugs
of abuse on adult hippocampal neurogenesis and by comparing neurogenesis in animals that differ in their vulnerability to developing drug abuse.
I) Opiates. Among the multiple actions of opiates in
the brain, their influence on cognition and reward is without a doubt the most relevant parameter with regard to
opiate addiction. Eisch et al. (137) were the first to demonstrate that the exogenous chronic (daily implantation
of subcutaneous pellets containing 75 mg morphine during 5 days) and not acute (10 mg/kg) administration of
morphine decreases cell proliferation in the GCL by 28%
(measured 2 h after an injection of BrdU, 100 mg/kg, on
day 6). When cells are allowed to mature for 4 wk,
survival of BrdU-labeled cells is halved and 90% of the
newly born cells differentiate into neurons. More relevant
to addiction, the influence of heroin self-administration
has been investigated. After 26 days of heroin intake (60
␮g · kg⫺1 · injection⫺1), a downregulation of cell proliferation (⬃30%) is observed in both the GCL and the hilus
while cell death is unaffected. The downregulation of cell
proliferation is independent of corticosterone secretion
(137), a hormone known to have a major influence in
addiction (343). Finally, it was recently reported that in
vitro reduced signaling through ␮- and ␦-opioid receptors
present on adult hippocampal progenitors, although decreasing cell proliferation, leads to a net increase in the
number of newly generated neurons (437).
II) Nicotine. The neuroactive compound nicotine is
considered to be responsible for the development and the
maintenance of tobacco addiction. To analyze the effects
NEUROGENESIS IN THE ADULT BRAIN
Physiol Rev • VOL
or during drug withdrawal (211). Because drug-seeking
and -taking behaviors are sensitive to the presence of
drug-associated stimuli (contextual cues), initially low
hippocampal plasticity and a drug-induced decrease in
hippocampal plasticity may be involved in the vulnerability and the maintenance of drug abuse. Changes in hippocampal activity could lead to a dysregulation of the
dopaminergic mesoaccumbens reward system (283, 402)
through the hippocampal glutamatergic output that gates
information in the nucleus accumbens (173) and/or
through the hippocampal glutamatergic output to the
mesencephalic dopaminergic cell bodies. Indeed, stimulation of the ventral subiculum increases the firing of
dopaminergic neurons (51) and enhances dopamine release within the nucleus accumbens (302). Finally, drugtaking in subjects vulnerable to drug addiction most probably further increases corticosterone secretion, stimulates the dopaminergic reward system, and decreases
hippocampal neurogenesis, thereby constituting a pathophysiological loop.
IV. CONCLUSION
The discovery of neoneurogenesis in discrete areas
of the adult brain has opened up an extremely interesting
field of research in itself. Indeed, although it was initially
confronted with the universal belief that after a certain
period of development neither neural cell genesis nor
divisions were any longer possible, it now constitutes a
prototypic model of developmental neuroscience. The
study of the mechanisms that preside over cell proliferation, migration, differentiation, and survival is essentially
performed in the SVZ-OB paradigm as these phenomena
occur in distinct compartments (cell proliferation in the
SVZ, migration in the RMS, differentiation in the OB) thus
rendering their analysis easier. However, the evaluation
of their behavioral consequences is most frequently examined in relation to the HF (with the exception of Ref.
464).
To conclude, the main issues raised by neurogenesis
are as follows.
1) From a cellular point of view, a true characterization, and thus definition of stemlike and progenitor cells
in the adult brain is still lacking. Although immense
progress has been achieved in the description of different
cell types (and their properties) in the SVZ, no consensus
has been reached. Furthermore, although it has been
suggested that adult neural stemlike cells could behave
similarly to embryonic stem cells as far as the generation
of neurons and differentiation into any neuronal type are
concerned, little is known regarding their intrinsic properties and the nature of the signals that lead to the generation of neurons in the adult brain. It is expected that
functional genomic technologies may help in defining the
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IV) Cannabinoid. Derivatives of cannabis sativa
such as marijuana are acknowledged to be the most commonly used illicit drugs (336). The structure of their active
components, the cannabinoids, the identification in the
brain of the cannabinoid-1 (CB1) receptors, and the isolation of an endogenous substance acting on these receptors, the endocannabinoid anandamide, have been reported only recently. It has been suggested that the CB1
receptors that are expressed in the HF by the GABAergic
interneurons are important in learning and memory (109).
Chronic treatment with anandamide (5 mg · kg⫺1 · day⫺1
for 4 days) inhibits neurogenesis in the DG by decreasing
the number of newly born cells that differentiate into
granule neurons 12 days after the cessation of the treatment (100 mg/kg BrdU on day 2). Conversely, blocking
the endogenous cannabinoid tone with SR14716 (1 mg ·
kg⫺1 · day⫺1 together with anandamide), an antagonist of
the CB1 receptors, increases hippocampal neurogenesis
by favoring neuronal differentiation (476). These effects
are in accordance with a potentiality to modulate neural
cell fate (197) in particular through the ERK signaling
pathway (476). In addition to showing that endocannabinoids constitute a physiological system regulating neurogenesis, these data raise the possibility that cannabinoid
addiction could be associated with an alteration in hippocampal neurogenesis.
V) Neurogenesis as a substrate for vulnerability to
addiction. The high responder rats (see sect. IIIB2) and
the prenatally stressed rats (see sect. IIIB3) characterized
by curtailed neurogenesis share some similarities that are
relevant to drug addiction. Indeed, the HRs spontaneously
develop amphetamine (443, 445) or nicotine (528) selfadministration behavior, and prenatally stressed rats exhibit greater sensitivity to the psychomotor-stimulant effects of nicotine (279) and amphetamine (215) and are
more vulnerable to drug addictive effects as they develop
intravenous amphetamine self-administration (116). Thus
subjects starting off with the lowest neurogenesis may be
most vulnerable to the development of addictive behavior. It is noteworthy that there is high comorbidity between drug abuse and many psychiatric illness, among
which depression and schizophrenia (34, 152). Because
hippocampal neurogenesis is reduced in preclinical models of these pathologies, it may be hypothesized that
impaired hippocampal neurogenesis may constitute a potential substrate for vulnerability to drug abuse, depression, and schizophrenia (see also Fig. 8).
VI) Conclusions. The downregulation of hippocampal neurogenesis, together with other maladaptive plasticity processes, i.e., dendritic remodeling and synaptic
plasticity modifications, are associated with permanent
functional alterations in behavioral inhibition and learning, hallmarks of addiction. An alteration in hippocampal
plasticity could be responsible for the cognitive deficits
that appear in the course of the “illness” (88, 109, 133, 194)
553
554
ABROUS, KOEHL, AND LE MOAL
rogenesis and experimentally induced cell proliferation,
cell death, and cell survival) and to other parameters
related to the anatomical (e.g., the presence of synaptic
contacts) and functional (electrophysiological properties, ERK phosphorylation, immediate early gene activation . . .) integration of new neurons into the preexisting
networks. Finally, the contribution of newly born neurons
to the functioning of the HF and its output should be
evaluated as well as their influence on the activity of other
related structures (e.g., the frontal cortex).
6) Functional evaluation of hippocampal neurogenesis has, in fact, been the object of relatively few studies
that have been restricted to a limited number of behavioral tasks (mainly the Morris water maze). A more complete diversified behavioral analysis is therefore necessary to understand the contribution of neurogenesis to
hippocampal functioning.
7) Except for the elegant work of Shors et al. (509),
which relies on the use of MAM which is unfortunately a
highly toxic compound, most studies correlate changes in
rates of neuron addition with behavioral changes, in particular cognitive functions. Thus it is not clear whether
these changes are coincidental or coregulated. A more
direct approach to address the existence of a causal relationship between behavioral changes and neurogenesis
will probably depend on the development of inducible
FIG. 7. Variation of hippocampal functioning as a
function of hippocampal neurogenesis and associated
pathological states.
Physiol Rev • VOL
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transcriptional program of neural progenitors and the
changes in gene expression in progenitors over time (105,
323).
2) Future studies will have to better characterize the
early development of adult-born neurons to dissect the
steps that are influenced by experience and vulnerable to
traumatic conditions (stress, drug, epilepsy. . .). This
raises the problem of tracking the fate of adult-born cells
using BrdU, [3H]dT, or a retrovirus, which may alter the
functioning of the adult-born neurons under investigation.
3) Undoubtedly one of the most interesting sets of
data accumulated concerns the factors that powerfully
regulate neurogenesis. However, the mechanisms by
which these regulations are exerted in the normal and
pathological brain remain obscure.
4) Although most work is focused on the generation
of glutamatergic excitatory granule neurons in the adult
DG, the recent discovery that GABAergic inhibitory neurons are also produced raises the important possibility
that external factors (from molecules to modifications in
animals’ environments) might diversely affect the genesis
of either type of neurons and thus have distinct functional
consequences.
5) Functional studies are too often restricted to the
evaluation of a single parameter; they should be extended
to the different components of neurogenesis (basal neu-
NEUROGENESIS IN THE ADULT BRAIN
555
transgenic models allowing a structure-specific blockade
of neurogenesis at a given time during behavioral testing.
However, this approach is a real challenge since it is
based on the invalidation of the crucial genes controlling
neurogenesis site specifically, which have not yet been
identified.
8) From a phylogenetic point of view, the apparent
reduction in neuropoiesis, when moving from rodents to
primates, raises the question of the associated evolutionary advantage.
9) From studies that have correlated changes in rates
of neuron addition with hippocampal functioning, an inverted U curve shape can be proposed (see Fig. 7). Thus
adult neurogenesis may be beneficial for adult brain functioning only within a physiological adaptive range. Beyond a critical level of neurogenesis, which is over passed
by stressful life events, aging, and drug abuse, dysfunction
appears. On the other hand, the addition of adult-born
neurons above a critical set point (i.e., following epileptiform status) may lead to pathological states and behavioral impairments most probably by introducing noise in
the networks, as a consequence of ectopic connectivity.
10) Within this framework, it is not known whether
an alteration in neurogenesis is the cause or the result of
psychiatric illness (Fig. 8). Indeed, in preclinical studies it
has been shown that phenotypes vulnerable to the development of affective or cognitive disorders are characterized by lower hippocampal neurogenesis. It may be hypothesized that these subjects who start off with impaired
neurogenesis may be predisposed to the development of
affective disorders, addictive behavior, and age-related
Physiol Rev • VOL
cognitive disorders. Alternatively, the onset of pathology
could produce changes in brain plasticity by acting
through several mechanisms (for example, stress and
HPA activity are important mediators in the genesis of
cognitive impairment, depression, addiction). Repeated
“traumatic” episodes, together with a genetic predisposition, may lead to reduced neurogenesis and participate in
the worsening of the symptoms. Although these propositions are highly speculative, they highlight the fact that
treatments that increase neurogenesis may help to cure or
prevent the development of affective and/or cognitive
disorders.
Address for reprint requests and other correspondence: D. N.
Abrous, INSERM U588, Univ. of Bordeaux 2, Institut François
Magendie, 146 rue Léo Saignat, 33077 Bordeaux Cedex,
France (E-mail: [email protected]).
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