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The Journal of Neuroscience, May 1, 1998, 18(9):3206-3212
Experience-Induced Neurogenesis in the Senescent Dentate
Gyrus
Gerd
Kempermann1,
H.
Georg
Kuhn1, 2, and
Fred H.
Gage1
1 The Salk Institute for Biological Studies,
Laboratory of Genetics, La Jolla, California 92037, and
2 Department of Neurology, University of Regensburg,
D-93053 Regensburg, Germany
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ABSTRACT |
We demonstrate here that under physiological conditions
neurogenesis continues to occur in the dentate gyrus of senescent mice
and can be stimulated by living in an enriched environment. Neurogenesis was investigated by confocal microscopy of three-channel immunofluorescent staining for the proliferation marker
bromodeoxyuridine (BrdU) and neuronal and glial markers. Quantification
was performed with unbiased stereological counting techniques.
Neurogenesis decreased with increasing age. Stimulation of adult and
aged mice by switching from standard housing to an enriched environment with opportunities for social interaction, exploration, and physical activity for 68 d resulted in an increased survival of labeled cells. Phenotypic analysis revealed that, in enriched living animals, relatively more cells differentiated into neurons, resulting in a
threefold net increase of BrdU-labeled neurons in 20-month-old mice
(105 vs 32 cells) and a more than twofold increase in 8-month-old mice
(684 vs 285 cells) compared with littermates living under standard
laboratory conditions. Corresponding absolute numbers of BrdU-positive
astrocytes and BrdU-positive cells that did not show colabeling for
neuronal or glial markers were not influenced. The effect on the
relative distribution of phenotypes can be interpreted as a
survival-promoting effect that is selective for neurons. Proliferation
of progenitor cells appeared unaffected by environmental stimulation.
Key words:
aging; brain; mouse; hippocampus; neurogenesis; stem
cell; progenitor cell; enriched environment; plasticity; stereology
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INTRODUCTION |
New neurons are continuously born in
the dentate gyrus of the hippocampal formation in adult mammals. At the
age of 2 months, the dentate gyrus of adult C57BL/6 mice produces an
average of approximately one new granule cell neuron per 1700 existing
granule cells per day (Kempermann et al., 1997a ). The functional
significance of these new cells, however, remains elusive.
The aging hippocampal formation is affected by a number of structural
and functional changes, including the loss of neurons in CA regions and
the hilus (West et al., 1994), reduced synaptic densities (Saito et
al., 1994), and reduced expression of growth factor and steroid
receptors (Bhatnagar et al., 1997). Neurogenesis in the dentate gyrus
occurs throughout the life of a rat (Altman and Das, 1965; Kaplan and
Bell, 1984; Cameron et al., 1993; Kuhn et al., 1996) but decreases with
increasing age (Kuhn et al., 1996). The extent to which the remaining
neurogenesis in the dentate gyrus is regulated and has functional
consequences is still unknown.
We have used the experimental paradigm of an enriched environment
(Rosenzweig et al., 1962; Rosenzweig and Bennett, 1996) to demonstrate
experience-induced plasticity of neuronal numbers in the dentate gyrus
(Kempermann et al., 1997b). This finding placed adult neurogenesis in
the dentate gyrus in a functional context and raised the question of
whether use-dependent neuroplasticity is possible in the old brain.
In the present study, we examined the effects of living in an enriched
environment on neurogenesis in the dentate gyrus of C57BL/6 mice at the
ages of 6 and 18 months. The four groups of mice in the study are
referred to as Ctr-6, 6-month-old control; Ctr-18, 18-month-old
control; Enr-6, 6-month-old enriched; and Enr-18, 18-month-old
enriched. At the end of the experiment the animals were 8 and 20 months
old, respectively. These ages represent midlife and senescence,
considering that the average life span of a female C57BL/6 mouse is 26 months (Kunstyr and Leuenberger, 1975) and the mouse menopause is at
~13 months of age (Silver, 1995). Before the experimental period,
which lasted 40 or 68 d, all animals were housed under standard
laboratory conditions. Neurogenesis was examined by (1) incorporation
of bromodeoxyuridine (BrdU) in the DNA of proliferating cells and
immunohistochemical detection of BrdU, (2) immunofluorescent
triple-labeling for BrdU and neuronal and glial markers and confocal
laser microscopy to examine the phenotypes of surviving BrdU-positive
cells, and (3) unbiased stereological counting techniques to obtain
absolute cell numbers. In addition, the animals were tested on a water maze task to examine spatial learning as a measure of hippocampal function.
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MATERIALS AND METHODS |
Housing conditions. Fifty female C57BL/6 mice, half 6 months old and the other half 18 months old, were obtained from the aging colony at the National Institute of Aging. Twelve animals per age
group were housed in four standard cages; 13 per age group were placed
in an enriched environment. Enriched living conditions are described in
Figure 1 and did not differ from the
set-up in our previous study (Kempermann et al., 1997b). There were
separate cages with enriched environments for each age group. The time course of the experiments is displayed in Figure
2. Animals lived in their respective
experimental conditions for 40 d. During the last 12 d they
received BrdU injections (see below). On day 41 five animals from each
group were killed with an overdose of anesthetics and perfused
transcardially with cold 4% paraformaldehyde in 0.1 M PBS.
The remaining animals continued to live under their respective experimental conditions for 28 d. During this time they were
tested on the water maze task (see below) and perfused on day 68.
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Figure 1.
A, One of the cages for an enriched
environment; B, One standard cage at the same scale (the
trays for food and water are removed). Enrichment consisted of social
interaction (13 mice in the large cage vs 3 in the standard cage),
stimulation of exploratory behavior with objects such as toys and a
rearrangeable set of tunnels, and C, physical activity
in a running wheel. In addition to standard food and water ad
libitum, enriched mice received occasional treats, including
cheese, crackers, and fruits.
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Figure 2.
Experimental design applied to each of the two age
groups (6 or 18 months at the beginning of the experiment). The 12 d period of daily BrdU injections is symbolized by syringes.
WMZ, Behavioral testing on the water maze task.
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BrdU injections. BrdU (Sigma, St. Louis, MO) was dissolved
in 0.9% NaCl and filtered sterile at 22 µm. The mice received single doses of 50 µg/gm of body weight at a concentration of 10 mg/ml, one
intraperitoneal injection per day for 12 consecutive days (Fig. 2).
Water maze testing. Seven mice from each group were tested
with two trials per day over 10 d. The platform was hidden below the surface of the opaque water. The two starting points were changed
daily. Each trial lasted either until the mouse had found the platform
or for a maximum of 60 sec. All mice were allowed to rest on the
platform for 10 sec. Analyses of time to reach the platform (latency),
length of swim path, and swim speed were recorded semiautomatically by
a video tracking system (San Diego Instruments). On day 11 a probe
trial with the platform removed was performed and did not show
differences among the groups.
Immunohistochemistry. Immunohistochemistry for BrdU and
immunofluorescent triple labeling for BrdU, NeuN, and S100 was
performed as described previously (Kuhn et al., 1997). All staining was done on free-floating 40 µm sections that were pretreated for BrdU
immunohistochemistry by denaturing DNA. The antibodies used were mouse
anti-BrdU (Boehringer Mannheim, Indianapolis, IN), 1:400; rat anti-BrdU
ascites (Accurate; for triple-labeling), 1:100; rabbit anti-S100
(Swant), 1:2500; and mouse anti-NeuN (kindly provided by R. J. Mullen, University of Utah, Salt Lake City, UT), 1:20. To determine the
number of BrdU-positive cells, staining for BrdU with the peroxidase
method was used (ABC system, with biotinylated horse anti-mouse
antibodies and diaminobenzedine as chromogen; Vector Laboratories,
Burlingame, CA). The fluorescent secondary antibodies used were
anti-mouse FITC, anti-rat Texas Red, and anti-rabbit CY-5 (Jackson
ImmunoResearch, West Grove, PA), 6 µl/ml.
Analysis of phenotypes. Sections from animals surviving 4 weeks after the last injection of BrdU were triple-labeled as described above and analyzed by confocal microscopy (Zeiss, Bio-Rad, Richmond, CA). In total, 50 BrdU-positive cells per animal were analyzed for
coexpression of BrdU and NeuN for neuronal phenotype and S100 for
glial phenotype. To achieve this number of analyses over the rostrocaudal extension of the dentate gyrus, a 1 of 12 series of 40 µm sections in Ctr-6 and Enr-6 and a one of six series in Ctr-18 and
Enr-18 were required. The microscopic analysis yielded a ratio of
BrdU-positive cells colabeling with (1) NeuN, (2) S100, or (3)
neither NeuN nor S100. These ratios were multiplied with the total
number of surviving BrdU-labeled cells to give an estimate of the total
number of BrdU-positive neurons, BrdU-positive astrocytes, and
BrdU-positive cells that acquired neither phenotype during the 4 weeks
after the last BrdU injection.
Stereology. The number of granule cells was determined in
every sixth section in a series of 40 µm coronal sections using unbiased stereology (optical disector; Gundersen et al., 1988). A
recent commentary seemed to suggest that the optical disector method
has few benefits over traditional, so-called intuitive counting
techniques, when these are combined with appropriate correction
procedures (Guillery and Herrup, 1997). Although the disector method is
not assumption-free and therefore not absolute or objective in a very
strict sense, it has the following advantages: (1) the structure volume
is taken into consideration; (2) the procedure can be computerized to a
large degree; and (3) the results are highly reliable and as absolute
or objective as technically possible (Gundersen et al., 1988;
Coggeshall and Lekan, 1996). The words absolute or total are used here
in a practical, not a theoretical or philosophical, sense.
Systematic samplings of unbiased counting frames of 15 µm on a side
with a 200 µm matrix spacing were produced using a semiautomatic stereology system (StereoInvestigator, MicroBrightfield, Inc.) and a
60× SPlan apo oil objective (1.4 numerical aperture). Granule cells
were stained with Hoechst 33342 (Molecular Probes, Eugene, OR; 0.5 mg/ml Tris-buffered saline for 15 min); those that intersected the
uppermost focal (exclusion) plane and those that intersected the
exclusion boundaries of the unbiased sampling frame were excluded from
counting. Cells that met the counting criteria through a 40 µm axial
distance were counted according to the optical disector principle. The
granule cell layer reference volume was determined by summing the
traced granule cell areas for each section multiplied by the distance
between sections sampled. The mean granule cell number per disector
volume was multiplied by the reference volume to estimate the total
granule cell number. Because BrdU-positive cells were so rarely
encountered, sampling of these cells was done exhaustively throughout
the extent of the granule cell layer, modifying the optical disector
procedure to exclude the top focal plane only, and omitting the
exclusion and inclusion boundaries of the unbiased sample frame. The
resulting number of BrdU-positive cells was then related to the granule
cell layer sectional volume and multiplied by the reference volume to
estimate the total number of BrdU-positive cells.
Statistical analysis. All statistical analyses were
performed with Statview 4.01 for Macintosh. For all comparisons of
morphological data factorial ANOVAs were performed followed by a
Fisher's post hoc test, when appropriate. The level of
significance was assumed to be 5%. To assess the percentage of
surviving BrdU-positive cells, the individual values of the numbers of
BrdU-positive cells at 4 weeks after injection were divided by the mean
number of BrdU-positive cells at 1 d after injection. Water maze
data were analyzed within each age group by ANOVA with repeated
measures, followed by Fisher's post hoc test. The mean
values of the two trials per day were regarded as repeated measures for
overall analysis over days.
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RESULTS |
Neurogenesis, defined as birth of new nerve cells, consists of a
series of distinct developmental steps, three of which can be examined
separately: proliferation, survival, and differentiation.
Proliferation of progenitor cells in the subgranular zone was addressed
by BrdU labeling of dividing cells and consecutive immunohistochemical
analysis with antibodies against BrdU 1 d after the last injection
of BrdU. At this time point we did not see any significant effect of
living in an enriched environment on proliferation of cells in the
dentate gyrus (Fig. 3A).
However, proliferation of hippocampal progenitor cells decreased with
age, because senescent mice (Ctr-18) had significantly fewer
BrdU-positive cells compared with mice at medium age (Ctr-6)
(p < 0.0001).
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Figure 3.
A, Total number of BrdU-positive
cells per dentate gyrus 1 d after the last injection of BrdU to
estimate ongoing proliferation (hatched bars) and 4 weeks later to assess survival of BrdU-positive cells (open
bars). B, C, Percentage of the
surviving BrdU-positive cells (compare with B) that
differentiated into either neuronal (filled bars)
or glial (hatched bars) phenotype or showed neither
differentiation (open bars). D, the total
number of BrdU-labeled neurons generated over the 12 d of BrdU
injections (values derived from the phenotypic ratio times the number
of BrdU-positive cells at 4 weeks). Note that because the number of
BrdU-positive cells is influenced by cell cycle parameters, no absolute
statements about the size of the population of proliferating neuronal
progenitor cells are possible. *p < 0.05;
**p < 0.005. For details on statistical analyses
see Materials and Methods.
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Survival of the progeny of dividing progenitor cells can be addressed
by staining for BrdU-positive cells 4 weeks after the last injection of
BrdU and comparing the number of labeled cells with the number obtained
at 1 d after the last injection (Fig. 3A). We found
that the total number of surviving BrdU-positive cells after 4 weeks
significantly decreased in old age (Ctr-6 vs Ctr-18; p = 0.0081). Living in an enriched environment increased the number of
surviving labeled cells by 68% at age 6 months
(p = 0.0025) and by 32% in 18-month-old mice
(p > 0.05; Fig. 3A). When the number
of surviving cells was expressed as a ratio of the number of cells at
1 d after the last injection, it was found that age alone had no
significant survival-promoting effect. In Ctr-6 on average 42.7 ± 1.8% of the labeled cells at 1 d after injection were detectable
4 weeks later, whereas 60.7 ± 7.3% were found in Ctr-18
(p = 0.1540; all values mean ± SEM).
Differentiation of the surviving BrdU-positive cells was examined 4 weeks after the last injection by determining the phenotypes into which
surviving BrdU-positive cells had differentiated by means of confocal
microscopy and immunofluorescent triple labeling for BrdU, neuronal
marker NeuN (Mullen et al., 1992), and glial marker S100 (Boyes et
al., 1986) (Fig. 4). In Enr-18, neurons (NeuN-positive cells) accounted for 28.6 ± 8.6% of the surviving BrdU-positive cells versus 12.6 ± 7.3% in Ctr-18
(p = 0.0002); in Enr-6 we found 58.0 ± 6.8% neurons versus 40.8 ± 4.7% in Ctr-6 (p < 0.0001; Fig. 3B,C).
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Figure 4.
Confocal microscopic analysis of immunofluorescent
triple-labeling of BrdU-positive cells (red) 1 d
(A) and 4 weeks (B-D)
after the last injection of BrdU. A, Overview of the
distribution of BrdU-positive cells along the border between the
arrowhead-shaped granule cell layer of the dentate gyrus and the hilar
area CA4 (compare with hatched columns in Fig.
3A). In addition there are some proliferating cells in
the hilus itself and in the molecular layer. No qualitative difference
among the four groups could be found. Four weeks after injection the
phenotypes of BrdU-labeled cells were examined
(B-D). Markers were NeuN
(green) for neurons and S100
(blue) for astrocytes. B, Two
BrdU-labeled neurons (orange = red + green) and one
BrdU-positive cell that is neither NeuN- nor S100-positive in an
Enr-6 animal. C, BrdU-labeled neuron with the typical
chromatin pattern of a granule cell in an Enr-18 animal.
D, One BrdU-labeled astrocyte (pink = red + blue, left) and one BrdU-labeled neuron (orange,
right). Scale bar (in A): A, 200 µm; B, C, 12 µm;
D, 20 µm.
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Enr-18 mice generated on average a total of 105 ± 18 BrdU-labeled
neurons per dentate gyrus versus only 32 ± 7 in Ctr-18 mice during the 12 d of BrdU injection (a threefold increase;
p = 0.0035) (Fig. 3D). By comparison, Enr-6
produced 684 ± 104 BrdU-labeled neurons, whereas Ctr-6 produced
an average of 285 ± 22 (a twofold increase; p = 0.0109). This effect was greater in absolute terms at 6 months but
greater in relative terms at 18 months.
At 4 weeks after the last injection of BrdU, astrocytes
(S100-positive cells) accounted for 19.7 ± 3.2% of surviving
BrdU-positive cells in Ctr-6, 15.5 ± 1.7% in Enr-6, 32.9 ± 2.0% in Ctr-18, and 26.6 ± 1.8% in Enr-18. There was no
significant difference between Ctr-6 and Enr-6
(p = 0.1864) and Ctr-18 and Enr-18
(p = 0.0553). In absolute terms, there were
133 ± 20 BrdU-labeled astrocytes in Ctr-6, 185 ± 38 in
Enr-6, 92 ± 13 in Ctr-18, and 99 ± 16 in Enr-6. Again, no
significant difference between Ctr-6 and Enr-6 (p = 0.1516) and Ctr-18 and Enr-18
(p = 0.8389) was found.
BrdU-positive cells that did not show colocalization with either NeuN
of S100 accounted for 39.4 ± 2.4% in Ctr-6 (absolute number,
275 ± 23), 26.5 ± 2.8% in Enr-6 (299 ± 49),
56.0 ± 1.6% in Ctr-18 (154 ± 20), and 44.8 ± 9.3%
in Enr-18 (160 ± 22). Statistical analysis showed that the
relative values were significantly different in both age groups
(p = 0.0027 for Ctr-6 vs Enr-6;
p = 0.0079 for Ctr. 18 vs Enr-18) but not the absolute
numbers (p = 0.6099 and p = 0.8965, respectively).
The effects of enrichment-induced neurogenesis on total granule cell
numbers were assessed by means of unbiased stereological techniques
(Table 1). However, in this comparison of
two cellular populations of very different size, the interindividual
variance in the total granule cell number within each group surpassed
the total number of neurons that were born during the 12 d
injection period (<4000 in Enr-6). Thus, we did not find any
differences in total granule cell numbers among the four groups;
neither was there any difference with regard to the mean neuronal
density in the granular layer or the volume of the granular layer.
It has been reported that old mice learn in the water maze task (Gower
and Lamberty, 1993). Overall analysis of the water maze test in our
study revealed significantly shorter times to reach the platform when
comparing Enr-18 versus Ctr-18 (p = 0.0422; Fig.
5A) and Enr-6 versus Ctr-6
(p = 0.0248). Although we found a significant
increase in swim speed in both Enr-18 versus Ctr-18 (p = 0.0307; Fig. 5B) and Enr-6
versus Ctr-6 (p = 0.0040), there was no
difference in the lengths of swim paths in enriched animals versus
controls.
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Figure 5.
Data from the water maze test for 18-month-old
mice. Performance curves for 6-month-old animals looked similar.
Overall analysis of time to reach the platform revealed significant
differences between controls and enriched living mice. The curve for
swim path paralleled A in appearance but in overall
analysis no significant difference between the groups could be found.
Although experience induced functional improvements, a causal relation
to neurogenesis remains to be established.
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DISCUSSION |
Neurogenesis means birth of new neurons, but is often used in the
restricted sense of cell proliferation leading to a new neuron,
although broader definitions are in use (Shepherd, 1994; Caviness et
al., 1995). The adult hippocampal formation contains multipotent stem
cells, differentiating to both neurons and glial cells in
vitro (Palmer et al., 1997). To base the definition of neurogenesis on a process that could also result in glia is ambiguous. In contrast to the precise temporospatial distribution of neurogenic events during embryonic development (Caviness et al., 1995), regions of
adult neurogenesis contain cells at all developmental stages. Consequently, the use of proliferation to define neurogenesis in the
adult brain is less precise than during development. Comparing data
from 1 d with 4 weeks after BrdU injection revealed that the
amount of proliferation is not indicative of the resulting net
production of new neurons (Kempermann et al., 1997a). We therefore use
a broader definition of neurogenesis that includes proliferation, survival, and differentiation.
Neurogenesis in the senescent dentate gyrus
Neurogenesis persists in the hippocampal formation of old mice. In
all four groups, proliferating cells (Fig. 4A) were
located in the subgranular zone, and differentiating cells migrated
into the granule cell layer. BrdU-labeled cells expressed the neuronal marker NeuN 4 weeks after injection of BrdU (Fig.
4B-D).
The decrease in neurogenesis with increasing age confirmed previous
results from rats (Kuhn et al., 1996). We found no significant difference in the total granule cell number between the two age groups,
indicating that in old age neurogenesis ceases to produce granule cells
in numbers that influence the total granule cell count at a detectable
rate. Comparison with data from our previous study reveals an increase
in the total granule cell number between 2 and 6 months by ~40,000
cells (Kempermann et al., 1997a). Comparable increases have been
described for rats (Bayer et al., 1982).
Little is known about the role of apoptosis in the regulation of adult
neurogenesis, although it is plausible that the decrease in
BrdU-positive cells during 4 weeks after injection is attributable to
elimination by programmed cell death. Apoptotic nuclei have been
described in the subgranular zone (Bengzon et al., 1997). Quantitatively, the loss of BrdU-positive cells might reflect an
overestimation of apoptosis, because BrdU itself could damage some
labeled cells.
Birth dating cells by BrdU incorporation is influenced by cell cycle
parameters (Cai et al., 1997). Because BrdU has a bioavailability of
~2 hr (Takahashi et al., 1992), only cells that are in S phase in
this short period incorporate BrdU. A lengthened S phase will increase
the probability of a cell being labeled during each injection; however,
during the period of injections fewer cell cycles are likely to occur.
BrdU-positive cells that divide again after BrdU is eliminated from the
bloodstream will give BrdU to their daughter cells. The rationale for
12 BrdU injections over 12 d was to minimize the impact of
divisions after discontinuation of BrdU, to label more cells, and to
compensate for dilution effects caused by continued divisions.
Experience-induced regulation of neurogenesis
The paradigm of environmental enrichment (Rosenzweig et al., 1962)
has been applied to study the environmental effect on cellular proliferation in the adult brain (Altman and Das, 1964). We have recently shown that stimulating mice with an enriched environment results in increased neurogenesis in the dentate gyrus (Kempermann et
al., 1997b).
Our present results indicate that experience-dependent regulation of
adult neurogenesis occurs in the aging dentate gyrus. As in younger
mice, survival of BrdU-labeled cells was promoted. The underlying
mechanism could lie in an interaction with the apoptotic cascade.
In addition, we found that in enriched-living animals of both age
groups relatively more BrdU-positive cells double labeled for neuronal
marker NeuN, an effect that was not apparent in 3-month-old mice
(Kempermann et al., 1997b). This can be interpreted as a survival-promoting effect on cells that are committed to a neuronal lineage. The absolute numbers of both BrdU-labeled astrocytes and
BrdU-positive cells, which did not double label for NeuN or S100,
were not influenced by environmental stimuli a finding that supports
this hypothesis.
An alternative hypothesis that remains to be tested is that
environmental stimuli could have an effect on the differentiation of
progeny of the dividing progenitor cells by directly or indirectly influencing mechanisms of cell fate decisions.
The microenvironmental conditions and their experience-dependent
alteration, which favor the survival of cells that have exited the cell
cycle and which lead these cells toward differentiation, remain to be
identified. Although gliogenesis was not significantly stimulated by
experience in old animals, it remains possible that environmental
influences on astrocytes contribute to the overall effects.
That there was no difference in proliferation between controls and
enriched-living mice does not allow conclusions about the size of the
progenitor population. In principle, our findings on proliferation
would be consistent with either a smaller proliferating population with
shorter cell cycles or a larger population with longer cell cycles in
enriched-living mice. Theoretically, increased neurogenesis could
deplete the population of progenitor cells in the subgranular zone, and
experience-dependent demand for new neurons could compensate for this
by shortening the cell cycle. The net result, that 4 weeks after BrdU
injection significantly more BrdU-labeled neurons are present in
enriched-living mice, is independent of these considerations. Future
experiments will have to examine how cell cycle kinetics themselves are
influenced by aging and by environmental stimulation.
Factors mediating the regulation of adult neurogenesis
Inheritable traits have different effects on three levels in the
regulation of adult neurogenesis: proliferation, survival, and
differentiation, suggesting the involvement of several regulatory genes
(Kempermann et al., 1997a).
Neonatal handling of rats prevents age-related cell losses in CA1 and
CA3 and deficits in spatial memory (Meaney et al., 1988). The
hypothesized mechanism underlying this effect involves downregulation of glucocorticoid secretion. Glucocorticoids have also been shown to
inhibit neurogenesis in the dentate gyrus (Gould et al., 1992). Glutamatergic afferents to the dentate gyrus also limit adult neurogenesis, as does psychosocial stress (Gould, 1994; Gould et al.,
1997). In contrast, temporal lobe seizures caused an increase in
neurogenesis in the dentate gyrus (Bengzon et al., 1997; Parent et al.,
1997). Both results indicate a regulatory influence of glutamate on
adult neurogenesis. In all of these cases effects on neurogenesis
included strong stimulation of proliferation. Environmental stimulation
is the first known modulator to interact with a later
regulatory step of adult neurogenesis.
Mitogenic effects of growth factors have been described for progenitor
cells from fetal and adult brain in vitro (Reynolds, 1992;
Vescovi et al., 1993; Bartlett et al., 1994; Palmer et al., 1995; Ray
et al., 1995). Epidermal growth factor, after intracerebroventricular infusion, shifted differentiation of BrdU-labeled cells in the granule
cell layer to a glial fate (Kuhn et al., 1997).
Does experience-dependent regulation imply a functional role?
The extent to which spatial learning contributes to the behavioral
improvements seen in our study remains undefined. However, even after
living under standard conditions for 6 or 18 months, old mice
stimulated by an enriched environment for as short as 68 d showed
better performance in the water maze. This behavioral effect does not
prove a causal link to the morphological results, but neurogenesis
occurs in a context of functional effects.
Although the results might suggest that the new neurons are recruited
for purposes of hippocampal function, further research is required to
determine how and to what extent the neurons that are born during
adulthood are integrated functionally into hippocampal circuitry.
Anatomically, the new neurons extend neurites to CA3 as do other
granule cells (Stanfield and Trice, 1988; Parent et al., 1997).
A functional interpretation of adult neurogenesis is supported by
results from chickadees in which neurogenesis in the adult dentate
gyrus has been shown to correlate with seasons in which the birds cover
larger territories and have to remember numerous food storage sites
(Barnea and Nottebohm, 1996).
The total numbers of neurons that can be generated in the senescent
dentate gyrus, however, are low and it is important to determine
whether these cells could contribute to the experience-related functional effects observed here. Various other hippocampal parameters have been shown to be inducible by living in an enriched environment (Jones and Smith, 1980). Some of these changes, such as plasticity of
synaptic properties (Greenough et al., 1978), synaptic density (Saito
et al., 1994), and dendritic arborization (Greenough and Volkmar,
1973), occur in older age and are likely to contribute to functional
effects. However, the fact that the aging brain maintains a complex
regulatory apparatus for the production of neurons in the dentate gyrus
suggests that this plasticity has functional benefits. Our data support
theories that place adult neurogenesis in a context of hippocampal
function and shed new light on the potential for plasticity in the old
brain.
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FOOTNOTES |
Received Dec. 3, 1997; revised Feb. 10, 1998; accepted Feb. 17, 1998.
This study was supported by grants from National Institute of
Neurological Diseases and Stroke, National Institute on Aging, American
Paralysis Association, and International Spinal Research Trust. G.K.
was supported by Deutsche Forschungsgemeinschaft, and H.G.K. was
supported by the Hereditary Disease Foundation. We thank D. A. Peterson for help with stereological questions and T. D. Palmer, P. J. Horner, J. Winkler, and M. L. Gage for comments on this
manuscript. We also thank A. Smith, T. Slimp, K. Suter, and their
colleagues from the Animal Research Facilities of the Salk Institute
for their support of these experiments.
Correspondence should be addressed to Dr. Fred H. Gage, The Salk
Institute for Biological Studies, Laboratory of Genetics, 10010 North
Torrey Pines Road, La Jolla, CA 92037.
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August 15, 2000;
20(16):
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[Abstract]
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H. E. Scharfman, J. H. Goodman, and A. L. Sollas
Granule-Like Neurons at the Hilar/CA3 Border after Status Epilepticus and Their Synchrony with Area CA3 Pyramidal Cells: Functional Implications of Seizure-Induced Neurogenesis
J. Neurosci.,
August 15, 2000;
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[Abstract]
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M.-C. Amoureux, B. A. Cunningham, G. M. Edelman, and K. L. Crossin
N-CAM Binding Inhibits the Proliferation of Hippocampal Progenitor Cells and Promotes Their Differentiation to a Neuronal Phenotype
J. Neurosci.,
May 15, 2000;
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[Abstract]
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M. A. I. Aberg, N. D. Aberg, H. Hedbacker, J. Oscarsson, and P. S. Eriksson
Peripheral Infusion of IGF-I Selectively Induces Neurogenesis in the Adult Rat Hippocampus
J. Neurosci.,
April 15, 2000;
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[Abstract]
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O. F. X. ALMEIDA, G. L. CONDÉ, C. CROCHEMORE, B. A. DEMENEIX, D. FISCHER, A. H. S. HASSAN, M. MEYER, F. HOLSBOER, and T. M. MICHAELIDIS
Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate
FASEB J,
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14(5):
779 - 790.
[Abstract]
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L. EISENBERG
Is psychiatry more mindful or brainier than it was a decade ago?
The British Journal of Psychiatry,
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176(1):
1 - 5.
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B. B. Johansson
Brain Plasticity and Stroke Rehabilitation : The Willis Lecture
Stroke,
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223 - 230.
[Abstract]
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P. J. Brasted, C. Watts, T. W. Robbins, and S. B. Dunnett
Associative plasticity in striatal transplants
PNAS,
August 31, 1999;
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[Abstract]
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D. R. Kornack and P. Rakic
Continuation of neurogenesis in the hippocampus of the adult macaque monkey
PNAS,
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[Abstract]
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B. Kolb, B. Pedersen, M. Ballermann, R. Gibb, and I. Q. Whishaw
Embryonic and Postnatal Injections of Bromodeoxyuridine Produce Age-Dependent Morphological and Behavioral Abnormalities
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A. D. Tramontin, J. C. Wingfield, and E. A. Brenowitz
Contributions of Social Cues and Photoperiod to Seasonal Plasticity in the Adult Avian Song Control System
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E. A. Maguire, D. G. Gadian, I. S. Johnsrude, C. D. Good, J. Ashburner, R. S. J. Frackowiak, and C. D. Frith
Navigation-related structural change in the hippocampi of taxi drivers
PNAS,
April 11, 2000;
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[Abstract]
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E. Gould, N. Vail, M. Wagers, and C. G. Gross
Inaugural Article: Adult-generated hippocampal and neocortical neurons in macaques have a transient existence
PNAS,
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[Abstract]
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Top
Abstract
Introduction
