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The Journal of Neuroscience, March 1, 2001, 21(5):1628-1634
Circulating Insulin-Like Growth Factor I Mediates
Exercise-Induced Increases in the Number of New Neurons in the Adult
Hippocampus
José Luis
Trejo,
Eva
Carro, and
Ignacio
Torres-Alemán
Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior
de Investigaciones Científicas, 28002 Madrid, Spain
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ABSTRACT |
Although the physiological significance of continued formation of
new neurons in the adult mammalian brain is still uncertain, therapeutic strategies aimed to potentiate this process show great promise. Several external factors, including physical exercise, increase the number of new neurons in the adult hippocampus, but underlying mechanisms are not yet known. We recently found that exercise stimulates uptake of the neurotrophic factor insulin-like growth factor I (IGF-I) from the bloodstream into specific brain areas,
including the hippocampus. In addition, IGF-I participates in the
effects of exercise on hippocampal c-fos expression and mimics several
other effects of exercise on brain function. Because subcutaneous
administration of IGF-I to sedentary adult rats markedly increases the
number of new neurons in the hippocampus, we hypothesized that
exercise-induced brain uptake of blood-borne IGF-I could mediate the
stimulatory effects of exercise on the adult hippocampus. Thus, we
blocked the entrance of circulating IGF-I into the brain by
subcutaneous infusion of a blocking IGF-I antiserum to rats undergoing
exercise training. The resulting inhibition of brain uptake of IGF-I
was paralleled by complete inhibition of exercise-induced increases in
the number of new neurons in the hippocampus. Exercising rats receiving
an infusion of nonblocking serum showed normal increases in the number
of new hippocampal neurons after exercise. Thus, increased uptake of
blood-borne IGF-I is necessary for the stimulatory effects of exercise
on the number of new granule cells in the adult hippocampus. Taken
together with previous results, we conclude that circulating IGF-I is
an important determinant of exercise-induced changes in the adult brain.
Key words:
insulin-like growth factor I; adult neurogenesis; brain
effects of exercise; blood-CSF barrier; brain uptake; neurotrophic
factors
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INTRODUCTION |
Recent evidence emphasizes the
pleiotropic effects of insulin-like growth factor I (IGF-I) on brain
cells. Although most of the work has focused on the actions of IGF-I in
the developing brain (Feldman et al., 1997 ), new data strongly suggest
an important role of this growth factor in adult brain physiology and
disease (Torres-Aleman, 1999). In this regard, it is intriguing to
consider as a possibility that blood-borne IGF-I might constitute an
essential trophic input to the adult brain because levels of
circulating IGFs are altered in all types of neurodegenerative diseases
studied so far, including major illnesses such as Alzheimer's disease or stroke (Busiguina et al., 2000). It is thus important to establish whether circulating IGF-I plays a role in the brain, possibly as a
physiological neuroprotectant. Of note, whereas serum IGF-I has long
been considered a major effector of growth hormone (GH) actions on
somatic growth, recent evidence with liver-specific IGF-I null mutants
showing normal body growth disputes this notion because these mice have
very low levels of circulating IGF-I (Sjogren et al., 1999). Thus, the
physiological role of blood-borne IGF-I is not clear.
To analyze the role of circulating IGF-I on brain function under
physiological conditions, we have taken advantage of the fact that
stimuli such as physical exercise activate the GH-IGF-I axis,
resulting in increased uptake of circulating IGF-I by target organs
such as the muscle (Eliakim et al., 1997) and the brain (Carro et al.,
2000). Furthermore, at least several of the effects of exercise on the
brain are likely mediated by IGF-I, including increased hippocampal
expression of brain-derived neurotrophic factor (BDNF) and c-fos
activation (Carro et al., 2000). Recently, it has been shown that
another effect of exercise on the adult brain is to increase the number
of new neurons in the adult hippocampus (van Praag et al., 1999).
Because peripheral administration of IGF-I also results in increases in
the number of new neurons in the hippocampus of hypophysectomized rats
(Aberg et al., 2000), we speculated that circulating IGF-I might be
mediating the stimulatory effects of exercise on the number of new
hippocampal neurons in normal adult rats.
There is now general agreement that new neurons are continuously
produced in the hippocampal dentate gyrus of adult mammals. These new
neurons are generated from a local population of progenitor cells
located in the subgranular zone (Gage et al., 1998), following an outside-in gradient with the oldest cells located on the molecular edge and the youngest ones on the hilar edge of the granule cell layer
(Crespo et al., 1986). Importantly, these new adult-generated neurons
develop dendritic and axonal processes and receive synaptic contacts on
their cell bodies (Stanfield and Trice, 1988).
There are at least two issues of great relevance in the study of the
production and survival of new neurons in the adult hippocampus. First,
it is possible that changes in the relative proportion of young neurons
produced by modulatory factors may influence hippocampal circuitry.
Second, factors and mechanisms underlying the formation and survival of
new neurons in the adult brain are of potential therapeutic importance.
Thus, external stimulators of the number of new neurons in the
hippocampal formation, such as exercise may modulate hippocampal
function as well as exert neuroprotective actions on
hippocampal-related pathological disturbances.
We now show that exercise-induced increases in the number of new
neurons in the adult hippocampus depend on the entrance of IGF-I from
the circulation into the brain.
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MATERIALS AND METHODS |
Experimental procedures. Male Wistar rats (300 gm) from our in-house colony were used. Because the aim of the
study was to determine the role of IGF-I on exercise-induced changes in
the number of new neurons in the hippocampus, we followed a protocol similar to that originally reported by van Praag et al. (1999) to
determine the effects of exercise on the number of new neurons in the
adult hippocampus. In a first series of experiments we administered an
IGF-I infusion through a subcutaneous osmotic minipump (Alzet 2001; 50 µg · kg 1 · d1,
rate of infusion 1 µl/hr) for 7 d to normal rats, as described (Fernandez et al., 1998). Control animals received a saline infusion. Simultaneously, both IGF-I-infused and control animals received daily
intraperitoneal injections of BrdU (Sigma, St. Louis, MO) dissolved in
0.9% NaCl at a dose of 50 mg/kg for 7 d. Animals were
anesthetized and killed either 24 hr (short-term) or 3 weeks (long-term) after the last injection of BrdU (days 8 and 30, respectively). BrdU+ cells found after
short-term and long-term survival will include newly formed cells that
have survived up to 1 week and 1 month, respectively.
In a second series of experiments aimed to determine the role of
endogenous blood-borne IGF-I in exercise-induced changes in the number
of new neurons in the adult hippocampus, we administered an infusion of
a blocking anti-IGF-I antiserum (20% in saline; Alzet osmotic minipump
1002, subcutaneously implanted, with an infusion rate of 0.25 µl/hr)
to a group of rats running in a treadmill for 15 d (see below).
The control group of exercising animals received an infusion of
nonimmune normal rabbit serum (NRS; 20% in saline) because pilot
experiments indicated that exercising rats receiving either a saline
infusion or NRS show identical increases in the number of labeled cells
in the hippocampus. All animals received BrdU injections during the
15 d of the study. Thereafter, one group was killed 24 hr after
the last injection of BrdU (day 16) to determine short-term survival of
BrdU+ cells, whereas a second group was
killed 2 weeks later for long-term survival analysis (day 30). In all
cases, a decrease in the number of BrdU+
nuclei in long-term cell survival experiments was found as compared with short-term studies. This indicates a natural cell death process of
the newly born cells along time (Cameron et al., 1993).
IGF-I antibody and immunoassay. The anti-IGF-I antiserum
used for blocking experiments has <1% cross-reactivity with either insulin or IGF-II, as determined by competition with
125I-IGF-I. IGF-I levels in the CSF were
determined by radioimmunoassay as described (Carro et al., 2000). CSF
samples (150-200 µl) were obtained from the cisterna magna.
Treadmill running. Animals were familiarized with the
treadmill apparatus (Letica, Germany) to minimize novelty stress
and then divided in two groups: exercised and nonexercised. The
procedures followed are described in detail elsewhere (Carro et al.,
2000).The exercise group ran for 1 hr at 17 m/min for 2 weeks, whereas
the control group remained in the treadmill without running.
Immunohistochemistry. Animals were perfused transcardially
with 4% paraformaldehyde in 0.1 M phosphate
buffer (PB, pH 7.4). Brains were removed and post-fixed 24 hr at 4°C.
The rostral-septal half of the right hippocampus was dissected out,
and the brain was cut rostrally at bregma  1.30 mm, caudally at bregma
5.80 mm, and ventrally at 4.5 mm (Paxinos and Watson, 1982). The
areas were serially sectioned rostrocaudally with a Leica vibratome at
50 µm and immersed free-floating in 0.1 M PB.
Ninety-six well plates were used to keep the sections separate to
preserve the order of the series. Left hippocampi were coronally
sectioned at 30-µm-thick for IGF-I immunohistochemistry.
A one-in-six series of sections of every animal was used for stereology
of cell counts. Four series were used for double-labeling and analysis
of phenotypes by confocal microscopy (Leitz, Wetzlar, Germany), and
another series was used for Nissl staining. Cell-specific markers used
were:  -tubulin-III for neurons (Easter, et al., 1993), glial
fibrillary acidic-protein (GFAP) (Boyes et al., 1986; Cameron et al.,
1993), and vimentin (Pixley and de Vellis, 1984; Cameron et al., 1993)
for glial cells. Incubations were performed in PB 0.1 M
with 0.5% Triton X-100 and 0.1% bovine serum albumin. Sections were
blocked by incubating for 15 min in a solution with 10% methanol and
3% hydrogen peroxide. For BrdU immunohistochemistry, DNA was denatured
with a 30 min incubation in HCl 2 N at room temperature. Primary
antibodies used were mouse anti-BrdU (Hybridoma Bank, Iowa City, IA)
1:20,000; mouse anti- tubulin III (Promega, Madison, WI) 1:60,000;
mouse anti-GFAP (Sigma) 1:2000; rabbit anti-vimentin (Boehringer
Mannheim, Mannheim, Germany) 1:100; and rabbit IGF-IR 1:1000
(Garcia-Segura et al., 1997). For single BrdU immunohistochemistry
performed for stereology counts, the secondary antibody used was a
biotinylated donkey anti-mouse IgG (Jackson ImmunoResearch, West Grove,
PA) 1:1,000 followed by the peroxidase-based ABC system (Vector
Laboratories, Burlingame, CA) using diaminobenzidine as the chromogen.
For double immunohistochemistry we used streptavidin-Alexa 488 (Molecular Probes, Eugene, OR) 1:2000 after the secondary biotinylated
antibody and anti-rabbit IgG-Alexa 594 or anti-mouse IgG-Alexa 594 (Molecular Probes) 1:2000. When both primary antibodies were generated
in mice, incubations with antibodies for each antigen were done
sequentially, taking advantage of the fact that BrdU staining localizes
to the cell nucleus, whereas cell-specific markers used are present in
the cytoplasm. In addition, the type of secondary antibody used
was inverted in several experiments to insure specificity: nuclear BrdU
staining is either green-yellow when using Alexa 488 or red with Alexa
594 (see Fig. 2C,F). IGF-I immunohistochemistry was performed with a polyclonal anti-IGF-I 1:500 (Carro et al., 2000), followed by a biotinylated goat anti-rabbit IgG (Pierce, Rockford, IL)
1:300. A third amplification step was used with streptavidin-Alexa 488 (Molecular Probes) 1:1000.
For stereology, BrdU-positive cells were counted in a one-in-six series
of sections (300 µm apart) with a 40× objective (Leica) throughout the rostral-septal half of the granule cell layer (from the
rostralmost extreme of the hippocampus, at bregma 1.30 mm, to the
caudal end, at bregma 5.80 mm). The same areas and number of sections
were studied for all the animals and all the experimental groups. We
considered as BrdU+ those nuclei
completely filled with DAB product or fluorescent marker or showing
patches of variable intensity. We used the optical dissector technique
to estimate the cell density of BrdU+
cells in the granule cell layer as described by Howard and Reed (1998),
and expressed it as the number of positive cells per cubic millimeter. We used total section thickness for dissector height (Hatton and von Bartheld, 1999) and a counting frame of 55 × 55 µm, as detailed elsewhere (Azcoitia et al., 1999). Adjacent
Nissl-stained sections were used to measure the width of the granule
cell layer. The granule cell area was traced using a camera lucida, and
drawings were scanned with a CanoScan 600 (Canon) and processed with
ScionImage 3b software to determine the mean width of the granule cell
layer throughout the rostrocaudal extent of the studied region. No
significant differences were found between experimental groups in the
width of the granule cell layer.
Double immunohistochemistry was performed in adjacent sections in
one-in-six series of every animal. We counted three or four areas in
each section for five or six sections in each animal. The assignment of
each BrdU-positive cell to a category of neuronal, glial, or other,
unidentified type was done by a researcher unaware of group treatments
by moving the confocal plane up and down of the z-axis along
the entire segment in which every cell appeared (see Fig.
2H-L). The width of the section studied in all cases oscillated between 15 and 20 µm. Only those
BrdU+ nuclei with colocalization of
-tubulin in the cytoplasm along the successive planes of the
z-axis were considered as neurons. Data are presented as
percentage of neurons per glial cells or other, unidentified
BrdU-positive cells. A t test was performed when
comparing two groups, and a one-way ANOVA was used for comparing multiple groups. Post hoc comparisons were made with a
Newman-Keuls test.
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RESULTS |
Inhibition of brain uptake of blood-borne IGF-I
We first tested whether chronic subcutaneous administration of an
anti-IGF-I antiserum could block the exercise-induced entrance of
circulating IGF-I into the brain. As shown in Figure
1A, infusion of the
anti-IGF-I antiserum to rats undergoing exercise training results in
absence of brain IGF-I labeling. However, control exercising rats
receiving a nonblocking, NRS infusion show the expected increase in
brain IGF-I labeling, as compared with normal sedentary rats. In
support of the idea that the IGF-I antiserum is blocking the entrance
of IGF-I from the blood stream into the CSF (Carro et al., 2000), we
also found that infusion of the blocking anti-IGF-I antiserum, but not
the NRS, results in blockade of exercise-induced increases in CSF IGF-I
levels (Fig. 1B). Although we cannot exclude the
possibility that the IGF-I rabbit antiserum, but not the normal rabbit
serum, crosses the blood-brain barriers and directly affect BrdU+ cells, our results support the idea
that the IGF-I antiserum blocks passage of IGF-I through the blood-CSF
barrier by its ability to bind circulating IGF-I. As shown in Figure
1C, the anti-IGF-I antiserum blocks interaction of IGF-I
with its receptor: IGF-I-induced tyrosine phosphorylation of the IGF-I
receptor is blocked in the presence of 20% anti-IGF-I but not 20%
NRS.
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Figure 1.
Infusion of an anti-IGF-I antiserum inhibits
exercise-induced brain uptake of circulating IGF-I. A,
Control sedentary animals show very low IGF-I labeling in the brain.
Rats running in a treadmill for 15 d and receiving a simultaneous
infusion of a nonblocking normal rabbit serum (NRS) show
marked increases in IGF-I labeling throughout the brain. However,
animals undergoing the same exercise schedule but receiving an infusion
of an anti-IGF-I antiserum do not show increased brain IGF-I labeling.
The cerebellar cortex and the hippocampus are shown as representative
areas accumulating IGF-I after exercise (see references for further
details). Arrows indicate typically labeled neurons.
Mol, Cerebellar molecular layer; PC,
Purkinje cell layer; Gr, cerebellar granule cell layer;
Py, hippocampal pyramidal cell layer;
StR, hippocampal stratum radiatum. B,
Levels of IGF-I in the CSF of exercising animals receiving an infusion
of NRS are 68% higher than in control, sedentary animals. However,
exercising rats receiving an anti-IGF-I infusion do not show increased
CSF IGF-I levels; n = 3 per group.
C, The anti-IGF-I antibody used for blocking uptake of
IGF-I blocks interaction of IGF-I with its receptor. The presence of
the anti-IGF-I antiserum (20% in culture medium) completely blocks
IGF-I-induced receptor tyr-phosphorylation in cerebellar neuronal
cultures (right). When 20% NRS was used instead, IGF-I
receptor was tyr-phosphorylated in response to IGF-I
(left), indicating normal biological activity of IGF-I.
Cerebellar cultures were lysed 3 min after addition of 100 nM IGF-I, immunoprecipitated (IP) with a
polyclonal anti-IGF-I receptor antibody, and blotted
(WB) with a monoclonal anti-pTyr antibody.
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IGF-I increases the number of BrdU-labeled cells in the hippocampus
of normal adult rats
Cells incorporating BrdU were found in the hippocampal formation
of all experimental groups. BrdU+ nuclei
were detected both in the granule cell layer and in the dentate hilus.
However, we only analized cells in the granule layer (GCL) because only
sparse BrdU+ nuclei could be found in the
dentate hilus, representing <5% of total labeled nuclei (Fig.
2A,B).
BrdU+ cells in the GCL appeared
distributed following a gradient. In the most-medial aspect, where the
suprapyramidal and infrapyramidal blades join, we frequently found a
dense group of positive nuclei. In the medial half of the granule layer
the nuclei arranged along a line, with some gaps in between. In the
lateral half of the layers BrdU+ cells
became uneven and more scarce. The great majority of positive nuclei
were found in the inner part of the granule layer. Distribution of
BrdU+ cells was similar in all groups.
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Figure 2.
Characterization of BrdU-labeled cells in the
granule cell layer of the adult hippocampus. A, Typical
BrdU-positive cells in the dentate gyrus of an adult rat hippocampus,
as revealed with DAB visualized with Nomarski optics. Immunopositive
nuclei are easily distinguishable and clearly separated, making them
well suited for stereology counts. B, A higher
magnification of the area marked in A to show
BrdU+ nuclei in greater detail. Orientation in
A is dorsal (D), ventral
(V), medial
(M), and lateral
(L). C, A BrdU+
cell (red nucleus) within the granule cell layer also
shows IGF-I receptor labeling (green signal
surrounding the nucleus). D, Representative
BrdU+ nuclei in the hippocampus of an animal after
15 d of treadmill exercise and simultaneous infusion of
nonblocking rabbit serum. E, BrdU+
nuclei in the hippocampus of an exercised animal receiving a
simultaneous infusion of anti-IGF-I blocking antibody. Note that the
number of BrdU nuclei is considerably lower after anti-IGF-I treatment.
In both D and E, image contrast is sharp
to delineate easily the granule cell layer. F,
Identification of BrdU-positive nuclei (green) as
neurons using double fluorescence immunohistochemistry for -tubulin
III (red cytoplasm). Cells shown are located in the
inner part of the granule layer. G, Whereas several
GFAP-positive astrocytes (green) appeared in the
dentate hilus with BrdU-positive nuclei (red), no
GFAP-positive astrocytes appeared inside the granule layer.
G, Granule cell layer; H, dentate hilus.
Arrows indicate positive cells. H-L,
Serial confocal microscopy images along the z-axis of
the same neuron showing colocalization of BrdU
(yellow-green patches) in the nucleus and
-tubulin (red) in the cytoplasm to demonstrate the
specificity of both signals.
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To determine a possible role of peripheral IGF-I in the increase of
BrdU-labeled cells induced by exercise in the hippocampus, we first
analyzed whether administration of IGF-I could mimic the stimulatory
effects of exercise. Although recent results indicate that peripheral
administration of IGF-I does increase the number of
BrdU+ nuclei in the hippocampus, this
effect was observed in hypophysectomized animals (Aberg et al., 2000),
making it difficult to rule out interferences by ensuing hormonal
derangements. In addition, the stimulatory effects of exercise on the
number of new hippocampal neurons have been reported on intact animals
(van Praag et al., 1999).
As shown in Figure 3A,
subcutaneous administration of IGF-I with a minipump for 7 d
results in a significant increase in the number of
BrdU+-positive cells in the hippocampal
dentate gyrus both after 24 hr (p < 0.05) as
well as 3 weeks after the last BrdU injection (p < 0.005).
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Figure 3.
Peripheral IGF-I increases the number of
hippocampal BrdU+ cells and is necessary for
exercise-stimulated increases in hippocampal BrdU+
cells in adult rats. A, Treatment for 7 d with a
subcutaneous infusion of IGF-I (50 mg · kg1 · d1)
results in significantly increased number of BrdU+
hippocampal granule cells. BrdU+ cells in the
granule cell layer of the hippocampus are significantly increased in
animals killed either 24 hr (p < 0.05) or 3 weeks (p < 0.005) after the last BrdU
injection to determine short-term and long-term effects of IGF-I on
BrdU+ cell numbers, respectively.
*p < 0.05; ***p < 0.005 versus controls. B, C, Animals undergoing
exercise training for 15 d and simultaneously receiving an
infusion of nonblocking rabbit serum (NRS + exercise) show significant
increases in BrdU+ cells both 24 hr
(B) as well as 2 weeks (C)
after the last BrdU injection as compared with nonexercising rats
(controls) receiving an infusion of saline. However, both 24 hr
survival as well as 2 week survival of BrdU+ cells
are significantly reduced when exercising animals receive an infusion
of blocking anti-IGF-I antiserum (anti-IGF-I + exercise).
Furthermore, infusion of anti-IGF-I to normal sedentary rats (control + anti-IGF-I) results in a significant decrease in long-term survival of
BrdU+ cells. *p < 0.01 versus
control; **p < 0.01 versus NRS + exercise;
***p < 0.01 versus control. Data are the mean ± SEM of the number of BrdU+ cells per cubic
millimeter.
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To determine whether BrdU+ cells can
directly respond to IGF-I, we labeled them with an anti-IGF-I receptor
antibody and found that BrdU+ cells
located in the granule cell layer express IGF-I receptors (Fig. 2). We
also determined the phenotype of BrdU+
cells in the hippocampus by double-labeling with cell-specific markers.
As previously reported (Kosaka and Hama, 1986), the great majority of
labeled nuclei in the GCL express the neuronal marker -tubulin III
(Fig. 2), whereas only a minority were labeled with a glial cell marker
(GFAP, Fig. 2; in the GCL, the number of glial cells is negligible).
Furthermore, and in agreement with previous observations (van Praag et
al., 1999), a substantial proportion of labeled nuclei could not be
clearly identified as glia or neurons. Unidentified cells were also
negative for calbindin-D28k and vimentin, a neuronal and glial cell
markers, respectively. Thus, the lineage of these cells cannot be
determined with these markers. Treatment with IGF-I did not favor any
particular cell type because the ratio of neuron to glia and other
types of cells did not differ between groups (Table
1).
Circulating IGF-I is necessary for exercise-induced increases in
the number of new hippocampal neurons
Treadmill running significantly increases the number of
BrdU+ nuclei in the hippocampus of adult
rats (Figs. 2I,J, 3B,C), confirming recent
results in mice (van Praag et al., 1999). When exercising rats
simultaneously received a chronic infusion of blocking anti-IGF-I antiserum, the enhancing effect of exercise on short-term survival (24 hr after last BrdU injection) as well as in long-term survival of
BrdU+ cells (3 weeks after last BrdU
injection) was obliterated (Fig. 3B,C). Because the number
of positive BrdU+ nuclei in
antiserum-injected animals was lower than in control sedentary animals
(Fig. 3B,C), we determined whether administration of the
anti-IGF-I antiserum to nonexercising rats would result in further
reduction in the number of BrdU+ nuclei in
the hippocampus and found a significant decrease in long-term survival
of BrdU+ cells after IGF-I antiserum
treatment (Fig. 3C). As shown in Table
2, the proportion of neurons to glia and
other cell types was not modified after any of the treatments.
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DISCUSSION |
The present results suggest that circulating IGF-I is necessary
for the observed increase in the number of
BrdU+ hippocampal neurons produced by
exercise. Two observations support this interpretation. First,
subcutaneous administration of IGF-I as well as exercise to otherwise
sedentary rats increase the number of
BrdU+ hippocampal granule cells. This
agrees with previous findings indicating a stimulatory effect of IGF-I
and of exercise on the number of new hippocampal neurons in adult
hypophysectomized rats and in intact mice, respectively (van Praag et
al., 1999; Aberg et al., 2000). Second, the stimulatory effect of
exercise on number of BrdU+ cells was
completely inhibited by simultaneous infusion of a blocking anti-IGF-I
rabbit antiserum but not by infusion of a normal rabbit serum. However,
this interpretation needs to be qualified in two ways. The number of
BrdU+ hippocampal granule cells was
comparable after 1 week of BrdU + IGF-I infusion or 2 weeks of BrdU + exercise. Because we did not check the IGF-I concentration in CSF under
both conditions or the effect of the same concentration of IGF-I for 1 or 2 weeks, we cannot really say that one treatment (IGF-I infusion)
mimics the effect of the other one (exercise), although this could well be the case. The other caveat is that we do not know it the anti-IGF-I antiserum entered the brain and affected directly the production, survival, or BrdU labeling of new hippocampal neurons. None of the
latter effects have been described, but in principle they are possible.
Despite these lacunae in our knowledge, we suggest that exercise
affected the number of BrdU+ hippocampal
granule cells by increasing the presence of IGF-I in brain tissue. We
also suggest that anti-IGF-I treatment cancelled the effect of exercise
by blocking the entrance of IGF-I into the brain.
These findings extend and reinforce our previous observations on the
role of circulating IGF-I as a mediator of the effects of exercise on
the brain (Carro et al., 2000). Thus, we found that after acute
exercise, accumulation of blood-borne IGF-I into specific areas of the
brain, including the hippocampus, can be inhibited by intraventricular
infusion of a blocking antibody plus an IGF-I receptor antagonist. This
procedure also inhibited the exercise-induced increase in c-fos
labeling of the hippocampus and other brain areas (Carro et al., 2000).
Because acute systemic administration of IGF-I mimics other effects of
acute exercise on the brain such as increased expression of BDNF in the
hippocampus and increased c-fos labeling throughout the brain (Carro et
al., 2000), we suggest that circulating IGF-I is critically involved in
the effects of exercise on brain function.
Both internal as well as external factors modulate the number of new
neurons in the adult mammalian brain (McKay, 1997). Among the latter,
enriched environment, psychosocial stress, learning, and exercise all
have been shown to stimulate proliferation and/or survival of new
dentate granule cells (Gould et al., 1999). In vitro and
in vivo studies have shown that intrinsic modulators of the
proliferation and survival of new hippocampal neurons include a variety
of growth factors and hormones, such as corticosteroids, IGF-I, or
fibroblast growth factor (FGF)-2 (Cameron and Gould, 1994). Our
present findings indicate that an extrinsic stimulator of the number of
new hippocampal granule cells such as physical exercise upregulates
brain IGF-I levels, which in turn also increases the number of
BrdU+ cells in the hippocampus. Other
stimuli of hippocampal cell proliferation and/or survival such as
seizures or ischemia also increase endogenous growth factors and
hormones (Hughes et al., 1999). It is thus possible that the mechanism
whereby extrinsic regulators of the number of new hippocampal neurons
in the adult operate is by modulation of endogenous neurotrophic
factors and hormones. In support of the latter, recent work in birds
indicates that an extrinsic modulator of new neuron survival such as
singing behavior upregulates expression of BDNF in relation to the
amount of singing, and this correlates with the extent of new neuron
survival (Li et al., 2000). We can also speculate that factors such as
aging or stress that reduce the number of new neurons through
upregulation of endogenous corticosteroids (McEwen, 1996; Gould and
Tanapat, 1999) may eventually modulate availability of endogenous
neurotrophic factors such as IGF-I. Indeed, corticosteroids exert
inhibitory effects on the synthesis of IGF-I by the liver, the main
source of blood-borne IGF-I (Yakar et al., 1999). Furthermore, blood
and brain levels of IGF-I decrease with age (Cohen et al., 1992). In
addition, previous observations indicated that blood-borne IGF-I
upregulates the number of BrdU+ cells in
the adult hippocampus under basal conditions because hypophysectomized
rats with very low levels of serum IGF-I have a lower number of new
neurons that recovers to levels seen in intact animals after injection
of IGF-I (Aberg et al., 2000). Our present results support these
findings because sedentary animals receiving an infusion of blocking
anti-IGF-I antiserum show long-term survival of
BrdU+ cells significantly lower than
control rats. Thus, it is possible that the basal number of new
hippocampal neurons in the adult is modulated by circulating
neurotrophic factors such as IGF-I.
Other neurotrophic factors such as FGF-2 and BDNF have also been
proposed to participate in exercise-induced increases in the number of
new hippocampal neurons (van Praag et al., 1999). This is based on the
observation that exercise stimulates their expression in the
hippocampus (Neeper et al., 1995; Gomez-Pinilla et al., 1997). However,
whereas recent findings indicate that IGF-I increases the number of new
hippocampal neurons (Aberg et al., 2000), this is not the case for
either BDNF or FGF-2. Although IGF-I induces expression of BDNF in the
hippocampus (Carro et al., 2000), potentially supporting a role for
BDNF in IGF-I stimulated increased survival of new neurons, BDNF does
not appear to be involved in hippocampal cell survival at least during
embryonic life because BDNF null mutants do not show major deficits in
this brain area (Jones et al., 1994). On the contrary, IGF-I knock-outs show specific decreases in hippocampal granule neurons (Beck et al.,
1995), suggesting an important role for IGF-I in fetal proliferation and/or survival of new neurons. This might be significant because regulation of these events by growth factors in the adult is thought to
be similar to the embryonic period (Brooker et al., 2000). Furthermore,
whereas FGF-2 increases the number of
BrdU+ cells in the adult olfactory bulb
and in the subventricular zone, it does not affect the number of new
cells in the hippocampus (Wagner et al., 1999).
BrdU+ cells in the granular zone of
dentate gyrus of the hippocampus express IGF-I receptors, which
suggests that IGF-I can directly affect them. In addition, neocortical
precursor cells in culture express IGF-I receptors and proliferate in
the presence of IGFs (Nielsen et al., 1991). These precursor cells also
secrete IGF-I, which acts in an autocrine-paracrine way to promote
their survival (Drago et al., 1991). Thus, IGF-I may increase the
number of BrdU+ cells in the adult
hippocampus by increasing proliferation of precursor cells, their
survival, or both. However, this has yet to be directly addressed in
future studies.
We and others have found that peripheral administration of IGF-I exerts
potent therapeutic effects in several models of brain damage (Fernandez
et al., 1998; Pulford et al., 1999). The possibility that IGF-I could
also prove of therapeutic value in hippocampal-related diseases, in
particularly those affecting memory processes, has already been
discussed (Aberg et al., 2000). Our results add further support to this
idea because exercise improves cognition (Kramer et al., 1999), and
IGF-I ameliorates memory deficits in aging rats (Markowska et al.,
1998). These data also provide a possible explanation for the
beneficial effects of physical exercise on the response to
neurodegeneration in diseases such as Alzheimer's, where IGF-I levels
are also altered (Tham et al., 1993). Furthermore, because recent
evidence indicates that new neurons appear in the adult brain in
response to injury in areas where under normal circumstances they are
not formed (Magavi et al., 2000), it is conceivable that the wide
neuroprotective effects of IGF-I include modulation of the number of
new neurons in damaged areas.
In summary, the present findings provide a possible mechanism whereby
physical exercise modulate the number of new hippocampal neurons in the
adult. We may start considering the brain as a major target organ for
blood-borne IGF-I.
| |
FOOTNOTES |
Received July 6, 2000; revised Dec. 13, 2000; accepted Dec. 13, 2000.
This work was supported by Grants PM97-0018 from Direccion General de
Enseñanza Superiore Investigación Científica
and 08.5/0051/98 from Comunidad Autonoma de Madrid (CAM). E.C.
is a CAM postdoctoral fellow. We thank Joaquin Sancho and Fernando Lozano for their expert help.
Correspondence should be addressed to Ignacio Torres-Aleman, Cajal
Institute, Consejo Superior de Investigaciones Científicas, Avenida Dr. Arce 37, 28002 Madrid, Spain. E-mail:
torres{at}cajal.csic.es.
| |
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B. Czeh, T. Michaelis, T. Watanabe, J. Frahm, G. de Biurrun, M. van Kampen, A. Bartolomucci, and E. Fuchs
Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine
PNAS,
September 26, 2001;
(2001)
211427898.
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E. Carro, J. L. Trejo, S. Busiguina, and I. Torres-Aleman
Circulating Insulin-Like Growth Factor I Mediates the Protective Effects of Physical Exercise against Brain Insults of Different Etiology and Anatomy
J. Neurosci.,
August 1, 2001;
21(15):
5678 - 5684.
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B. Czeh, T. Michaelis, T. Watanabe, J. Frahm, G. de Biurrun, M. van Kampen, A. Bartolomucci, and E. Fuchs
Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine
PNAS,
October 23, 2001;
98(22):
12796 - 12801.
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TOP
ABSTRACT
INTRODUCTION
Compound via MeSH
