REVIEW

Mechanisms of Neurogenesis in the Normal andInjured Adult Brain
Masato Sawada and Kazunobu Sawamoto

Department of Developmental and Regenerative Biology,
Nagoya City University Graduate School of Medical Sciences, Aichi, Japan(Received for publication on March 28, 2012)(Accepted for publication on May 18, 2012)

Even in the adult brain, new neurons are continuously generated from endogenous neural stem cells
that reside in two restricted regions: the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus. These new neurons are integrated into the mature neuronal circuitry
and become involved in various functions, thereby contributing to structural and functional plasticity
in the adult brain. In this review, we summarize our recent findings on the regulatory mechanisms of
SVZ neurogenesis under physiological and pathological conditions in various animal models. Some ofthese findings were presented in the Kitazato Prize Lecture at Keio University School of Medicine in
2011. (doi: 10.2302/kjm.2012-0005-RE; Keio J Med 62 (1) : 13–28, March 2013)
Keywords: adult neurogenesis, subventricular zone

Introduction

mals, and might be exploited for therapeutic strategies inhumans. In this review, we introduce our recent findings
on SVZ neurogenesis in the physiological and pathological conditions of various animals.

Until recently, it was commonly believed that the adultbrain does not produce new neurons. However, it is now
well accepted that neural stem cells continue to reside in
the subventricular zone (SVZ) of the lateral ventricle anddentate gyrus (DG) of the hippocampus, and that they
produce functional neurons in the adult brain throughout
life. In the SVZ, which is the largest neurogenic region in
the adult brain, neural stem cells continuously generate
new neurons via transit-amplifying neural progenitors.
The new neurons form chain-like cell aggregates and migrate toward the olfactory bulb (OB) through the rostralmigratory stream (RMS), a specialized route for migrating neurons. After arriving at the OB, the new neurons
differentiate into olfactory interneurons, which are implicated in olfactory processing. Recent studies demonstrated that this neurogenic potential in the adult brain
is widely conserved from nonmammalian vertebrates toprimates, including humans. Interestingly, SVZ neurogenesis can be activated by various injuries and neurological diseases, suggesting that endogenous neural stem
cells in the SVZ may be used for brain repair in lower ani-

Neural Stem Cells in the Subventricular Zone
In the adult rodent SVZ, there are four distinct typesof cells: ependymal cells (type E cells), astrocytes (typeB), transit-amplifying cells (type C), and migrating neuroblasts (type A) (Fig. 1).1,2 Ependymal cells line thewall of lateral ventricles and have multiple motile cilia.
The beating of these cilia is involved in controlling the
cerebrospinal fluid flow in the lateral ventricles. Glial
fibrillary acidic protein-positive (GFAP+) astrocytes in
the SVZ generate new neurons and oligodendrocytes.3 In
vitro, these cells exhibit the two distinct characteristics
of stemness: multipotency and self-renewal. Moreover, a
recent study demonstrated that individual radial glia-like
GFAP+ cells self-renew and generate neurons and astrocytes in the adult DG, indicating that they have the potential to function as adult neural stem cells in vivo.4 However, differentiative potentials of individual SVZ astrocytes

Reprint requests to: Kazunobu Sawamoto, PhD, Department of Developmental and Regenerative Biology, Nagoya City University Graduate
School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho, Nagoya, Aichi 467-8601, Japan, E-mail: sawamoto@med.nagoya-cu.ac.jp
Copyright © 2013 by The Keio Journal of Medicine
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Sawada M and Sawamoto K: Neurogenesis in the Adult Brain

Fig. 1 Neurogenesis in the adult subventricular zone.
In the subventricular zone (SVZ) of the lateral ventricle, there are four distinct types of cells: ependymal cells (purple), astrocytes(blue), transit-amplifying cells (green), and neuroblasts (red). SVZ astrocytes contact the lateral ventricle and act as neural stem cells
that generate neural progenitors called transit-amplifying cells. The transit-amplifying cells actively proliferate and generate neuroblasts. Blood vessels surrounding these cells have important roles in regulating neurogenesis in the SVZ. Neuroblasts generated in the
SVZ migrate toward the olfactory bulb (OB) through the rostral migratory stream (RMS). These cells form chain aggregates, which aresurrounded by tunnels composed of astrocytic processes. After arriving at the OB, the chain-forming neuroblasts are dissociated into
individual cells and migrate radially inside the OB. Most of the neuroblasts differentiate into granule cells (pink) and form synapses
with mitral/tufted cells (yellow), which are projection neurons in the OB. A small portion of the neuroblasts continue their radial migration to the glomeruli located in the superficial layer of the OB, where they differentiate into periglomerular cells (orange) and form
synapses with both olfactory sensory neurons (gray) and the mitral/tufted cells.

in vivo have yet to be clarified. In addition, the precise
identification and classification of neural stem cells in theadult SVZ are still difficult because of the lack of an adultneural stem cell-specific marker. Like embryonic neuralstem cells, GFAP+ astrocytes in the adult SVZ express
neural stem cell markers, including Musashi, LeX/ssea-1,
Sox2, Id, and Nestin.1,5–9 GFAP+ astrocytes in the SVZ
proliferate very slowly and generate rapidly dividing
transit-amplifying progenitors that generate migratingneuroblasts. In addition, blood vessels in the SVZ thatare in contact with these cells play important roles in thecontrol of neurogenesis.10–13
Several extracellular signals and their downstream
pathways cooperatively regulate cell proliferation anddifferentiation in the SVZ. Because SVZ cells are packed
into narrow regions lining the lateral ventricles and are inclose contact with each other, cell–cell interaction signals
could affect their proliferation state. For example, cellsurface carbohydrates could regulate the intercellularinteractions of adult neural stem cells in the SVZ. The
carbohydrate-binding protein Galectin-1, a key regulator of various stem cells, is secreted by the majority of
GFAP+ astrocytes in the adult SVZ.14 Cell proliferationin the SVZ is reduced by galectin-1 deficiency and activated by the infusion of exogenous Galectin-1, indicatingthat Galectin-1 positively regulates the proliferation ofneural stem cells in the SVZ. The Eph-ephrin system isalso important for intercellular interaction. The receptor
tyrosine kinases EphA/B are expressed in the SVZ andregulate cell proliferation, although their downstream
signaling molecules are currently unknown.15
Notch signaling is another key factor in many cell–cellinteraction systems. During embryonic brain development, Notch is the most critical regulator of neural stemcell maintenance. Ligand binding to Notch induces cleavage of the Notch intracellular domain, which translocates
into the nucleus and induces the expression of transcriptional repressor proteins such as those encoded by theKeio J Med 2013; 62 (1): 13–28

Hes gene family, which repress the activities of proneuralgenes. One Notch ligand, Delta-like homologue 1 (Dlk1),
is expressed by GFAP+ astrocytes in the postnatal SVZ
and is required for the maintenance of neural stem cells.16
Even in the adult brain, Notch signaling activity is observed in GFAP+ astrocytes in the SVZ. The conditional
knockout of Rbpj, a Notch-signaling component, in the
Nestin-expressing cell lineage causes the complete lossof neural stem cells in the SVZ, indicating that Notch
signaling is also important for the maintenance of neuralstem cells in the adult SVZ.17 Interestingly, Notch signaling in neural stem cells in the SVZ is modulated byother extrinsic factors. For example, enhanced epidermal
growth factor receptor (EGFR) signaling reduces both
Notch1 expression and the number of GFAP+ neural stem
cells in the SVZ, and it increases the number of transitamplifying cells, suggesting that interplay between the
Notch and EGFR pathways regulates the balance of thenumber of neural stem/progenitor cells.18 In addition,
pigment epithelium-derived factor, which is secreted
from ependymal cells and blood vessels in the SVZ, enhances the Notch-dependent transcription of target genes,
including Hes1 and Egfr, in GLAST+Sox2+ neural stem
cells with low Notch activity, suggesting that a vascular
modulation of neural stem cells in the adult SVZ is mediated by Notch signaling.19,20
Because neural stem cells are widely distributed
throughout the SVZ and generate various types of OB
neurons, it is possible that they have distinct regional
identities. The precise regional labeling of neural stem
cells by adenovirus injection revealed that neuronal fatesin the OB are pre-determined by the region of the SVZ
inhabited by their precursors.21 Sonic hedgehog (Shh)signaling, which is the determinant for the ventral axis inearly neural development, is restricted to the ventral region of the adult SVZ.22,23 Shh signaling also determines
the ventral specification of neural stem cells, which generate specific neuronal progeny in the OB.24 Bone morphogenic protein (BMP) signaling, which is the determinant of the dorsal axis in the embryonic brain, is also
involved in neurogenesis in the adult SVZ,25 althoughwhether this signaling determines the dorsal specification of neural stem cells is currently unknown. Thus, inaddition to Notch signaling, the regional specification bydorsoventral determinants such as Shh and BMP signaling could regulate the proliferation of neural stem cells
and contribute to the diversity of neuronal progeny.
Wnt proteins are important soluble regulators of mammalian neural development and have two distinct downstream pathways. The canonical Wnt pathway is mediated by β-catenin, which acts as both a cytoskeletalcomponent and a transcription factor. In the absence ofWnt stimulation, β-catenin is phosphorylated by casein
kinase I and GSK3β and is constantly degraded by theubiquitin–proteasome system. However, Wnt-mediatedinhibition of GSK3β blocks this degradation of β-catenin;

15

the unphosphorylated β-catenin then translocates into the
nucleus, where it promotes the transcription of developmentally important genes. On the other hand, the noncanonical Wnt pathway is mediated by Wnt/planar cell
polarity (PCP) signaling, which mainly regulates cytoskeletal dynamics and cell polarity through c-Jun N-terminal kinase (JNK) and Rho GTPase. However, the rolesof these distinct Wnt pathways in the adult SVZ werecompletely unknown until recently.
Using Axin2-d2EGFP mice, in which the activation of
β-catenin signaling can be monitored in vivo, we foundthat canonical Wnt/β-catenin signaling is activated in astrocytes and transit-amplifying cells in the adult SVZ.26
The injection of a retrovirus carrying a constitutively active form of β-catenin or a highly selective GSK3β inhibitor, both of which activate Wnt/β-catenin signaling,increased the proliferation of transit-amplifying cells,
which ultimately led to an increased number of newneurons in the OB. These results indicated that Wnt/βcatenin signaling positively regulates the proliferation ofneuronal progenitors in the adult SVZ (Fig. 2).
Diversin, the mammalian homolog of the Drosophila
PCP protein Diego, is a component of both canonicaland non-canonical Wnt signaling (Fig. 2). We found that
Diversin is expressed by neuroblasts in the neonatal andadult SVZ and DG.27 In the adult SVZ, retrovirus-mediated overexpression of full-length Diversin increased theproliferation of neuroblasts. A mutant Diversin lacking
the ankyrin repeat domain, which is important for activating the Wnt/PCP pathway, did not have this activity,
suggesting that the Wnt/PCP pathway is necessary for the
proliferation of neuroblasts. Interestingly, phosphorylated JNK, a downstream component of the Wnt/PCP pathway, could be observed in neuroblasts undergoing mitosis. Taken together, these results suggest that the Wnt/
PCP pathway is active in the proliferation of neuroblasts(Fig. 2).
Thus, the two Wnt pathways have distinct functions inregulating the proliferation of transit-amplifying cells andneuroblasts in the SVZ (Fig. 2). Canonical Wnt/β-cateninsignaling controls the proliferation of transit-amplifying
cells, whereas the non-canonical Wnt/PCP pathway regulates the proliferation of neuroblasts. Since Diversin is
involved in both the canonical and non-canonical Wnt
pathways, it could act as a molecular switch for the transition from neuronal progenitors to migrating neuroblasts
in the SVZ.
Neuronal Migration in the Rostral Migratory Stream
Neuroblasts generated from neural stem cells migrate
at high speed from the SVZ toward the OB (Fig. 1). Thesecells form elongated cell aggregates called “chains.”28 In
the chains, each neuroblast migrates along its neighbors,
indicating that neuroblasts use other neuroblasts as a
scaffold for efficient migration. In the lateral wall of the16

Sawada M and Sawamoto K: Neurogenesis in the Adult Brain

Fig. 2 Regulation of SVZ neurogenesis by Wnt signaling.
Wnt proteins have two distinct downstream signaling pathways. The canonical Wnt pathway is mediated by β-catenin. In the absenceof Wnt stimulation, β-catenin is constantly phosphorylated by casein kinase I/GSK3β complex and degraded by the ubiquitin-proteasome system. This process is inhibited by Wnt-mediated inhibition of GSK3β; the unphosphorylated β-catenin then accumulates in
the cytosol and translocates into the nucleus. In the adult SVZ, Wnt/β-catenin signaling is activated in the astrocytes and transit-amplifying cells and regulates their proliferation. The non-canonical Wnt pathway is mediated by Wnt/planar cell polarity (PCP) signaling,which regulates cytoskeletal dynamics and cellular polarity through JNK and Rho family small GTPases. Diversin is a component ofboth the canonical and non-canonical Wnt signaling pathways. The Diversin-mediated Wnt/PCP pathway regulates the proliferationof neuroblasts in the adult SVZ.

lateral ventricle in the adult brain, an extensive networkof neuronal chains can be observed, which converge into
bundles of chains when entering the RMS, a restricted
pathway for migrating neuroblasts.29 In the RMS, thechain-forming migrating neuroblasts are surrounded bytunnels formed by astrocytic processes. The chain formation of migrating neuroblasts and surrounding glial tubes
are two distinct features of the adult RMS (Fig. 1).30
Several proteins that regulate chain formation havebeen identified. For example, mice lacking the cellsurface receptors ErbB4 and ApoER2 show defective
chain formation and migration in the RMS, resulting
in decreased numbers of newly arriving neurons in the
OB.31,32 Extracellular matrix-related molecules such asα6β1-integrin and ADAM2 protease are also involvedin neuroblast chain formation.33–35 These findings raise
the possibility that various extracellular stimuli actively
regulate the chain formation of neuroblasts.

Keio J Med 2013; 62 (1): 13–28

To migrate at high speed within the neuronal chains, thechain-forming neuroblasts need to slide along each otherefficiently. Polysialylated neural cell adhesion molecule(PSA-NCAM), a cell adhesion molecule with a negatively
charged polysialic acid (PSA) moiety, is highly expressedon the cell surface of chain-forming neuroblasts in the
RMS. NCAM gene deletion or enzymatic digestion of the
PSA moiety cause migrating neuroblasts to accumulate
in the RMS without any defect in chain formation.36,37
The negative charge of the PSA moiety might increase
the cellular motility by decreasing the adhesion between
neuroblasts, leading to smooth chain migration in theRMS.38Since chain-forming neuroblasts must migrate over along distance from the SVZ to the OB, the determination of directionality is important for their appropriate
migration. We demonstrated that the direction of migrating neuroblasts in the SVZ is determined by the repulsive
factor Slit,39 which is reported to control axonal guidance in the developing brain by regulating the cytoskeleton.40,41 Several studies have shown that Slit is secreted
from the septum and choroid plexus and can repel migrating neuroblasts generated in the SVZ.42–44 However, themechanism by which the Slit proteins reach the migratingneuroblasts in the SVZ was not known.
We found that migrating neuroblasts in the SVZ follow
the direction of cerebrospinal fluid (CSF) flow created by
the beating of ependymal cilia.39 Exogenous Slit protein
injected into the lateral ventricle formed a concentration
gradient within the dorsal SVZ, with the highest signal
in the caudal region and the weakest in the rostral area,
in parallel with the direction of CSF flow (Fig. 3A). The
Tg737orpk mouse, a mutant strain with cilia-formation defects, showed an impaired Slit gradient and disoriented
chain migration in the SVZ (Fig. 3A). These results suggest that the concentration gradient of Slit in the SVZ
created by the beating of ependymal cilia determines the
direction of migrating neuroblasts.
Our findings indicated that the beating of ependymal
cilia plays an important role in neuronal migration in
the SVZ. During the early postnatal stage, the developing ependymal cells acquire two types of cellular polarity, translational and rotational polarity.45,46 The anterior
migration of basal bodies (translational polarity) andcoordinated ciliary beating (rotational polarity) in theependymal cells are both important for appropriate ciliary beating and the formation of CSF flow. We showedthat non-muscle myosin II and the Wnt/PCP pathway
distinctly regulate the processes responsible for generating translational and rotational polarity, respectively.47,48
These results suggest that the distribution and orientationof basal bodies are regulated by distinct mechanisms, andthat both contribute to the control of CSF flow.
Although repulsive mechanisms could be crucial forneuroblast movement from the SVZ toward the RMS,
such mechanisms seemed less effective for cells migrat-17

ing in the RMS toward the OB because of the long distances involved. Instead, attractant factors released fromthe OB could be involved in directionality in the RMS.
The secreted protein prokineticin 2 (PK2) is expressed in
the granule and glomerular layer of the OB, whereas PK2
receptor (Prokr2) is expressed in the neuroblasts migrating in the RMS.49,50 PK2 knockout and Prokr2 mutant
mice show an accumulation of migrating neuroblasts in
the rostral RMS, indicating that PK2 is a possible attractant for neuroblasts toward the OB.49,50 Other growth/trophic factors such as hepatocyte growth factor, brain-derived neurotrophic factor (BDNF), glial cell line-derived
neurotrophic factor, and Netrin-1 also show attractant activity for neuroblasts in vitro, although in vivo evidence
for their involvement remains to be demonstrated.51–54
In the RMS, neuroblasts move inside the glial tube,
which is reported to support their long-distance cell migration through intercellular molecular interactions. For
example, the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) secreted by migrating neuroblasts
is taken up by the RMS astrocytes, leading to negative
regulation of the migration speed.55 Conversely, glutamate released by RMS astrocytes activates N-methyld-aspartate receptor in the migrating neuroblasts, which
promotes their survival before they enter the synaptic
network in the OB.56 RMS astrocytes also interact withblood vessels inside the glial tube and capture BDNF secreted from endothelial cells, which leads to the vasculature-associated migration of neuroblasts in the RMS.57,58
It was reported that Slit1 and its receptors Robo2/3, whichmediate the repellant properties of Slit1, are expressed bymigrating neuroblasts in the RMS, suggesting that Slit1
has a cell-autonomous role in the RMS.59 We showed that
Robo2 is strongly expressed by tunnel-forming astrocytes
in the RMS. Slit1-secreting migrating neuroblasts repel
the Robo-expressing astrocytes to actively regulate theastrocytes’ morphology, leading to efficient neuroblast
migration.60 In the RMS of Slit1-/- mice, cellular organization and neuronal migration are disturbed (Fig. 3B). To
examine whether neuroblasts regulate the formation of
the glial tube, we eliminated migrating neuroblasts pharmacologically by Ara-C treatment. After the eliminationof migrating neuroblasts, the glial-tube structure became
disorganized (Fig. 3B). These results indicated that Slit–
Robo-mediated repulsive signaling is required for boththe efficient migration of neuroblasts and the formationof the glial tube in the RMS.
Extracellular cues, such as Slit proteins, dynamicallyreorganize the cytoskeleton of each migrating neuroblast
through various intracellular pathways. Migrating neuroblasts have a bipolar shape with a long leading process
and a short trailing process. Because neuroblasts migrate
in a saltatory manner, with repeated steps of leading-process extension followed by movement of the cell soma,
it is necessary to maintain the cell polarity and cooperatively regulate the cytoskeleton of each neuroblast. For

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Sawada M and Sawamoto K: Neurogenesis in the Adult Brain

Fig. 3 Slit-mediated regulation of neuronal migration in the SVZ and RMS.
(A) In the lateral ventricles of wild-type mice, the beating of ependymal cilia generates the flow of cerebrospinal fluid (CSF) (blue arrow). This flow forms a concentration gradient of Slit proteins within the dorsal SVZ (yellow), leading to the repulsion of neuroblasts(red) from the SVZ toward the RMS. Tg737orpk , a mutant mouse strain with cilia-formation defects, showed an impaired Slit gradientand disoriented chain migration in the SVZ. (B) Migrating neuroblasts (red) express Slit proteins (yellow), whereas the surrounding
astrocytes (blue) express Robo receptors (green) in the RMS of wild-type mice. Slit secreted from neuroblasts actively repels astrocytes, leading to efficient neuronal migration and the formation of glial tubes. In Slit1-/- mice, this cellular organization and neuronalmigration are disturbed. Pharmacological elimination (Ara-C infusion) of the migrating neuroblasts also causes disorganization of the
glial-tube structure.

example, PKCζ and GSK3β orchestrate neuronal polarity by controlling the centrosomal positioning, leading
to dynamic reorganization of the cytoskeleton, includingchanges in microtubules and actin filaments.61 The actinbinding Akt substrate Girdin is necessary for the chain
migration of neuroblasts, suggesting that regulation of
the actin cytoskeleton is important for chain migration.62
Consistent with this idea, mDia, a downstream effector of
Rho GTPase, is involved in centrosomal movement andnuclear translocation in neuroblast migration by regulating F-actin dynamics.63 Nuclear translocation is disturbed in the neuroblast migration of doublecortin mutant
mice, suggesting a role of microtubule-related factors.64
We found that CDK5, a microtubule regulator for neuronal migration in the developing brain, also has an essential role in neuroblast migration in the postnatal RMS.
Conditional knockout CDK5 mice showed defects in the
chain formation, migration speed, and polarity of neuro-

blasts in the RMS, suggesting that CDK5 is required forchain formation and efficient migration of neuroblasts.65
These studies demonstrated the mechanisms regulating
the directional control and chain formation of migratingneuroblasts as well as the formation of glial tubes. However, how the activation and dynamics of intracellular cytoskeletal regulators are integrated during chain migration remains unknown. Unlike the processes involved inother types of cell migration, chain-forming neuroblasts
in the RMS migrate along their neighbors by constantly
changing their adhesive properties. It is possible that neuronal chains provide not only a simple migratory scaffold
but also actively instructive cues for the efficient migration in chains. More detailed analyses of chain migration
are still needed to gain further insight into neuroblast migration in the adult brain.

Keio J Med 2013; 62 (1): 13–28

Neuronal Maturation and Turnoverin the Olfactory Bulb
After arriving at the OB, the chain-forming migrating neuroblasts dissociate into individual cells and start
to migrate radially within the OB (Fig. 1). In the transition from chain migration to radial migration, the neurons must detach from the neuronal chains at the core of
the OB. PK2 has a role in the detachment of cells fromthe chains within the OB in addition to its role in theattraction of neuroblasts in the RMS toward the OB.49
Reelin, which is important for neuronal positioning in thedeveloping brain, is secreted by mitral cells in the adult
OB and promotes chain dissociation.66 Interestingly, theexpression of Tenascin-R, another detachment signaling
molecule, is regulated by olfactory input, suggesting that
activity-dependent detachment from the neuronal chainsoccurs.67
Most new neurons differentiate into granule cells in the
granule cell layer (Fig. 1). In addition, a small portionof the new neurons continue their radial migration andreach olfactory glomeruli located in the superficial layerof the OB, where they differentiate into periglomerularcells (Fig. 1). These two types of adult-born neurons are
GABAergic interneurons and are constantly replaced
throughout life.68–70 These neurons are reported to havevarious olfactory functions, such as in olfactory learningand odor discrimination.71–75
The maturation process of new neurons in the OB is
dynamically regulated by both intrinsic and extrinsic
factors. Several studies using knockout mice suggest thattranscriptional factors such as Pax6 and Sp8 are required
for the genesis of distinct subtypes of olfactory interneurons.76–79 On the other hand, extrinsic factors including
olfactory input from olfactory sensory neurons and centrifugal inputs from higher brain centers are also important for the maturation of new neurons in the OB.
Since the OB is a primary processing center for olfactory stimulations, it directly receives olfactory input
transmitted by olfactory sensory neurons in the olfactory epithelium. Olfactory input is a critical factor for thesurvival of new neurons in the OB. Several studies using
anosmic mice,80 olfactory deprivation,81–83 and various
odorants84,85 revealed that olfactory input promotes thesurvival of newly arrived neurons in the OB. A recent
study revealed that new granule cells are eliminated during the postprandial period, and this elimination is enhanced by olfactory deprivation.86 Thus, olfactory input
regulates the integration process of newly arrived neurons in the OB.
In addition, the OB receives various kinds of centrifugal input from higher brain centers. Several neurotransmitter systems such as noradrenergic input and serotonergic input are reported to innervate within the OB.87
Acetylcholine (ACh) is an important neurotransmitter inlearning and memory formation. The granule cell layer

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and glomerular layer of the OB are extensively innervatedwith basal forebrain cholinergic neurons, suggesting thatcholinergic input may affect mature or immature interneurons in the OB. We found that both PSA-NCAM-expressing migrating neuroblasts and mature granule cells
express multiple types of ACh receptors and often makecontact with cholinergic fibers in the OB.88 Inhibiting thecholinergic system by injecting the acetylcholinesterase
inhibitor Donepezil increased the survival of new neurons in the OB without affecting cell proliferation in the
SVZ. These results suggested that the survival of newneurons in the OB is partly regulated by the activity of
the centrifugal cholinergic system, which can be affectedby various physiological and pathological aspects of ananimal. Thus, the survival of new neurons is regulatedby the combination of peripheral and centrifugal inputs,
which can be dynamically affected by the conditions, behaviors, and environment of an animal.
The surviving new neurons are functionally integrated
into mature circuits in the adult OB. During this process, the new neurons show high synaptic and dendritic
plasticity, which is promoted by olfactory input.89,90 A
recent study demonstrated that the synaptic plasticityof new neurons lasts for several months, contributing to
the plasticity of OB circuits.91 At the same time, olderinterneurons in the OB are eliminated by apoptotic cell
death. Thus, olfactory interneurons are continuously replaced throughout life, and this process can be regulated
by olfactory input. Although this neuronal turnover was
thought to underlie plasticity and stability in the adultOB, the relationship between lost and replaced cells was
not fully understood, largely due to the difficulty of monitoring individual neurons over time in live adult animals.
It was recently reported that the turnover of periglomerular cells can be visualized in live animals using invivo two-photon laser-scanning microscopy.92,93 Since
this methodology enables the same region of olfactory
glomeruli to be observed over time, it can be used to detect new additions and eliminations of neurons in addition
to stably existing neurons. Using this method and a naris
occlusion plug that can reversibly regulate olfactory input(Fig. 4A), we showed that, in live animals, the additionand elimination of periglomerular cells are dynamicallycontrolled by olfactory input in a neuronal subtype-specific manner.94 To examine the spatiotemporal relationship between lost and replaced neurons, we developed amethod for in vivo two-photon laser-ablation of periglomerular cells (Fig. 4B), by which we could selectively
eliminate targeted neurons in live animals. Interestingly,
the positions of neurons ablated by the two-photon laser
were filled by neurons of the same subtype in an olfactory-input-dependent manner. These results suggested thatneuronal turnover is spatiotemporally regulated by olfactory input in a neuronal subtype-specific manner, which
could contribute to the structural stability of olfactory
glomeruli. Another notable finding was that the dendritic

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Sawada M and Sawamoto K: Neurogenesis in the Adult Brain

Fig. 4 Olfactory input-dependent spatial regulation of neuronal turnover in the adult olfactory bulb (modified from Sawada et al., J.
Neurosci., 2011).94(A) Fluorescent protein-labeled periglomerular cells (PGCs, green) could be observed over time in live animals under two-photon
laser-scanning microscopy (2PLSM). To reversibly regulate the olfactory input, a naris occlusion plug was used. (B) Two-photon laserablation enables the selective elimination of targeted PGCs (red asterisks). Twenty-eight days after laser-ablation, newly added PGCs
could be observed (yellow arrows and circles). The positions that lost PGCs (pink circles) by laser-ablation were filled by new PGCs
(black asterisks) in an olfactory input-dependent manner. (C) Maximum projection images of lost and replaced PGCs shown in (B). In
the replaced positions, the dendritic directions (yellow open arrowheads) of lost and replaced PGCs were different. Numbers indicate
PGCs whose positions were stable during the imaging period. Scale bar: 10 µm.

directions of the lost and replaced neurons at the same positions were different, indicating that these neurons maintain their dendritic plasticity (Fig. 4C). Taken together,
we propose that the activity-dependent reiterated use of
the same positions by new neurons enables both active
remodeling of neuronal circuits by cellular turnover andmaintenance of the glomerular structure.
Several studies have shown that the survival of newneurons in the OB is regulated by olfactory input; however, the mechanisms regulating neuronal turnover are justbeginning to be clarified. A recent study showed that depleted granule cells are compensated for by new cells of
the same neuronal subtype in a local area of the granulecell layer.95 Thus, it is possible that adult-born olfactoryinterneurons show subtype-specific turnover patterns.94
The turnover of olfactory interneurons is thought to beimportant for both the maintenance and the plasticity ofolfactory functions. Further analysis of the spatiotemporal regulation of neuronal turnover will be needed to understand how neuronal turnover contributes to structuraland functional plasticity and/or stability in the adult OB.
Neurogenesis in the Adult Injured Brain
Recent studies suggest that neurogenesis in the adultbrain can be affected by various pathological conditions.
Experimental models of brain injury (such as trauma, hypoxia, and ischemia) and of neurodegenerative diseases(including Alzheimer’s disease, Parkinson’s disease, andHuntington’s disease) are reported to stimulate neurogenesis in the SVZ of the adult rodent brain.96 Of these disease models, middle cerebral artery occlusion (MCAO)
is widely used for investigating neurogenesis in the SVZof the injured brain. In the MCAO model, the striatumKeio J Med 2013; 62 (1): 13–28

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Fig. 5 Neurogenesis in the injured adult brain.
(A) Experimental ischemic model in which middle cerebral artery occlusion (MCAO) causes infarction in the striatum and cerebral
cortex (brown). (B) After MCAO, the proliferation of SVZ cells (green) is activated. Angiogenesis also occurs surrounding the damaged region (red). (C) Dcx+ neuroblasts (red) derived from SVZ astrocytes migrate along both newly formed and preexisting bloodvessels toward the damaged region. In some cases, these migrating neuroblasts form chains in the striatum. Despite the appearanceof many migrating neuroblasts in the damaged striatum, only a small number of them survive and differentiate into mature neurons(yellow).

and dorsolateral cerebral cortex are damaged, and matureneurons in these regions undergo cell death (Fig. 5A).
After MCAO, neurogenesis in the adult SVZ is upregulated, followed by the appearance of many neuroblasts expressing Dcx in the vicinity of the injured area, called theischemic penumbra (Fig. 5B, C). However, only a small
portion of these cells differentiate into mature neurons inthe striatum.97,98 We have focused on this experimental
model and investigated the regenerative potential of SVZ
cells after injury.
The first reactive response after MCAO is an increased
proliferation of SVZ cells (Fig. 5B). Several reports suggest that various chemokines and growth factors, including EGF, are upregulated in the damaged striatum99 andvascular endothelial cells,100 which could stimulate theproliferation of SVZ cells after MCAO. However, it was
unknown what kind of cells could respond to EGF in the
SVZ. We determined that EGFR is expressed by transitamplifying type C cells in the SVZ after MCAO.101 In
addition, these cells dynamically expand their number
in response to EGF infusion. EGF infusion increased thenumber of neuroblasts in the damaged area, suggestingthat neuronal replacement in the injured striatum might
be enhanced by the EGF-induced expansion of transitamplifying cells in the SVZ.
The second reactive response is the appearance of
Dcx+ cells in the ischemic penumbra (Fig. 5C). These
Dcx+ cells show a migratory morphology, suggestingthat they are migrating from somewhere toward the damaged area.97 Several angiogenic and inflammatory factors such as angiopoietin-1 and SDF-1 are involved in thismigration.102–104 However, the origin of these Dcx+ cells
remained unknown. We demonstrated using a virus infection-mediated fate-mapping technique that these Dcx+
cells are derived from GFAP+ astrocytes in the SVZ andmigrate toward the damaged regions.105 In addition, someof the migrating Dcx+ neuroblasts form chains and closely associate with blood vessels and astrocytic processes.
These results raised the possibility that in the injured striatum, migrating cells use the blood vessels as a scaffold
for their efficient migration. Using time-lapse recording
in slice culture, we demonstrated that SVZ-derived neuroblasts migrate along blood vessels toward the damaged
striatum.106 Furthermore, the migration speed of theseneuroblasts was decreased by the pharmacological inhibition of CXCR4, suggesting that chemokine signaling is
involved in this vasophilic migration.
In contrast to the adult RMS, which provides a specialized, permissive environment for cell migration, neuroblasts in the damaged striatum must migrate throughcomplex neuronal circuits. Furthermore, the activationof reactive astrocytes and microglia, and the subsequent
formation of a glial scar, could worsen the conditions for
migrating neuroblasts to reach the damaged area. Moreover, many questions remain to be answered. Why doneuroblasts form chains and migrate along the blood ves-

22

Sawada M and Sawamoto K: Neurogenesis in the Adult Brain

Fig. 6 Adult neurogenesis in various vertebrates (modified from Garcia-Verdugo et al., Brain Res. Bull., 2002).111
Illustrations of the fish, reptile, bird, rodent, marmoset, and human brain are shown in the upper row. Coronal sections of the brain
hemispheres at the location of the dotted lines in the illustrations are shown in the middle row. Red lines indicate the neurogenic
regions. The neural stem cell niche in the adult brain is widely conserved at the ventricular wall (blue). The cytoarchitecture of theventricular wall in various vertebrates is shown in the bottom row. In fish, the ventricular wall is covered with radial glia (blue). The
ratio of ependymal cells (gray) to radial glia or astrocytes in lower species is smaller than in higher species. In primates (marmosets
and humans), the ventricular wall is fully covered with ependymal cells. Moreover, the hypocellular gap layer is a typical feature of
the primate ventricular wall. In all species except for adult human, neuroblasts (red) are observed beneath the ventricular wall. In the
neonatal human SVZ, many neuroblasts are observed at birth, but disappear by 18 months of age.113 In fish, rodents, and marmosets,transit-amplifying neuronal progenitors (green) are also observed.

sels in the damaged brain? What mechanisms direct the
migrating neuroblasts toward the damaged area? How doneurons migrate through the complex, disadvantageous
environment? Understanding the mechanisms regulating the interactions between migrating neuroblasts andtheir surrounding microenvironment may provide new
insights for novel therapies involving the regeneration oflost neuronal circuits using endogenous neural stem cells
in the adult brain.96,107–110
Adult Neurogenesis in Various Species
Most of the studies on adult neurogenesis cited above
used rodents. However, neurogenesis is observed in theadult brain of many vertebrates, from fish to humans.

A comparable neural stem cell niche in the adult brain
is widely conserved at the ventricular wall1,111–115 (Fig.
6), where embryonic neural stem cells are located in thedeveloping brain. Neural stem cells in the adult humanbrain are a promising endogenous cell source for brain
regeneration after various injuries and diseases. Thus,
comparative studies of neurogenesis in the adult brain
among different species are needed to better understandthe features and regulatory mechanisms of adult neuralstem cells.
We have focused on zebrafish as a nonmammalian vertebrate model in which genetic and pharmacological manipulations are available. Recent studies suggested that,as in rodents, neuronal progenitors are generated in thetelencephalic ventricular zone (VZ) and migrate towardKeio J Med 2013; 62 (1): 13–28

the OB in the adult zebrafish.116–119 However, the cytoarchitecture of the VZ–OB pathway was unknown. We
demonstrated that the telencephalic VZ of the zebrafish
consists of three types of cells: GFAP+ radial glial cells,
PCNA+ proliferative cells, and PSA-NCAM+ neuroblasts(Fig. 6).112 Moreover, a continuous migratory stream of
PSA-NCAM+ neuronal progenitors extends from the VZ
to the OB, but the neurons do not move through glial tunnels. Time-lapse imaging using Tg(ngn1:gfp) fish demonstrated that neuronal progenitors migrate rostrally along
blood vessels in the RMS toward the OB, indicating that
the PSA-NCAM+ stream is the functional route for the
migration of neuronal progenitors in the adult zebrafish
brain. In the rodent RMS, the chain-forming new neurons
also migrate along blood vessels,57,58 suggesting the existence of common mechanisms for vasophilic migration.
Thus, these results reveal similarities and differences inthe ventricular neurogenic niche between zebrafish androdent brains.
Compared with rodents, zebrafish have a higher regenerative potential after brain injury. We established a traumatic brain injury (TBI) model in the adult zebrafish anddemonstrated that the glutamatergic neurons lost fromthe dorsolateral telencephalon after TBI are regenerated
from VZ-derived neuronal progenitors.120 This process
was abolished by the pharmacological inhibition of Notch
signaling, indicating that Notch signaling is required forneuronal repair. Thus, the zebrafish is a useful and powerful model for genetic and pharmacological screening
to investigate the mechanisms regulating adult neurogenesis under physiological and pathological conditions.
To understand evolutionarily conserved neurogenesis
in the adult brain, we need to examine the primate brain
in addition to that of nonmammalian vertebrates and rodents. The SVZ–OB pathway has been reported in the
Old World primates Macaca mulatta and Macaca fascicularis.121–123 However, there are several limitations
associated with the use of these macaque monkeys forstudying adult neurogenesis, including their low availability, slow sexual maturation, and large body size. In
contrast, the common marmoset, Callithrix jacchus, a
New World primate, has advantages in terms of its small
size (300–500 g at maturity) and stable supply because of
its availability from breeding colonies. In addition, several neurological disease models and transgenic animals
are already available ,124,125 indicating that the common
marmoset is useful for studying adult neurogenesis.
We recently reported the cellular composition and organization of the SVZ and RMS in the common marmoset.115 Interestingly, the SVZ–OB pathway in the
marmoset is more similar to that of humans than to thatof rodents. Like the adult human SVZ,114 the adult marmoset SVZ consists of three distinct layers: the ependymal, hypocellular gap, and astrocytic ribbon layers (Fig.
6).115 Moreover, although an extensive network of PSANCAM+ elongated cell aggregates can be observed in the

23

SVZ, only individually migrating neuroblasts are foundin the olfactory tract and OB. These findings indicate that
the SVZ–OB pathway in the adult marmoset has several
characteristics in common with that in humans. However, the anterior SVZ contains some putative progenitors
similar to the transit-amplifying cells in rodents, but thisfeature is not conserved in the human brain (Fig. 6). Notably, in the neonatal (postnatal day 0–1) marmoset, theSVZ contains chains of migrating neuroblasts that continue toward the OB.115 This active neonatal neurogenesis
and rodent-like chain migration was also recently reported in the neonatal human SVZ, in which many Dcx+ neuroblasts exist in the layer corresponding to the hypocellular gap of the adult stage.113 Thus, again, the SVZ–OB
pathway in marmosets is very similar to that in humans.
The neurogenic potential of the SVZ–OB pathway differs among animal species, probably because of differences in how much the animal depends on olfaction for
its survival. In primates such as humans and marmosets,
which depend on the visual system more than the olfactory system, new neurons generated in the SVZ may
migrate to different locations and have different functions. Indeed, the human brain has an additional migratory stream of neurons that branches off from the RMS
and ends in the ventromedial prefrontal cortex, raising
the possibility that new neurons derived from SVZ neural stem cells are involved in functions other than olfaction in higher primates.113 Further characterization of thefates of the neural stem/progenitor cells in the primate
SVZ using marmoset models of neurological disorders
should contribute to novel strategies for brain repair using endogenous neural stem cells.
Conclusion
Since the discovery of neural stem cells in the adultbrain, many features of adult neurogenesis have been
described.2,96,126–129 We now know that neurogenesis in
the adult brain consists of complex biological events including the genesis, migration, differentiation, and maintenance of new neurons (Fig. 1). Although a variety ofmolecular and cellular mechanisms have been shown toregulate each aspect of adult neurogenesis, it is important
to integrate these findings to obtain a comprehensive understanding of this complex system. Adult neurogenesis
could enable the dynamic remodeling of mature neuronal
circuits by adding new neurons, contributing to structural and functional plasticity in the adult brain. Adult
neurogenesis could also have an important role in the injured brain, in regenerating the lost neurons from adultneural stem cells. This endogenous potential needs to befurther investigated in future studies. Importantly, adultneurogenesis is regulated not only by developmental genetic programs but also by environmental and internalchanges in animals. Thus, adult neurogenesis could be afundamental mechanism for experience-dependent plas-

24

Sawada M and Sawamoto K: Neurogenesis in the Adult Brain

ticity, which is the most important feature of the adultbrain. We hope that future studies on the physiologicaland pathological conditions of various animals will improve our understanding of the biological functions andsignificance of neurogenesis in the adult brain.
Acknowledgments
This article summarizes our studies presented by K.S.
in the Kitazato Prize lecture (2011) at Keio University
School of Medicine. We apologize to all those whose
work we could not cite because of space limitations. We
thank all our collaborators for their contributions to original research, and past and current members of Sawamotolaboratory for their encouragement and discussions. M.S.
is a Research Fellow of the Japan Society for the Promotion of Science. This work was supported by the Keio
University Medical Science Fund, by the Funding Program for the Next Generation World-Leading Researchers, a Grant-in-Aid for Young Scientists (S), by the International Human Frontier Science Program Organization,and by the Project for Realization of Regenerative Medicine from MEXT.
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