Article

Injury-induced neurogenesis in the mammalian forebrain

Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 11/2010; 68(10):1645-56. DOI: 10.1007/s00018-010-0552-y
Source: PubMed

ABSTRACT

It has been accepted that new neurons are added to the olfactory bulb and the hippocampal dentate gyrus throughout life in the healthy adult mammalian brain. Recent studies have clarified that brain insult raises the proliferation of neural stem cells/neural progenitor cells existing in the subventricular zone and the subgranular zone, which become sources of new neurons for the olfactory bulb and the dentate gyrus, respectively. Interestingly, convincing data has shown that brain insult invokes neurogenesis in various brain regions, such as the hippocampal cornu ammonis region, striatum, and cortex. These reports suggest that neural stem cells/neural progenitor cells, which can be activated by brain injury, might be broadly located in the adult brain or that new neurons may migrate widely from the neurogenic regions. This review focuses on brain insult-induced neurogenesis in the mammalian forebrain, especially in the neocortex.

Full-text

Available from: Koji Ohira
REVIEW
Injury-induced neurogenesis in the mammalian forebrain
Koji Ohira
Received: 23 June 2010 / Revised: 30 September 2010 / Accepted: 30 September 2010 / Published online: 2 November 2010
Ó Springer Basel AG 2010
Abstract It has been accepted that new neurons are
added to the olfactory bulb and the hippocampal dentate
gyrus throughout life in the healthy adult mammalian
brain. Recent studies have clarified that brain insult
raises the proliferation of neural stem cells/neural pro-
genitor cells existing in the subventricular zone and the
subgranular zone, which become sources of new neurons
for the olfactory bulb and the dentate gyrus, respectively.
Interestingly, convincing data has shown that brain insult
invokes neurogenesis in various brain regions, such as
the hippocampal cornu ammonis region, striatum, and
cortex. These reports suggest that neural stem cells/
neural progenitor cells, which can be activated by brain
injury, might be broadly located in the adult brain or that
new neurons may migrate widely from the neurogenic
regions. This review focuses on brain insult-induced
neurogenesis in the mammalian forebrain, especially in
the neocortex.
Keywords Insult Ischemia Neurogenesis Stem cells
Progenitor cell Proliferation
Abbreviations
BrdU Bromodeoxyuridine
CA Cornu ammonis
L1-INP Layer 1 inhibitory neuron progenitor
MGE Medial ganglionic eminence
NSC Neural stem cell
NPC Neural progenitor cell
SGZ Subgranular zone
SVZ Subventricular zone
Introduction
It has long been believed that almost all neurons in the
adult mammalian brain are produced during development
and do not regenerate even after injury. ‘No new neurons
after birth’ has been a central dogma in the neuroscience
field [14]. However, recent in vitro and in vivo studies of
adult neurogenesis have identified neural stem cells (NSCs)
and neural progenitor cells (NPCs) in the adult mammalian
brain [3, 4]. This great discovery in the field of neuro-
genesis has been achieved by innovations in detection
methods for neurogenesis, such as molecular cell markers
for NSCs, NPCs, and new neurons, DNA replication
markers [tritiated thymidine and bromodeoxyuridine
(BrdU)], retrovirus, and genetically modified animals
[17].
In the subventricular zone (SVZ) and the subgranular
zone (SGZ), NSCs and NPCs show self-renewal and con-
tinue to produce new neurons even under healthy
conditions [8, 9]. Besides, new neurons in the olfactory
bulb and the hippocampus are needed for olfactory mem-
ory [10, 11], and contextual and spatial memory [1217],
respectively. These findings suggest that new neurons play
important roles in the neuronal plasticity of the adult brain.
Recently, adult neurogenesis has been reported in vari-
ous regions of the adult mammalian brain, including the
cortex, striatum, and hippocampal cornu ammonis (CA)
region. Importantly, neurogenesis in these regions may be
induced by brain insults, suggesting that therapeutic inno-
vation for brain insults may be created using endogenous
K. Ohira (&)
Division of Systems Medical Science,
Institute for Comprehensive Medical Science,
Fujita Health University, Toyoake, Aichi 470-1192, Japan
e-mail: ohira@fujita-hu.ac.jp
Cell. Mol. Life Sci. (2011) 68:1645–1656
DOI 10.1007/s00018-010-0552-y
Cellular and Molecular Life Sciences
123
Page 1
NSCs and NPCs. However, the mechanism of insult-
induced neurogenesis remains to be determined. In this
review, we summarize the recent findings of insult-
induced, especially ischemia-dependent, neurogenesis in
the SVZ and the SGZ. In addition, since neocortical adult
neurogenesis under pathological conditions has been a hot
subject in the field of adult neurogenesis, we further focus
on neocortical adult neurogenesis.
Neurogenesis in the olfactory bulb
and the hippocampus of the adult mammal
under healthy and ischemic conditions
It is now widely accepted that constitutive neurogenesis in
the healthy adult mammalian forebrain occurs in the
anterior SVZ and the SGZ [3, 4]. Since NSCs and NPCs in
the anterior SVZ and the SGZ were first identified in the
adult forebrain [12, 13], research into neurogenesis in these
regions has advanced, while research of neurogenesis in
other brain regions, such as the neocortex and striatum, has
lagged behind. The basic phenomena of adult neurogenesis
in the anterior SVZ and the SGZ have been well described
(Fig. 1).
In the SVZ, four main cell types exist: A, B, C, and
ependymal cells, which are defined by morphological and
immunohistochemical characteristics (Fig. 1a) [14]. Type-A
cells (neuroblasts) are born throughout the SVZ, migrate in
chains toward the olfactory bulb, and differentiate into
granule and periglomerular interneurons [15]. The chains
of type-A cells are ensheathed by type-B cells (SVZ
GFAP-positive cells) [14, 16]. Some of the type-B cells
have been reported to work as NSCs. Type-C cells are
clusters of rapidly dividing immature cells on the migration
pathway physically located between type-B and type-A
cells [14]. Altogether, the SVZ neurogenic lineage is type-B
cell ? type-C cell ? type-A cell.
In the adult hippocampus NSCs, NPCs, and postmitotic
granule cells are each distributed in a distinctive location
(Fig. 1c) [1719]. NSCs (type-1 cells) exist near the border
between the hilus and the dentate granule cell layer. Neu-
roblasts (type-3 cells) produced from transient multiplying
cells (type-2 cells) in the SGZ migrate radially a short
distance into the granule cell layer. Then, neuroblasts are
integrated into the deepest portion of the granule cell layer,
where they differentiate into granule cells, extending
dendrites and axons and receive synaptic inputs [20].
The above description of persistent adult neurogenesis in
the SVZ and the SGZ is based on evidence under healthy
conditions. In addition, recent studies have been gradually
clarifying that adult neurogenesis can be regulated by various
factors, for example, exercise, environmental enrichment,
pregnancy, and ischemia up-regulate neurogenesis, while
stress and aging down-regulate it [4]. Among them, ischemia
is one of the most widely used methods in adult neurogenesis
research.
Here, we focus on the effects of brain ischemia on adult
neurogenesis in the SVZ and the SGZ. Brain ischemia is
defined as the condition by which a stroke, such as cerebral
infarction, intracerebral hemorrhage, or subarachnoid
hemorrhage, brain injury, or transient cardiorespiratory
arrest critically decreases or completely interrupts the
blood flow of the whole brain or a certain region of the
brain [21, 22]. Brain ischemia is mainly divided into two
types, focal brain ischemia and global brain ischemia. The
Fig. 1 Schematic representation of adult neurogenesis in the SVZ
and the SGZ. a In the SVZ-olfactory bulb (OB) system, the NSCs
(type-B cells, cyan) give rise to neuroblast cells (type-A cells, red) via
transient intermediate cells (type-C cells, green). Type-A cells
migrate to the OB through the rostral migration stream (RMS) and
differentiate to granule cells and periglomerular cells. b The sagittal
section of the adult mouse brain after drowning. Two well-known
neurogenic regions, the SVZ (yellow) and the DG (red), are indicated
with the colored boxes. c The NSCs (type-1 cells, cyan), which exist
in the SGZ, the thin lamina between the hilus and granule cell layer
(GCL), produce transient progenitor cells (type-2 cells, green). The
neuroblast cells (type-3 cells, red) derived from type-2 cells migrate
shortly to the GCL and differentiate to granule cells. Newly generated
granule cells are integrated into the existing neural network.
EP ependymal cell, LV lateral ventricle
1646 K. Ohira
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former reduces blood flow to a specific brain region
because a blood clot occludes a cerebral vessel, whereas
the latter is a drastic reduction of blood flow in the whole
brain caused by events such as cardiac arrest [21]. The
most common experimental model of focal cerebral
ischemia is induced by transient middle cerebral artery
occlusion (MCAO). Global ischemia occurs when the aorta
or vena cava is occluded.
Historically, adult neurogenesis in the SVZ and SGZ
was established in the late 1990s [35]. Then, in the next
decade from the late 1990s, adult neurogenesis research
moved to examine whether new neurons from NSCs and
NPCs can replace dying cells or lost ones, which would be
the starting point of regenerative medicine for brain injury
with endogenous NSCs and NPCs [2326]. The first
researchers used brain ischemia [23]. If neurogenesis is
up-regulated by brain ischemia, endogenous NSCs and
NPCs may be useful for therapy of brain insults. Using brain
ischemia as an experimental method, almost all studies in
the recent decade have reported that brain ischemia
potently stimulates adult neurogenesis in the SVZ and the
SGZ (Table 1)[2354]. Proliferating cells in the SVZ and
the SGZ are significantly increased by ischemia, and
increases in the number of new neurons could be detected.
In addition, it is important that NPCs in the SVZ have been
found to migrate to ischemic regions and appear to form
proper neuronal subtypes to replace damaged neurons in
the striatum and cortex [29, 41, 43, 5560]. These ectopic
migrations have not been found under healthy conditions.
Thus, brain ischemic stimulation might evoke a molecular
Table 1 A list of experimental studies that examine whether adult neurogenesis in the SVZ and the SGZ is promoted by ischemia
Species Regions Treatment Effect Reference
Gerbil SGZ Global ischemia for 2–10 min Up-regulated [23]
Gerbil SGZ Global ischemia for 10 min Up-regulated [24]
SD rat aSVZ, SGZ Focal ischemia for 90 min Up-regulated [25]
Wistar rat aSVZ, SGZ Focal ischemia until killing Up-regulated [26]
Wistar rat SGZ Global ischemia for 10 min Up-regulated [27]
Wistar rat SGZ Focal ischemia for 30 min or 2 h Up-regulated [28]
Wistar rat aSVZ Focal ischemia until killing Up-regulated [29]
Wistar rat SGZ Focal ischemia until killing Up-regulated [30]
Gerbil SGZ Global ischemia for 5 min Up-regulated [31]
Wistar rat aSVZ Focal ischemia for 2 h Up-regulated [32]
SD rat aSVZ Focal ischemia for 90 min Up-regulated [33]
SD rat SGZ Focal ischemia for 90 min Up-regulated [34]
Macaque monkey aSVZ, SGZ Global ischemia for 20 min Up-regulated [35]
SD rat aSVZ Focal ischemia for 90 min Up-regulated [36]
Wistar rat aSVZ Focal ischemia until killing Up-regulated [37]
Wistar rat SGZ Global ischemia for 15 min Up-regulated [38]
SD rat SGZ Focal ischemia for 90 min Up-regulated [39]
Hypertensive rat aSVZ Focal ischemia until killing Up-regulated [40]
Wistar rat SGZ Focal ischemia until killing Up-regulated [41]
Hypertensive rat aSVZ Focal ischemia for 60 min or 2 h Up-regulated [42]
Wistar rat aSVZ Focal ischemia for 2 h Up-regulated [43]
Macaque monkey aSVZ, SGZ Focal ischemia until killing Up-regulated [44]
Human aSVZ Ischemic brain autopsy Up-regulated [45]
Hypertensive rat aSVZ Focal ischemia until killing Up-regulated [46]
C57BL mouse aSVZ Focal ischemia for 15 min Up-regulated [47]
C57BL mouse aSVZ Focal ischemia until killing Up-regulated [48]
C57BL mouse aSVZ Focal ischemia until killing Up-regulated [49]
Macaque monkey SGZ Global ischemia for 20 min Up-regulated [50]
Wistar rat aSVZ Focal ischemia until killing Up-regulated [51]
SD rat aSVZ Focal ischemia for 90 min Up-regulated [52]
SD rat aSVZ Global ischemia for 10 min Up-regulated [53]
Human aSVZ Ischemic brain autopsy Up-regulated [54]
aSVZ anterior subventricular zone,
SGZ subgranular zone
Neurogenesis induced by brain injury 1647
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mechanism of migration for damaged regions, such as
various attractive and repulsive humoral factors and
extracellular matrices that have not yet been identified.
Neurogenesis in the neocortex of the adult mammal
both under healthy and pathological conditions
Adult neocortical neurogenesis has been an interesting
subject since the last century. In the 1890–1900s, a few
studies identified cell proliferation in all parts of the CNS
of newborn animals and infants [42]. Identifying cell pro-
liferation in the adult neocortex was first reported at 1912.
Using tritiated thymidine, a marker of DNA synthesis,
Altman [65] rediscovered the addition of new neurons in
the neocortex of adult rats. However, as these findings were
based on chemical stain or radioautography, it was not
clear whether or not the new cells were neurons. Then,
using a combination of autoradiography and serial thin
sectioning electron microscopy, Kaplan [66] showed that in
the adult rat neocortex, the new cells containing tritiated
thymidine are stellate cells that have an axonal hillock,
initial segment, and synapses on the dendrites and cell
bodies. On the contrary, using the same tritiated thymidine
and primates as experimental animals, Rakic [2, 6769]
provided convincing evidence beginning in the late 1970s
that neurogenesis occurs during early embryo develop-
ment. Thereafter, several studies on neocortical
neurogenesis have been reported, but there is a major
conflict regarding neurogenesis in the adult neocortex of
healthy mammals, from rodents to primates. This discrep-
ancy might be caused by the experimental methods and
animals’ conditions, i.e., housing conditions, histories,
genetic background, and technical considerations [4]. One
reliable reason why adult neocortical neurogenesis is
highly controversial is that the new neurons are generated
at very low levels in healthy animals [70]. Even in the
reports that show positive data for neocortical adult neu-
rogenesis, the percentages of new neurons to total neurons
are in the range of only 0.005–0.03% of all existing neu-
rons [7175]. In addition, if new neurons in the neocortex
are inhibitory interneurons, the newly generated cell bodies
may be rather small. Thus, it is not hard to suppose that we
cannot efficiently detect new neurons in the adult neocor-
tex. Furthermore, animals’ breeding conditions may be
more important. In particular, non-human primates, such as
macaque monkeys, have the ability for higher cognition
and complicated emotions at almost the same level with
humans, so that the dominant-subordinate status among
monkeys in the breeding room is not negligible [76]. In an
experimental condition where each monkey is housed in a
separate cage and animals cannot see one another, but
auditory and olfactory exposure are not prevented,
subordinate animals might experience mental stress [76].
Stress has been reported to be one of the repressors of adult
neurogenesis [4]. In fact, hippocampal neurogenesis in
adult rats is reduced by the dominant-subordinate status
[77]. Thus, methods that are devised to reduce stress to
experimental animals may be needed. Although it is not
clear whether the neocortical neurogenesis is decreased by
stress, it would be more difficult to detect neocortical
neurogenesis under stressful conditions. Other factors that
have not been identified at present might also make the
detection of neocortical neurogenesis difficult.
Are there any factors that invoke or enhance adult
neocortical neurogenesis? Recent studies have reported the
production or addition of new neurons in the adult mam-
malian neocortex under various pathological conditions,
such as focal and global ischemia, chromophore-targeted
neuronal degeneration, aspiration lesion, chemical-induced
spreading depression, and electrolytic lesions of the thal-
amus (Table 2). In fact, although the stimulus intensities of
these pathological conditions cannot be compared, the
production of new neurons in the adult neocortex is up-
regulated by a factor of 0.06–1% of total neurons [80, 83,
88, 99]. Almost all studies that employed a combination of
the double-staining of BrdU and neuronal markers and
three-dimensional confocal microscopy to resolve closely
apposed cells clearly identified neocortical neurogenesis
[46, 57, 71
, 72, 74, 75, 8091, 9399].
Where are the neocortical NSCs and NPCs?
One of the reasons why neocortical neurogenesis has
remained unclear for such a long time is that NSCs and
NPCs of the adult neocortex were not found. The above
studies also suggest that NSCs and NPCs, which can be up-
regulated by brain injury or stroke, may be maintained
within or around the neocortex. Recent studies have
gradually clarified NSCs and NPCs of the adult neocortex.
Currently, there seem to be neocortical NSCs and NPCs
mainly in four regions, the SVZ [57, 71, 80, 85, 90], white
matter [87, 96], gray matter [75], and marginal zone
[96, 97, 99] (Fig. 2).
The SVZ is historically the oldest putative source of
neocortical new neurons. Migrating neuroblasts from the
SVZ have been observed, even if the neocortex is in healthy
condition [71, 85], although the number of new neurons is
quite small in these studies. In contrast, pathological treat-
ments, such as ischemia, seem to increase in the new
neurons from the SVZ. After 90 min of focal cerebral
ischemia in adult rats, neuroblasts, which express double-
cortin, a migrating neuron marker, have been observed to
migrate from the anterior SVZ, to the lateral cortical stream
along the corpus callosum, and finally to the ischemic
1648 K. Ohira
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Table 2 A list of experimental studies that examined neurogenesis in the adult neocortex
Species/age Condition Evaluation of neurogenesis/proliferation Positive of negative Reference
Albino rat/1 day–2 years Healthy Histological analysis of mitotic cells by
thionine
Positive [64]
Long evans rat/young adult Lesion of LGN Autoradiography with tritiated thymidine Positive [78]
Long evans rat/4 months Healthy Autoradiography with tritiated thymidine Positive [65]
Cats/2,500 g Healthy Autoradiography with tritiated thymidine Positive [65]
Long evans rat/1–60 day Healthy Autoradiography with tritiated thymidine Positive [79]
Rat/90 day Healthy Electron microscopy/autoradiography
with tritiated thymidine
Positive [66]
Macaque monkey/5–16 years Healthy IF with BrdU, NeuN, NSE, MAP-2,
TOAD-64
Positive [71]
C57BL mouse/over 6 weeks Chromophore-targeted degeneration IF with BrdU, NeuN, DCX, HuCD/axon
elongation with FluoroGold
Positive [80]
Wistar rat/12 weeks Photothrombotic stroke for 2 min IF with BrdU, MAP-2, NeuN Positive [81]
Macaque monkey/over 5 years Healthy IF with BrdU, NeuN, TuJ1 Negative [82]
Macaque monkey/5–5.7 years Healthy IF with BrdU, NeuN, TuJ1 Positive [72]
Wistar rat/9–10 weeks Focal ischemia for 2 h IF with BrdU, NeuN, TuJ1, MAP-2 Positive [83]
Wistar rat/300–350 g Focal ischemia until killing (7–42 day) IF with BrdU, PSA-NCAM, NeuN,
MAP-2
Negative [84]
Macaque monkey/6–12 years Healthy IF with BrdU, NeuN, MAP-2, TuJ1,
TUC-4
Positive [85]
Squirrel monkey/3–6 years Healthy IF with BrdU, NeuN, MAP-2, TuJ1,
TUC-4
Positive [85]
C57BL mouse/2 months Healthy after run and enrichment IF with BrdU, NeuN Negative [86]
Macaque monkey/2–5 years Healthy IF with BrdU, NeuN, DCX Positive [74]
SD rat/280–310 g Focal ischemia for 90 min IF with BrdU, nestin, TuJ1, NeuroD,
ENCAM, DCX, NeuN
Positive [57]
Human white matter/1–69 years In vitro neurosphere assay/IF with TuJ1,
GAD67
Positive [87]
C57BL mouse/? Chromophore-targeted degeneration IF with BrdU, NeuN, DCX/axon
elongation with FluoroGold
Positive [88]
Macaque monkey/5–11 years Whole brain ischemia for 20 min IF with BrdU, Ki67, phospho-histone H3,
musashi1, nestin, NeuN, TuJ1, DCX,
GAD65/67
Positive [89]
Mouse/12 weeks Aspiration lesion IF with BrdU, DCX Positive [90]
Wistar rat/11–12 weeks Healthy IF with BrdU, nestin, vimentin, phospho-
histone H3, DCX, NeuN, TuJ1, HuC/D,
Pax6
Positive [91]
Neurogenesis induced by brain injury 1649
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Table 2 continued
Species/age Condition Evaluation of neurogenesis/proliferation Positive of negative Reference
SD rat/9–10 weeks Healthy IF with BrdU, NeuN, NSE, HuC/D,
GABA, GAD67, calbindin, calretinin,
parvalbumin, EAAC-1
Positive [75]
Human/33–73 years Healthy
14
C in DNA/IF with BrdU, NeuN,
neurofilament
Negative [92]
Human/25–48 years Stroke IF with Ki67, PCNA, DCX, TUC-4,
ENCAM, TuJ1
Positive [93]
Wistar rat/250–350 g Healthy IF with BrdU, Ki67, DCX, NeuN,
PSA-NCAM
Positive [94]
Hypertensive rat/? Focal ischemia for 7–90 day/bFGF AAV
injection
IF with BrdU, NeuN, SOX2, nestin, Pax6,
Mash1
Positive [46]
129S2/Sv mouse/2.5–3 months Focal ischemia for 10 min/whisker
stimulation
IF with BrdU, NeuN, DCX Positive [95]
Wistar rat/? Laser-induced lesion Neurosphere assay/IF with nestin,
vimentin, 473HD, DCX
Positive [96]
SD rat/8–9 weeks Spreading depression IF with BrdU, PCNA, vimentin, nestin,
DCX, TuJ1
Positive [97]
Human/34–84 years Stroke IF with nestin, musashi-1, TuJ1 Positive [98]
Wistar rat/6 months Global forebrain ischemia for 10 min Retrovirus/IF with BrdU, TuJ1, HuC/D,
GABA, GAD67, calretinin,
neuropeptide Y, somatostatin, choline
acetyltransferase, sodium channel
Positive [99]
BrdU bromodeoxyuridine, DCX doublecortin, EAAC1 excitatory amino acid carrier 1, ENCAM embryonic neural cell adhesion molecule, GAD glutamic acid decarboxylase, HuC/D human
neuronal protein C and D, IF immunofluorescence, Ki67 MKI67 gene product antibody clone, LGN lateral geniculate nucleus, MAP-2 microtubule-associated protein 2, Mash1 mammalian
Achaete-Schute Homolog 1, NeuN neuronal nuclei, NSE neuron-specific enolase, PSA-NCAM polysialylated neural cell adhesion molecule, SOX2 SRY (sex determining region Y)-box 2,
TOAD-64 turned on after division 64 kDa (Synonyms TUC-4, TOAD/ulip/crmp-4), TuJ1 anti-neuron-specific class III beta-tubulin clone TuJ1
1650 K. Ohira
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regions of the neocortex [57]. However, in the control rat
brains, such migration of neuroblasts has not been found.
The same finding is also reported in the aspiration lesion
model of the adult mouse neocortex [90]. Since these
experiments explored the migrating neurons up to 2 weeks
after injuries, the detailed characteristics of neuronal mor-
phology and the chemical features were not clarified. In
other words, it remains unclear whether the new neurons are
excitatory or inhibitory, and projection neurons or inter-
neurons. These questions are challenged by Magavi et al.
[80]. When layer VI corticothalamic projection neurons are
killed by chromophore-targeted neuronal degeneration in
the mouse anterior neocortex, projection neurons are newly
generated, replaced in layer VI, and interestingly establish
long-distance connections. The projection neurons seem to
be generated in and migrate from the SVZ.
NSCs are isolated from the white matter of the adult
human brain [87]. The isolated NSCs generate neuro-
spheres in vitro, which give rise to neurons and glial cells
both in vitro and after transplantation to the fetal rat brains.
These white matter samples are surgically taken from
patients with epilepsy, arterial aneurysm, dysplasia, and
traumatic injury, so that these white matter NSCs might be
pathology-inducible ones. In fact, the laser-lesions activate
endogenous NSCs and NPCs in the white matter of the
adult rat visual neocortex and in layer 1 as described in a
later paragraph [96].
Dayer et al. [75] have reported that in the adult rat
neocortex in healthy condition, newly generated GAB-
Aergic interneurons are found to comprise up to *0.01%
of total neurons. They used the double-staining technique
of BrdU and some neural markers. One of the neural
markers, doublecortin, is not contained in BrdU/CRMP-4-
double-positive immature neurons in the neocortex,
whereas in the striatum, doublecortin is expressed in
immature neurons that are definitely migrating and their
origin may be the SVZ [75]. Furthermore, more than 90%
of BrdU-positive cells in the neocortex are immunoreactive
for NG2 (neuroglia proteoglycan 2) 2 h after BrdU injec-
tion. At 4–5 weeks after BrdU injection, about 30% of
BrdU/NeuN (neuronal nuclei)-double-positive cells have
faint to moderate NG2 immunoreactivity. Hence, the
authors speculate that in the neocortex, new neurons arise
from in situ NG2-positive progenitors rather than from the
SVZ or the white matter. However, since these data are
derived from immunohistological experiments, they do not
constitute direct evidence that NG2-positive cells produce
new neurons. In fact, there are a few reports that show that
NG2-positive proliferating cells do not produce new neu-
rons at all, by using genetically modified mice [100103].
In contrast, there are a few reports that some NG2-positive
cells might function as NSCs in the hippocampus and the
SVZ [104106]. Thus, there is a big conflict in light of
NG2-positive proliferating cells. Further studies to exam-
ine whether these progenitors generate neurons, glial cells,
or both cell types are needed.
Recently, three groups have independently reported on
NSCs and NPCs in the neocortical layer 1. The focal laser-
lesion of the rat visual cortex newly induces NSCs/NPCs in
layer 1 and white matter of the ipsilateral side, the cells
which are detected by the molecular markers of NSCs/
NPCs, including nestin, vimentin, and the 473HD epitope
[96]. Similar NSCs/NPCs are induced in layer 1 by
spreading depression treatment [97]. The NSCs/NPCs are
defined as the vimentin- or nestin-positive cells. However,
the two reports described above cannot provide direct
evidence that new neurons are produced from the vimentin-
or nestin-positive NSCs/NPCs, because these data are
based on immunohistological data. The direct labeling
method of progenitor cells with GFP-expressing retrovirus
vectors has identified NPCs in layer 1 of the adult rat [99,
107]. Generally, when retrovirus vectors are used, the exact
location of NSCs/NPCs should be determined before virus
injection, as the weak infectivity of retroviruses is opera-
tive only at mitosis in the cell cycle, and the injected virus
is rapidly diffused in the tissues. The genome of the virus
vector is integrated into the genome of host cell, so that it is
easy to trace daughter cells from NSCs/NPCs labeled with
the virus vector. Interestingly, the layer 1 NPCs produce
subclasses of GABAergic interneurons, which express
Fig. 2 Neurogenesis in the adult neocortex. There are four putative
subregions in the neocortical parenchyma, where the NSCs/NPCs
exist, the SVZ, white matter, gray matter, and layer 1. Bold lines and
dotted lines are based on direct and indirect evidence, respectively
Neurogenesis induced by brain injury 1651
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calretinin, but not calbindin and parvalbumin, among the
calcium-binding proteins, and also contain neuropeptide Y,
somatostatin, and choline acetyltransferase. At present,
although mother cells of the layer 1 NPCs have not been
identified, the layer 1 NPCs express the markers of the
medial ganglionic eminence (MGE), Nkx2.1 and MafB
[108, 109]. In the developing neocortical layer 1, similar
NSCs/NPCs have been found [110]. Thus, such NSCs/
NPCs that are observed during development might be
maintained into adulthood. It is also shown that new neu-
rons seem to form neural networks with existing neighbor
neurons. Thus, the layer 1 NPCs are designated as L1-INP
cells (layer 1 inhibitory neuron progenitor cell). The dif-
ference between L1-INP cells and nestin- or vimentin-
positive NSCs/NPCs as described above [96, 97] is that
L1-INP cells are found in layer 1 in healthy brains. L1-INP
cells also have the potency to be increased by ischemia.
Thus, there may be a few types of NSCs/NPCs in the
neocortical layer 1. The neocortical layer 1 is composed of
neurons from diverse origins such as the neuroepithelium,
the olfactory primordium, and the GE [111113]. In con-
trast, almost all excitatory neurons in layers 2–6 are
generated from the ventricular zone during development
[114], and the neocortical GABAergic interneurons are
produced in and tangentially migrate from the MGE [115].
The critical difference between L1-INP cells and nestin- or
vimentin-positive NSCs/NPCs is that newborn immature
neurons from the layer 1 nestin- or vimentin-positive
NSCs/NPCs express Pax6 [96], which is essential for
proliferation and differentiation of excitatory neocortical
neurons, such as pyramidal neurons, but not for acquisition
of phenotypes of neocortical GABAergic interneurons
from the MGE [116]. In contrast, almost all new neurons
produced from L1-INP cells are GABAergic neurons.
Although it is not determined whether new neurons from
L1-INP cells express Pax6, GABAergic interneurons from
the MGE do not contain Pax6 [116]. Thus, the possibility
that L1-INP cells are distinct from the layer 1 nestin- or
vimentin-positive NSCs/NPCs may be high.
Why do these various NSCs/NPCs exist in the adult
neocortex? One possibility may be that damage-induced
neurogenesis differs in its origin depending on the degree
and the kind of brain damage. For example, in normal
circumstances, new neurons are generated at very low
levels from NSCs/NPCs in gray matter [75]. After animals
are subjected to a mild injury, such as ischemic insult
resulting from a 10-min occlusion of both common carotid
arteries, layer 1 NSCs/NPCs, including L1-INP cells,
generate new neurons. More intense injuries, such as focal
cerebral ischemia caused by 90-min or permanent clamp
(7–90 days until perfusion) [46, 57], aspiration- [90]or
laser-lesion [96] of the neocortex, and chromophore-tar-
geted neuronal degeneration [80, 88], cause the generation
of new neurons from the SVZ, gray and white matter, and
layer 1. Taken together, it is gradually becoming clear that
the NSCs/NPCs exist in the adult neocortex and their
neurogenesis can be promoted by brain insults. However, at
present, an unshakeable definition of the neocortical NSCs/
NPCs, such as their chemical properties and neurogenetic
kinetics for insults, remains largely unclear. Furthermore,
the functional implications of adult neocortical neurogen-
esis have not been absolutely understood. These questions
are critical issues to be addressed in the future.
Conclusion and perspectives
Adult neurogenesis in the SVZ and the SGZ has been
widely accepted by a great number of studies during the
past two decades. In contrast, it remains controversial
whether adult neurogenesis of the CNS occurs in other
regions. Recently, the phenomena of neocortical adult
neurogenesis and neocortical NSCs/NPCs have been
widely reported, as described above. Neurogenesis in the
adult neocortex may be induced or promoted by brain
insults, such as ischemia and lesions. It has also been
shown that new neurons are present in the striatum, and
that, as expected, neurogenesis in the striatum is greatly
increased under pathological conditions [
41, 43, 5560, 75,
89, 117120]. Surprisingly, there have been several results
for adult neurogenesis in regions other than the neocortex
and the striatum, including the amygdala [71, 85, 117, 120
122], the hippocampal CA region [123], the hypothalamus
[117, 120, 122, 124126], the substantia nigra [127], the
cerebellum [128], the spinal cord [129134], the olfactory
tubercle [135], and the piriform cortex [136]. Of course,
there is some controversy regarding adult neurogenesis
among these regions [82, 86, 92, 137139]. However, at
least in the SVZ, the SGZ, and the neocortical layer 1,
endogenous NSCs and NPCs that can be activated by
physiological stimuli, such as brain insults, are consistently
maintained, suggesting that these NSCs and NPCs might be
the basis for endogenous regenerative therapy for brain
damage.
Currently, two major strategies for regeneration treat-
ment for CNS injury are postulated. One is cell
transplantation to the injured regions. Another is the acti-
vation of endogenous NSCs and NPCs. Each method has
both advantages and disadvantages. For example, the for-
mer depends on a technology to differentiate NSCs and
NPCs into mature functional neurons from ES and iPS cells
in vitro and in vivo [140143]. If a cell differentiation
technology is established, it may be relatively easy to
produce the requirements of cells for the regeneration of a
brain that is completely damaged or deleted. However,
after ES cells and iPS cells are differentiated into mature
1652 K. Ohira
123
Page 8
functional neurons in vitro, it is essential to surgically
transplant the mature neurons. Elderly persons, and those
without physical strength, cannot endure such a surgical
operation. On the other hand, if the mechanisms for
proliferation of endogenous NSCs and NPCs and differ-
entiation of neurons from the endogenous NSCs and NPCs
are clarified, oral preparations that will be developed based
on the mechanism may abolish the surgical burdens on
patients, although the problem of the drugs’ side-effects
should be resolved. Development of a drug-delivery system
and nanotechnology seem to be important. Furthermore,
there is a great advantage in using endogenous NSCs and
NPCs, which might have a lower risk for tumorigenesis.
However, the existence of both endogenous NSCs and
NPCs in damaged tissues must be fundamentally confirmed
to realize the regenerative therapy, namely, if there are no
stem/progenitor cells, there can be no neurogenesis. Thus,
further detailed exploration is necessary to identify
endogenous NSCs and NPCs in the whole brain. The
advantages and disadvantages of the above two methods,
i.e., the activation of endogenous NSCs and NPCs and the
transplantation of exogenous cells, may well complement
each other.
Acknowledgments I thank Dr. Greta Anderson for critical reading
of the manuscript. This work was supported by the Ministry of
Education, Culture, Sports, Science and Technology, Grants-in-Aid
for Young Scientists (B), 21700384.
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    • "Besides physiological levels of adult neurogenesis, injured brains can initiate specific regeneration programs to recover internal homeostasis. In particular acute brain injury can stimulate proliferation of adult NSCs in a wide range of organisms, although their capabilities to form new neurons varies greatly (Arvidsson et al., 2002; Fernandez-Hernandez et al., 2013; Kyritsis et al., 2012; Ohira, 2011). Brain injuries including traumatic brain injury and stroke are frequent and have long-lasting disabling consequences for cognition , sensorimotor function and even personality (Blennow et al., 2012; Xiong et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Neuronal circuits in the adult brain have long been viewed as static and stable. However, research in the past 20 years has shown that specialized regions of the adult brain, which harbor adult neural stem cells, continue to produce new neurons in a wide range of species. Brain plasticity is also observed after injury. Depending on the extent and permissive environment of neurogenic regions, different organisms show great variability in their capacity to replace lost neurons by endogenous neurogenesis. In Zebrafish and Drosophila, the formation of new neurons from progenitor cells in the adult brain was only discovered recently. Here, we compare properties of adult neural stem cells, their niches and regenerative responses from mammals to flies. Current models of brain injury have revealed that specific injury-induced genetic programs and comparison of neuronal fitness are implicated in brain repair. We highlight the potential of these recently implemented models of brain regeneration to identify novel regulators of stem cell activation and regenerative neurogenesis. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jun 2015 · Neuroscience & Biobehavioral Reviews
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    • "Indeed, POSTN treatment significantly enhanced NSC differentiation into neurons and astrocytes in vitro (Fig 2). Consistent with results from previous studies [40, 41] , following hypoxic-ischemic injury, POSTN treatment in neonatal rat brains also enhanced the proliferation and differentiation of NSCs in two neurogenic regions, the SVZ (Fig 3) and the SGZ (Fig 4). HI in itself increases NSC self-renewal, differentiation and maturation [42] . "
    [Show abstract] [Hide abstract] ABSTRACT: Neural stem cell (NSC) proliferation and differentiation are required to replace neurons damaged or lost after hypoxic-ischemic events and recover brain function. Periostin (POSTN), a novel matricellular protein, plays pivotal roles in the survival, migration, and regeneration of various cell types, but its function in NSCs of neonatal rodent brain is still unknown. The purpose of this study was to investigate the role of POSTN in NSCs following hypoxia-ischemia (HI). We found that POSTN mRNA levels significantly increased in differentiating NSCs. The proliferation and differentiation of NSCs in the hippocampus is compromised in POSTN knockout mice. Moreover, NSC proliferation and differentiation into neurons and astrocytes significantly increased in cultured NSCs treated with recombinant POSTN. Consistently, injection of POSTN into neonatal hypoxic-ischemic rat brains stimulated NSC proliferation and differentiation in the subventricular and subgranular zones after 7 and 14 days of brain injury. Lastly, POSTN treatment significantly improved the spatial learning deficits of rats subjected to HI. These results suggest that POSTN significantly enhances NSC proliferation and differentiation after HI, and provides new insights into therapeutic strategies for the treatment of hypoxic-ischemic encephalopathy.
    Full-text · Article · Apr 2015 · PLoS ONE
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    • "Migration to these brain areas from the SVZ has been associated to pathological conditions and to the contribution to tissue regeneration subsequent to injury [12,13,414243, but the controversy remains as to whether these processes also occur in the non-pathological mammal brain. This controversy relays largely in the existence of negative reports that have been counter-argued on the basis of the low level rate of neocortical neurogenesis and the rather small size of the new generated neurons which could render their detectability difficult [44] . Using a combination of doublestaining of BrdU and DCX we were able to detect a small number of new migrating cells in the corpus callosum and striatum of control mice. "
    [Show abstract] [Hide abstract] ABSTRACT: Abuse of toluene-containing inhalants is associated to various cognitive impairments that have been partly associated to deviation of the hippocampal neurogenesis processes during adulthood. In the present study we analyzed the effect of chronic toluene exposure (6000 ppm) on cell proliferation and migration in the other selected area of the rodent brain where neurogenesis persist throughout adulthood, the subventricular zone of the lateral ventricle (SVZ). We used an anti-Ki67 antibody to evaluate SVZ cell proliferation, BrdU to evaluate cell survival and double-staining with BrdU and the migration marker doublecortin (DCX) to evaluate migration, by immunofluorescence 2 h, 1, 5, 10 or 15 days after 20 sessions of toluene exposure. We found that toluene induced an initial burst of cell proliferation in the SVZ but not a significant increase in migration toward the rostral migratory stream (RMS) or the number of cells that migrate to the olfactory bulb. In addition, we detected a small number of new migrating cells in the corpus callosum and striatum of control mice that was similar in toluene-exposed brains. These results may underline the homeostatic capabilities of the populations of dividing cells, previously demonstrated using other drugs of abuse and demonstrate that toluene misuse can alter cellular proliferation in the postnatal brain.
    Full-text · Article · Jul 2014 · Neuroscience Letters
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