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The Journal of Neuroscience, February 1, 2002, 22(3):614-618
MINI REVIEW
Adult Neurogenesis in Mammals: An Identity Crisis
Pasko
Rakic
Department of Neurobiology, Yale University School of Medicine, New
Haven, Connecticut 06520
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ARTICLE |
The study of neurogenesis in the
adult brain is among the most exciting and fastest moving areas of
neuroscience today. In contrast to the high rate of neurogenesis in
some vertebrates (Nottebohm, 2002 ), unambiguous evidence for new
neurons in normal adult mammals ranging from rodents to primates has
been confined to the dentate gyrus and olfactory bulb (Lois and
Alvarez-Buylla, 1964; Kaplan and Hinds, 1977; Kempermann et al.,
1996; Kornack and Rakic, 1999, 2001a,b). These may serve as important
model systems from which we can learn to introduce new neurons into more resistant brain structures (Rakic, 1998). However, the
compelling desire for curing neurological disorders has fostered an
uncommon willingness to accept unsound evidence for adult neurogenesis under normal and experimental conditions. Therefore, it is important to
review the methods for identification of new neurons in the adult brain.
The realization that nerve cells in the adult are not renewed initially
came from the observed paucity of mitotic divisions and a lack of
transient forms from simple to more complex neuronal morphologies
(Ramón y Cajal, 1928). The introduction of the
3H-thymidine
(3H-dT) autoradiographic method for
detecting cell division revealed that, unlike most somatic cells that
are continuously renewed or can be regenerated, neurons behave as a
nonrenewable epithelium (Leblond, 1964).
3H-dT is incorporated into nuclear DNA
during the S phase of the cell cycle, and the amount of incorporation
in a given cell is directly proportional to the number of silver grains
overlaying it; a high level of silver grains in autoradiograms,
after a single intraventricular injection, can be used as a sign of the
"birthday" of a neuron (Fig.
1a,b). In
macaque monkey after intraventricular injection,
3H-dT is present in the bloodstream for
<10 min, and thus provides a highly precise tool for dating the time
of last cell division (Nowakowski and Rakic, 1974). Neurons are
considered new only if the number of overlaying silver grains is at
least 50% of that recorded in maximally labeled nuclei in the same
specimen (Rakic 1973, 1977). Such a stringent criterion is needed to
avoid misinterpreting light labeling caused by background or other
artifacts as a sign of cell division (Nowakowski and Hines, 2000, 2002;
Rakic, 2002). Indeed, the presence of both heavily and lightly labeled
cells has been used as a criterion for confirming that the detected DNA
synthesis is actually caused by cell proliferation (Angevine, 1965).
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Figure 1.
a, Graphic representation of the
level of DNA during different phases of cell cycle
(G1 and
G2, gap phases; D,
mitotic division; S, synthesis phase). The synthesis of
DNA can be detected by the incorporation of 3H-dT or its
analog BrdU. The method of 3H-dT incorporation after a
single injection of the isotope is stoichiometric, and thus allows
distinction between doubling of DNA content during the S phase,
signifying mitotic division, and the light label of <50% of the
maximum grain counts. b, The Purkinje cells in the
middle and on the left can be considered
as heavily labeled, whereas the five grains over the cell nucleus on
the right may be caused by the variety of biological and
technological factors, some of which are discussed in the text.
Importantly, if the animal
were injected with 10, instead of a single
3H-dT dose, this cell may be as heavily labeled as the one
in the middle and could be falsely interpreted as divided.
c, Interference (Nomarski) contrast microphotograph of a
heavily labeled satellite glial cell in the frontal lobe of a monkey
found 35 d after a single injection of 3H-dT (10 mCi/kg). d, Image of a cell in the adult macaque monkey
prefrontal cortex that appears to be double-labeled for BrdU and NeuN,
but was proven to belong to two closely apposed single-labeled cells by
the use of z-series analyses on a confocal microscope. An NeuN-positive
neuron (red) appeared to be colabeled with BrdU
(green) at +0 level (arrow in
d), but examination of a different focal plane (+2.8
µm level) reveals that the NeuN-positive nucleus and nucleolus
actually belong to a neuron that is not BrdU-labeled
(arrowhead in e). The BrdU-labeled
nucleus apparently belongs to adult-generated satellite glia, which in
the cerebral cortex typically associate with neuronal perikarya as seen
also in c. Astrocytes in d and
e are indicated by GFAP immunoreactivity
(blue). For further information, see Kornack and Rakic
(2001b) and Rakic (2002).
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Over the past few decades 3H-dT
autoradiography has been used as a method of choice for determination
of the time of neuron origin in mammals. The most comprehensive data
are available for rodents (rat) and primates (macaque monkey). All
mayor classes of neurons in the structures that range from the spinal
cord to the cerebral cortex have been examined, and their survey is
beyond the scope of this mini-review. For the purpose of the present article, it is sufficient to state that with the exception of interneurons in the olfactory bulb and dentate gyrus, each CNS structure in both of these mammals was found to acquire its neurons during a specific developmental time window. Importantly, the duration
of this time window is not related to the final quantity of neurons in
a given structure [e.g., 1.2 million retinal ganglion cells in macaque
monkey are generated during 40 d (E30-E70), whereas 1.5 million
geniculate neurons are produced in <8 d (E36-E43) (Rakic, 1977;
LaVail et al., 1991)]. Altogether, the results of these studies
indicate that a species-specific size of a given structure is
determined early in the proliferative zone by genes controlling cell
production (i.e., onset, cessation, length of cell cycle,
symmetric-asymmetric mode of cell division, and the rate of programmed
cell death) as well as by regulation of the allocation of postmitotic
cells by the gradients of attractive and repulsive molecules. These
findings in mammals stand in contrast to the high rate of neurogenesis
in many adult vertebrates (Nottebohm, 2002). Thus, overcoming the
resistance of the brain to the acquisition of functionally competent
new neurons will require an understanding of why neurogenesis ceases at
the end of specific developmental time windows and why there are
species-specific and regional variations in this phenomenon (Rakic,
2002).
More recently, evidence for neurogenesis is being obtained by the use
of the thymidine analog bromodeoxyuridine (BrdU), which also
incorporates into DNA during S phase (Nowakowski et al., 1989). The
advantage of this method is that its immunohistochemical detection is
more easily combined with that of various cell class-specific markers
to determine cell phenotype in small neurons such as granule cells that
are difficult to distinguish from astrocytes. It was particularly
useful for the detection of newly generated granule cells that were
difficult to identify with the autoradiographic method. This approach
also allowed for the analysis of changes in the production of specific
cell types under various experimental conditions. However, the
immunohistochemical approach can also lead to false conclusions if
potential technical problems are ignored (Nowakowski and Hayes, 2000,
2002; Rakic 2002). At this time there are no established criteria for
the use of BrdU as a marker of neuronal birth date. It is therefore
crucially important to establish basic standards for detecting the
genesis of new cells and their identity.
Are all BrdU-labeled cells new?
Labeling with BrdU is necessary, but not sufficient, to prove that
a given cell has divided. Thus, BrdU is not a marker for cell division,
but rather a marker for DNA synthesis. Furthermore, in contrast to
3H-dT autoradiography, BrdU
immunohistochemistry is not stoichiometric (Nowakowski and Hines,
2000). Thus, the intensity or extent of labeling is highly
dependent on the methods used for detection and does not necessarily
reflect the magnitude of DNA replication. For this reason, BrdU
labeling as a measure of cell division is especially vulnerable to
misinterpretation. High and multiple doses of BrdU exacerbate this
problem. Although <50 mg/kg is commonly used to label dividing neurons
in the developing brain, the multiple doses of 50-500 mg/kg often used
in adult mammals can produce various artifacts. For example, a high
dose may expose even low levels of normal DNA turnover or minor repairs
as a heavy label in both 3H-dT and BrdU
experiments (Fig. 1). However, BrdU is also considered to be a mutagen
(Morris, 1991), and thus the higher doses may complicate the
results in unpredictable ways. Significantly, many factors and external
agents that modulate the proliferation of granule cells, such as
seizures, are also known to cause cell damage leading to their death
(Bengzon et al., 1997). Furthermore, damaged or degenerating neurons
are known to activate cell cycle-associated proteins such as cyclins
and ubiquitins and initiate abortive DNA synthesis leading to
polyploidy that can persist for many months before the death of a cell
(Neve et al., 2000; Katchanov et al., 2001; Copani et al., 2001; Yang
et al., 2001). Finally, although not demonstrated directly in neurons,
unscheduled DNA synthesis is an evolutionary device to provide
additional gene copies to enhance transcription in metabolically more
active cells or in situations of higher demand, as shown in hepatocytes
(Anatskaya et al., 1994). This may occur in cells that have very little
RNA to meet such demands. Indeed, granule cells may be particularly vulnerable to oxidative or other adverse conditions (e.g.,
NMDA-receptor-mediated cytotoxicity) and respond with a higher
level of DNA repair (Pieper et al., 2000). Thus, the change of BrdU
incorporation in response to various experimental conditions and
exposure to drugs based solely on immunohistochemistry leaves open the
possibility that the labeled nuclei belong to "old neurons" that
have increased incorporation of exogenous nucleotides into their DNA
(Fig. 2).
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Figure 2.
Exogenous 3H-dT (red
dots) or BrdU (blue squares) compete with the
natural endogenous H-dT for incorporation into nuclear DNA.
a, During S phase of cell cycle, incorporation occurs
predominately into new stands of DNA, and provided that the cell stops
dividing, significant presence of these marks indicates the time of
final cell division. b, Incorporation of nucleotides
occurs at a slower rate as part of DNA turnover or repair (of both
strands) or at the higher rate during an abortive cell cycle
(predominately in a single strand) leading to recovery or death (for
further explanation, see text and Fig. 1).
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Because BrdU labeling is not a sufficient sign of cell division,
neurogenesis must be demonstrated by independent means. Other markers
used to detect "new" neurons in the adult brain, such as the
nuclear antigen proliferating cell nuclear antigen, can also be
expressed by nonproliferating neurons and are not valid substitutes
(Ino and Chiba, 2000). An appropriate increase in the number of mitotic
figures should be demonstrated after various experimental
manipulations. Because the presence of mitotic figures itself cannot be
used for the phenotypic fate determination of the cell, it is important
to show that there is an appropriate increase in BrdU-labeled mitotic
figures to establish that the labeling is attributable to DNA
replication associated with proliferation and not caused by unscheduled
DNA synthesis. Tracing cell history from the phase of mitotic division
through the bipolar migratory stage to the final differentiated states
should be done by either 3H-dT or BrdU
sequential experiments or by the retroviral gene transfer method. The
use of TuJ1 expression in immature neurons is helpful. However,
continuous generation of neurons should also be documented by an
increase in the absolute number of neurons. If the numbers of neurons
remain unchanged, an increase in the number of pyknotic cells,
equivalent to the proposed neuronal addition, should be demonstrated
(Nowakowski and Hayes, 2000).
Are new cells neurons?
As a next step, each newly generated cell must be unambiguously
identified as a neuron. Double labeling is not necessary for identification of most CNS neurons, such as Purkinje cells or cortical
neurons that are easily recognized (Fig. 1b,c), but is essential for identification of granule cells that are similar to glia
in size, shape, and tinctorial properties in classical histological
preparations. The use of BrdU immunodetection theoretically allows the
use of other antibodies or methods for the determination of cell type,
neurotransmitter phenotype, and even receptors on the surface of the
labeled cell. Unfortunately, many of the so-called "neuron-specific" markers also label other cell classes as well. For example, the often used "neuron specific enolase",
mitogen-activated protein-2, and TOAD 64 (TUC-4Ulip1),
are inappropriate as specific markers for neurons, because they also
react with astrocytes and/or oligodendrocytes (Deloulme et al., 1996;
Sensenbrenner et al., 1997; Nacher et al., 2000; Ricard et al.,
2001). The antigenic target of the NeuN antibody, used universally
(including in our laboratory) as a neuron-specific marker has not as
yet been identified. This antibody also has been reported to stain
non-neuronal cells ranging from ependymoma (Parker et al., 2001) to
bone marrow cells under certain conditions (Woodbury et al., 2000;
Brazelton et al., 2001; Lu et al., 2001). On the other hand,
NeuN does not recognize all neurons, and thus paradoxically, mitral or
Purkinje cells (Fig. 1b), which do not immunoreact with
NeuN, would not be considered as neurons! Is a single antigen to the
unknown molecule sufficient to identify a "neuronal phenotype"?
Demonstrating the connections of a cell (Stanfield and Trice, 1988;
Markakis and Gage, 2000) or existence of synapses (Kaplan and Hinds,
1977) seems to be a reasonable requirement.
False-positive identification of neurons can also be obtained because
of nonspecific binding of antibodies. Likewise, an antibody specific in
rodents may not be equally specific in other species that may harbor
molecules with similar epitopes in their non-neural cells. Thus, when
the results are unusual or have extraordinary implications, it would
seem wise to run essential controls and to establish antibody
specificity. Finally, superimposition of small satellite glial cells
closely apposed to the neuronal soma can mimic neuronal labeling, and
Z-stacks of serial optical planes should be used to insure double
labeling of a neuron (Fig. 2d,e) (Kuhn et al., 1997; Kornack
and Rakic 2001b).
What is an adult?
Another parameter that should be more precisely defined in all
studies is the term "adult." Notation of the precise age of experimental animals is particularly important in research on brain
repair or on models of neurological and psychiatric diseases that
afflict humans predominantly at middle or advanced age (Stewart et al.,
2000). It has been shown, for example, that neurogenesis in the rodent
dentate gyrus decreases with age, and that at 21 months, approximately
the midpoint in their life span, is <10% of that observed at 6 months
(Kuhn et al., 1996). Furthermore, the rate of survival of newly born
dentate granule cells in response to experimental conditions changes
with age (Kempermann et al., 1988). It follows that results obtained in
4- to 6-week-old rats or monkeys <3 years old should not be
generalized to the adult brain. Sometimes juvenile animals are
classified as adults. The common use of weight as an index of an animal
age is also not a sufficient criterion. The time of the initial
mortality rate (IMR) and the time required for mortality to double
(MRD) are more useful criteria as in studies of aging (Finch et al.,
1990). The midpoint of the average life span, which is ~1.5 years of age in mice, 10 years in macaque, and ~30 years in human (Finch, 1990), may serve as a rough estimate of the tempo of aging among mammalian species. Because the aging process and duration of the life
span vary greatly among mammalian species, among different strains of
animals, as well as between genders, it seems obvious that a consensus
should be developed and applied on what constitutes an adult organism
in each species that serves as subjects in studies of adult neurogenesis.
A need for uniform standards
We have witnessed some remarkable discoveries and expect exciting
advances in this field. However, even a cursory examination of the
recent literature indicates that some studies do not satisfy even one
basic criterion for neurogenesis, and very few met rigorous criteria. A
more detailed discussion of the pitfalls of the methods used, as well
as a criticism of the specific studies in primates is provided
elsewhere (Korr and Schmitz, 1999; Nowakowski and Hayes, 2000; Kornack
and Rakic, 2001b; Rakic, 2002). Those interested in the controversy
about the claim for a large daily addition and/or turnover of neurons
in the primate association neocortex should consult the recent detailed
evaluation of the evidence (Rakic, 2002). It seems also prudent that
some reports of the generation of "new neurons" after various
experimental manipulations and exposure to drugs be re-evaluated using
more stringent criteria. This is also true for the studies directing
differentiation of stem cells along neuronal lineages or their
transplantation to replenish normally nonrenewable neurons that have
therapeutic promise (Anderson et al., 2001). Isolation of well
characterized neuronal stem cells from the subependymal zone of a
variety of adult species, including human, is a first step in this
direction (Kakita and Goldman, 1996; Kirshenbaum et al., 1996; Doetsch
et al., 1999; Laywell et al., 2000; Gage, 2001). However, standard and
uniform criteria for the identification of "new cells" as well as
"neuronal phenotype" should be applied by authors as well as by
journal reviewers to assure scientifically sound advances in this
promising field.
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FOOTNOTES |
This work was supported in part by the National Institutes of Heath. I
am grateful to P. Goldman-Rakic, K. Herrup, D. R. Kornack, E. A. Markakis, and N. Sestan for their insightful discussion and comments
on this manuscript.
Correspondence should be addressed to Dr. Rakic at the above address.
E-mail: pasko.rakic{at}yale.edu.
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REFERENCES |
-
Anatskaya OV,
Vinogradov AE,
Kudryavtsev BN
(1994)
Hepatocyte polyploidy and metabolism/life-history traits: hypotheses testing.
J Theor Biol
168:191-199[Medline].
-
Anderson JD,
Gage FH,
Weissman IL
(2001)
Can stem cells cross lineage boundaries.
Nat Med
7:393-395[Web of Science][Medline].
-
Angevine Jr JB
(1965)
Time of neuron origin in the hippocampal region. An autoradiographic study in the mouse.
Exp Neurol [Suppl]
2:1-70.
-
Bengzon J,
Kokaia Z,
Elmer E,
Nanobashvili A,
Kokaia M,
Lindvall O
(1997)
Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures.
Proc Natl Acad Sci USA
94:10432-10437[Abstract/Free Full Text].
-
Brazelton TR,
Rossi FM,
Keshet GI,
Blau HM
(2000)
From marrow to brain: expression of neuronal phenotypes in adult mice.
Science
290:1775-1779[Abstract/Free Full Text].
-
Copani A,
Uberti D,
Sortino AM,
Bruno V,
Nicoletti F,
Memo M
(2001)
Activation of cell cycle-associated proteins in neuronal death: a mandatory or dispensable path.
Trends Neurosci
24:25-31[Web of Science][Medline].
-
Deloulme JC,
Lucas M,
Gaber C,
Bouillon P,
Keller A,
Eclancher F,
Sensenbrenner M
(1996)
Expression of the neuron-specific enolase gene by rat oligodendroglial cells during their differentiation.
J Neurochem
66:936-945[Web of Science][Medline].
-
Doetsch F,
Caille I,
Lim DA,
Garcia-Verdugo JM,
Alvarez-Buylla A
(1999)
Subventricular zone astrocytes are neural stem cells in adult mammalian brain.
Cell
97:703-716[Web of Science][Medline].
-
Finch CE
(1990)
In: Longevity, senescence and the genome. Chicago: University of Chicago.
-
Finch CE,
Pike MC,
Witten M
(1990)
Slow mortality-rate accelerations during aging in some animals approximate that of humans.
Science
249:902-905[Abstract/Free Full Text].
-
Gage FH
(2000)
Mammalian neural stem cells.
Science
287:1433-1438[Abstract/Free Full Text].
-
Ino H,
Chiba T
(2000)
Expression of proliferating cell nuclear antigen (PCNA) in the adult and developing mouse nervous system.
Mol Brain Res
78:163-174[Medline].
-
Kakita A,
Goldman JE
(1999)
Patterns and dynamics of SVZ cell migration in the postnatal forebrain: monitoring living progenitors in slice preparations.
Neuron
23:461-472[Web of Science][Medline].
-
Kaplan MS,
Hinds JW
(1977)
Neurogenesis in the adult rat: Electron microscopic analysis of light radiographs.
Science
197:1092-1094[Abstract/Free Full Text].
-
Katchanov J,
Harms C,
Gertz K,
Hauck L,
Waeber C,
Hirt L,
Priller J,
von Harsdorf R,
Bruck W,
Hortnagl H,
Dirnagl U,
Bhide GP,
Endres M
(2001)
Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death.
J Neurosci
21:5045-5053[Abstract/Free Full Text].
-
Kempermann G,
Kuhn HG,
Gage FH
(1988)
Experience-induced neurogenesis in the senescent dentate gyrus.
J Neurosci
18:3206-3212[Abstract/Free Full Text].
-
Kempermann G,
Kuhn HG,
Gage FH
(1996)
Genetic influence on neurogenesis in the dentate gyrus of adult mice.
Proc Natl Acad Sci USA
9:19409-19414.
-
Kirschenbaum B,
Nedergaard M,
Preuss A,
Barami K,
Fraser RA,
Goldman SA
(1994)
In-vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain.
Cereb Cortex
4:576-589[Abstract/Free Full Text].
-
Kornack DR,
Rakic P
(1999)
Continuation of neurogenesis in the hippocampus of the adult macaque monkey.
Proc Natl Acad Sci USA
96:5768-5773[Abstract/Free Full Text].
-
Kornack RD,
Rakic P
(2001a)
Generation and migration of new olfactory neurons in adult primates.
Proc Natl Acad Sci USA
98:4752-4757[Abstract/Free Full Text].
-
Kornack RD,
Rakic P
(2001b)
Cell proliferation without neurogenesis in adult primate neocortex.
Science
294:2127-2130[Abstract/Free Full Text].
-
Korr H,
Schmitz C
(1999)
Facts and fictions regarding post-natal neurogenesis in the developing human cerebral cortex.
J Theor Biol
200:291-297[Medline].
-
Kuhn HG,
Dickinson-Anson H,
Gage FH
(1996)
Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation.
J Neurosci
16:2027-2033[Abstract/Free Full Text].
-
Kuhn HG,
Winkler J,
Kempermann G,
Thal LJ,
Gage FH
(1997)
Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain.
J Neurosci
17:5820-5829[Abstract/Free Full Text].
-
LaVail MM,
Rapaport DH,
Rakic P
(1991)
Cytogenesis in the monkey retina.
J Comp Neurol
309:86-114[Web of Science][Medline].
-
Laywell ED,
Rakic P,
Kukekov VG,
Holland EC,
Steindler DA
(2000)
Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain.
Proc Natl Acad Sci USA
97:138883-13888.
-
Leblond CP
(1964)
Classification of cell populations on the basis of their proliferative behavior.
Nat Cancer Inst Monog
14:119-150.
-
Lois C,
Alvarez-Buylla A
(1964)
Long-distance neuronal migration in the adult mammalian brain.
Science
264:1145-1148.
-
Lu D,
Mahmood A,
Wang L,
Li Y,
Lu M,
Chopp M
(2001)
Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome.
NeuroReport
12:559-563[Medline].
-
Markakis EA,
Gage FH
(2000)
Adult-generated neurons in the dentate gyrus send axonal projections to field CA(3) and are surrounded by synaptic vesicles.
J Comp Neurol
406:449-460.
-
Morris SM
(1991)
The genetic toxicology of 5-bromodeoxyuridine immunohistochemical determination of the in mammalian cells.
Mutant Res
258:161-188[Web of Science][Medline].
-
Nacher J,
Rosell DR,
McEwen BS
(2000)
Widespread expression of rat collapsin response-mediated protein 4 in the telencephalon and other areas of the adult rat central nervous system.
J Comp Neurol
4:628-639.
-
Neve R,
McPhie DL,
Chen Y
(2000)
Alzheimer's disease; a dysfunction of the amyloid precursor protein.
Brain Res
886:54-66[Web of Science][Medline].
-
Nottebohm F
(2002)
Why are some neurons replaced in adult brain?
J Neurosci
22:624-628[Free Full Text].
-
Nowakowski RS,
Hayes NL
(2000)
New neurons: extraordinary evidence or extraordinary conclusion?
Science
288:771a[Free Full Text]. See details in Technical Comment on line: http://www.sciencemag.org/cgi/content/ful/288/5467/771a.
-
Nowakowski RS, Hayes NL (2002) Stem cells: the promises and
pitfalls. Neuropsychopharmacology, in press.
-
Nowakowski RS,
Rakic P
(1974)
Decrease of exogenous thymidine-H3 in the plasma of pregnant rhesus monkeys.
Cell Tissue Kinet
7:l89-l94.
-
Nowakowski RS,
Lewin SB,
Miller MW
(1989)
Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population.
J Neurocytol
18:311-318[Web of Science][Medline].
-
Parker JR,
Armstrong DL,
Strother D,
Rudman DM,
Dauser RC,
Laurent JP,
Deyd J,
Rouah PE
(2001)
Antineuronal nuclei immunohistochemical staining patterns in childhood ependymomas.
J Child Neurol
8:548-552.
-
Pieper AA,
Blackshaw S,
Clements EE,
Brat DJ,
Krug DK,
White AJ,
Pinto-Garcia P,
Favit A,
Conover JR,
Snyder SH,
Verma A
(2000)
Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission.
Proc Natl Acad Sci USA
97:1845-1850[Abstract/Free Full Text].
-
Rakic P
(1973)
Kinetics of proliferation and latency between final cell division and onset of differentiation of cerebellar stellate and basket neurons.
J Comp Neurol
l47:523-546.
-
Rakic P
(1977)
Genesis of the dorsal lateral geniculate nucleus in the rhesus monkey: site and time of origin, kinetics of proliferation, routes of migration and pattern of distribution of neurons.
J Comp Neurol
l76:23-52.
-
Rakic P
(1998)
Young neurons for old brains?
Nat Neurosci
1:643-645[Web of Science][Medline].
-
Rakic P
(2002)
Neurogenesis in adult primate neocortex: an evaluation of the evidence.
Nat Rev Neurosci
3:65-71[Web of Science][Medline].
-
Ramón y Cajal S
(1928)
In: Degeneration and regeneration of the nervous system (Day RM, translator, from the 1913 Spanish edition). London: Oxford UP.
-
Ricard D,
Rogemond V,
Charrier E,
Aguera M,
Bagnard D,
Belin M-F,
Thomasset N,
Honnorat J
(2001)
Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3A-sensitive oligodendrocytes.
J Neurosci
21:7203-7214[Abstract/Free Full Text].
-
Sensenbrenner M,
Lucas M,
Deloulme JC
(1997)
Expression of two neuronal markers, growth-associated protein 43 and neuron-specific enolase, in rat glial cells.
J Mol Med
75:653-663[Web of Science][Medline].
-
Stanfield B,
Trice JE
(1988)
Evidence that granule cells generated in the dentate gyrus of adult rat extend axonal projections.
Exp Brain Res
72:399-406[Web of Science][Medline].
-
Steward O,
Schauwecker PE,
Guth L,
Zhang Z,
Fujiki M,
Inman D,
Wrathall J,
Kempermann G,
Gage FH,
Saatman KE,
Raghupathi R,
McIntosh T
(1999)
Genetic approaches to neurotrauma research: opportunities and potential pitfalls of murine models.
Exp Neurol
157:19-42[Web of Science][Medline].
-
Woodbury D,
Schwarz EJ,
Prockop DJ,
Black IB
(2000)
Adult rat and human bone marrow stromal cells differentiate into neurons.
J Neurosci Res
61:364-370[Web of Science][Medline].
-
Yang Y,
Geldmacher DS,
Herrup K
(2001)
DNA replication precedes neuronal cell death in Alzheimer's disease.
J Neurosci
15:2661-2668.
Copyright © 2002 Society for Neuroscience 0270-6474/02/223614-05$05.00/0
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|
|
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|
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|
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|
|
|
|
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|
|
|
|
|
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|
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[Full Text]
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|
|
|
|
|
|
|
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[Full Text]
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|
|
|
|
|
|
|
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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206(17):
3085 - 3093.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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|
|
|
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|
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[Full Text]
[PDF]
|
|
|
|
|
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|
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23(3):
937 - 942.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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10864 - 10870.
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[Full Text]
[PDF]
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|
|
|
|
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16(23):
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[Full Text]
[PDF]
|
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