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The Journal of Neuroscience, December 15, 2000, 20(24):9104-9110
Chronic Antidepressant Treatment Increases Neurogenesis in Adult
Rat Hippocampus
Jessica E.
Malberg,
Amelia J.
Eisch,
Eric J.
Nestler, and
Ronald S.
Duman
Laboratory of Molecular Psychiatry, Departments of Psychiatry and
Pharmacology, Yale University School of Medicine, Connecticut Mental
Health Center, New Haven, Connecticut 06508
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ABSTRACT |
Recent studies suggest that stress-induced atrophy and loss of
hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of
antidepressants on hippocampal neurogenesis in the adult rat, using the
thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing
cells. Our studies demonstrate that chronic antidepressant treatment
significantly increases the number of BrdU-labeled cells in the dentate
gyrus and hilus of the hippocampus. Administration of several different
classes of antidepressant, but not non-antidepressant, agents was found
to increase BrdU-labeled cell number, indicating that this is a common
and selective action of antidepressants. In addition, upregulation of
the number of BrdU-labeled cells is observed after chronic, but not
acute, treatment, consistent with the time course for the therapeutic
action of antidepressants. Additional studies demonstrated that
antidepressant treatment increases the proliferation of hippocampal
cells and that these new cells mature and become neurons, as determined
by triple labeling for BrdU and neuronal- or glial-specific markers.
These findings raise the possibility that increased cell proliferation
and increased neuronal number may be a mechanism by which
antidepressant treatment overcomes the stress-induced atrophy and loss
of hippocampal neurons and may contribute to the therapeutic actions of
antidepressant treatment.
Key words:
proliferation; granule cell; fluoxetine; tranylcypromine; reboxetine; depression
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INTRODUCTION |
Depression is a devastating illness
that is estimated to affect 12-17% of the population at some point
during the lifetime of an individual (Kessler et al., 1994 ).
Antidepressants are commonly prescribed for depression and other
affective disorders, although the molecular and cellular mechanisms by
which these agents exert their therapeutic effects are not well
understood. Preclinical and clinical research has focused on the
interactions between stress and depression and their effects on the
hippocampus, among other brain regions (Duman et al., 1999; McEwen,
1999). For example, the hippocampus has been shown to undergo
morphological changes in response to stress, including atrophy and loss
of CA3 pyramidal neurons after exposure to physical or psychosocial
stress (Watanabe et al., 1992c; Stein-Behrens et al., 1994; Margarinos
et al., 1996; McEwen, 1999). In addition, brain-imaging studies
demonstrate that hippocampal volume is decreased in patients with
stress-related psychiatric illnesses, including depression and
post-traumatic stress disorder (Sapolsky, 1996; Sheline et al.,
1996).
The hippocampus is one of only a few brain regions where production of
neurons occurs throughout the lifetime of animals, including humans
(Eriksson et al., 1998). Hippocampal neurogenesis can be influenced by
several environmental factors and stimuli (Kuhn et al., 1996;
Kempermann et al., 1997; Gould et al., 1999a; van Praag et al., 1999b).
Importantly, it has been shown that stressful experiences, including
both physical and psychosocial stress, suppress the formation of
hippocampal granule cells in a number of mammalian species (Gould et
al., 1997, 1998; Tanapat et al., 1998). Decreased cell proliferation
has also been reported in response to both acute and chronic stress
paradigms (Fuchs et al., 1997). It is conceivable that the
stress-induced downregulation of granule cell genesis, as well as
atrophy and death of CA3 pyramidal neurons, contributes to the
reduction in hippocampal volume that is clinically observed (Sapolsky,
1996; Sheline et al., 1996; Duman et al., 1999).
The possibility that antidepressant treatment could oppose or reverse
the actions of stress on the morphology and proliferation of
hippocampal neurons is suggested by studies demonstrating that antidepressants upregulate the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus (Nibuya et al., 1995). BDNF has been
shown to promote the differentiation and survival of neurons during
development and in adult brain, as well as in cultured cells (Memberg
and Hall, 1995; Palmer et al., 1997; Takahashi et al., 1998). In
addition, chronic antidepressant treatment completely blocks the
stress-induced downregulation of BDNF expression in the hippocampus,
demonstrating that antidepressant treatment can oppose the dystrophic
actions of stress (Nibuya et al., 1995).
Given the association between depression, stress, and hippocampal
neurogenesis, the current series of studies was performed to determine
whether antidepressant administration influences hippocampal
neurogenesis in the adult rat. After administering different classes of
antidepressant drugs or electroconvulsive seizure (ECS), we
administered bromodeoxyuridine (BrdU), a thymidine analog that labels
dividing cells in S-phase (Takahashi et al., 1992). The effects of
antidepressant treatment on proliferation, differentiation, and
survival of cells in the dentate gyrus and hilus of the hippocampus
were determined using several treatment paradigms.
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MATERIALS AND METHODS |
Antidepressant treatment. Adult male Sprague Dawley
rats (Harlan Sprague Dawley, Indianapolis, IN) weighing 250-300 gm
were used for all experiments. All animal treatments and maintenance of
the rat colony were in accordance with National Institutes of Health
laboratory care standards. Animals were group-housed (12 hr light/dark
cycle) with ad libitum access to food and water. After at
least 3 d of habituation to the rat colony, rats were administered
either an antidepressant or vehicle. ECS was administered via earclip
electrodes (50 mA, 0.3 sec) once daily for 10 d. Earclips were
applied to control animals, but no electrical current was administered.
Drugs and their vehicles were administered intraperitoneally according to standard regimens (Nibuya et al., 1995, 1996):
tranylcypromine, 7.5 mg/kg for the first 7 d and then 10 mg/kg for
14 d; reboxetine, 20 mg/kg, 2× per day for 21 d; fluoxetine,
5 mg/kg for 1, 5, 14, or 28 d; haloperidol, 1 mg/kg for the first
7 d and then 2 mg/kg for 7 d; vehicles, 1 ml/kg saline for
tranylcypromine and reboxetine, 1 ml/kg distilled water for fluoxetine,
and 1 ml/kg DMSO for haloperidol (n = 8 for each group).
BrdU labeling. For analysis of BrdU-positive cells,
rats were administered BrdU (4 × 75 mg/kg every 2 hr; Sigma, St.
Louis, MO) 4 d after the last antidepressant or haloperidol
treatment (Fig. 1A).
The 4 d time point was chosen because a similar paradigm has been
used in a previous study of chemical-induced seizures on hippocampal
neurogenesis (Parent et al., 1997). Twenty-four hours after the last
BrdU injection, rats were killed and transcardially perfused (0.1 M cold PBS for 5 min followed by 4% cold
paraformaldehyde for 17 min). For determination of cell phenotype, ECS-
or fluoxetine (14 d)-treated rats were allowed to survive 28 d
after the last BrdU injection (Fig. 1A). To
investigate the effect of antidepressant treatment specifically on cell
proliferation, ECS- or fluoxetine (14 d)-treated rats were given one
injection of BrdU (75 mg/kg) and perfused 2 hr later (Fig.
1A).
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Figure 1.
Experimental paradigms. A,
Proliferation and differentiation paradigms. Animals were administered
antidepressants for 1-28 d. Four days after the last antidepressant
treatment, animals were given BrdU and killed (S)
24 hr after BrdU administration. In one experiment designed to measure
cell proliferation, animals were killed 2 hr after BrdU injection. To
determine cell differentiation or phenotype, rats were killed 28 d
after BrdU injection. B, Survival paradigm. To examine
the influence of antidepressant treatment on the survival of
BrdU-labeled cells, BrdU was given to drug-naïve animals before
initiating antidepressant treatment (14 d). Rats were then killed
28 d after BrdU injection (14 d after the last antidepressant
treatment).
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To determine the effects of antidepressants on cell survival, BrdU was
administered before chronic administration of fluoxetine (Fig.
1B). BrdU (4 × 75 mg/kg every 2 hr) was
administered to drug-naive rats, and 24 hr after the last BrdU
injection, rats were started on a chronic regimen of fluoxetine (5 mg/kg for 14 d). Twenty-eight days after the last BrdU
injection (~14 d after ECT or fluoxetine treatment, respectively)
rats were perfused, and brains were processed for immunohistochemistry.
After perfusion, all brains were post-fixed overnight in
paraformaldehyde (with shaking) at 4°C and stored at 4°C in 30%
sucrose. Serial sections of the brains were cut (35 µm sections)
through the entire hippocampus (plates 26-40; Paxinos and Watson,
1986) on a freezing microtome, and sections were stored in
PBS/NaN3.
Immunohistochemistry. Free-floating sections were
used in the determination of BrdU labeling. DNA denaturation was
conducted by incubation for 2 hr in 50% formamide/2× SSC at 65°C,
followed by several PBS rinses. Sections were then incubated for 30 min in 2N HCl and then 10 min in boric acid. After washing in PBS, sections
were incubated for 30 min in 3%
H202 to eliminate
endogenous peroxidases. After blocking with 3% normal horse serum
(NHS) in 0.01% Triton X-100, cells were incubated with
anti-mouse BrdU (1:1000; Boehringer-Mannheim, Indianapolis, IN)
overnight at 4°C. Sections were then incubated for 1 hr with
secondary antibody (biotinylated horse anti-mouse; Vector Laboratories,
Burlingame, CA) followed by amplification with an avidin-biotin
complex (Vector Laboratories), and cells were visualized with DAB
(Vector Laboratories).
For double and triple labeling, sections were slide-mounted and boiled
in citric acid, pH 6.0, for 10 min followed by PBS rinses and then
treatment with 0.01% trypsin in Tris/CaCl2 for 10 min. Brain sections were incubated for 30 min with 2N HCl and blocked with 10% NHS (Vector Laboratories). Sections were then incubated for 3 d at 4°C with anti-rat BrdU (1:200; Accurate; Harlan Olac, Bicester, UK) and one of the following: anti-mouse neuronal nuclei (NeuN) (1:50; Chemicon, Temecula, CA) or
anti-mouse glial fibrillary acidic protein (GFAP) (1:100; ICN
Biochemicals, Costa Mesa, CA). For triple labeling, BrdU, NeuN, and
anti-rabbit GFAP (1:50; ICN Biochemicals) were used.
After washes, secondary antibodies Cy2 (1:200), Cy3 (1:500), and Cy5
(1:500) (Jackson ImmunoResearch, West Grove, PA) were applied for 1 hr and visualized with confocal z-plane sectioning (Zeiss LSM 510).
Quantitation of BrdU labeling. A modified unbiased
stereology protocol was used that has been reported to successfully
quantitate BrdU labeling (West et al., 1991; Gould et al., 1999a; Eisch
et al., 2000). Two major considerations in stereological analyses are
that no BrdU-labeled cells be counted twice and that the area counted
be consistent in each section.
Every sixth section throughout the hippocampus was processed for BrdU
immunohistochemistry. Using this spacing ensures that the same neuron
will not be counted in two sections. All BrdU-labeled cells in the
dentate gyrus (granule cell layer) and hilus were counted in each
section by an experimenter blinded to the study code. To distinguish
single cells within clusters, all counts were performed at 400× and
1000× under a light microscope (Olympus BX-60), omitting cells in the
outermost focal plane. A cell was counted as being in the subgranular
zone (SGZ) of the dentate gyrus if it was touching or in the
SGZ. Cells that were located more than two cells away from the SGZ were
classified as hilar. The total number of BrdU-labeled cells per section
was determined and multiplied by 6 to obtain the total number of cells
per dentate gyrus. ANOVA and post hoc Tukey tests were
performed on these totals with Bonferroni correction for multiple comparisons.
To control for a nonspecific effect of antidepressant treatment on BrdU
uptake and labeling and to determine whether the effects are specific
to hippocampal neurogenesis, striatal sections were processed for BrdU
labeling in the subventricular zone of the lateral ventricle.
BrdU-positive cells on the lateral side of the lateral ventricle were
counted (1000× magnification; 10.0-9.0 µm intra-aural; Paxinos and
Watson, 1986). At least eight sections were examined per animal
(n = 5 rats per group), and statistical analysis was
performed on the average number of BrdU-positive cells per section.
For double labeling, slices were analyzed on a confocal microscope
(Zeiss Axiovert LSM510). At least 50 BrdU-positive cells per animal
were analyzed using Z-plane sectioning (1 µm steps) to confirm the
colocalization of both BrdU and the markers NeuN, neuron-specific
enolase (NSE), or GFAP. Triple labeling was performed for
further verification of cell phenotype.
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RESULTS |
Chronic antidepressant treatment increases the number of
BrdU-positive cells
A modified stereology protocol was used to count the number of
BrdU-positive cells throughout the SGZ and hilus (West et al., 1991;
Gould et al., 1999a). The SGZ, the border between the granule cell
layer and hilus, has been shown to contain the progenitor cells that
divide and migrate into the granule cell layer where they mature into
neurons or astrocytes (Cameron et al., 1993). The percentage of
BrdU-positive cells in the hilus and SGZ was the same in control and
antidepressant-treated groups, so the cell counts in the two regions
were summed to give the total number of labeled cells per dentate gyrus
used in the statistical analysis.
Analysis of the number of BrdU-labeled cells demonstrated that chronic
antidepressant administration significantly increased the number of
BrdU-positive cells in the dentate gyrus (Fig.
2) relative to control. Chronic
administration of ECS increased the number of BrdU-labeled cells by
~50%, whereas the chemical antidepressants increased the BrdU
labeling by 20-40% (Fig. 3). ECS is
clinically the most effective treatment for refractory depression, and
this increase in BrdU-positive cells is in agreement with a report by
previous investigators (Madsen et al., 2000). The chemical antidepressants tested include a monoamine oxidase inhibitor
(tranylcypromine), a serotonin-selective reuptake inhibitor
(fluoxetine), and a norepinephrine-selective reuptake inhibitor
(reboxetine).
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Figure 2.
The number of BrdU-positive cells in the adult
hippocampus is increased after chronic antidepressant treatment. Rats
received injections of BrdU 4 d after the last ECS (10 d) or drug
(14-21 d) treatment and were killed 24 hr after the last BrdU
injection. Shown are representative photomicrographs (10×
magnification) from vehicle (A), tranylcypromine
(B), ECS (C), or fluoxetine
(D). The majority of the BrdU-labeled cells are
located in the subgranular zone (SGZ, indicated by
arrow in A) of the hippocampus, the
region between the granule cell layer (GCL) and hilus
(H).
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Figure 3.
Chronic antidepressant treatment increases BrdU
labeling in the adult hippocampus. Rats received BrdU injections 4 d after the last ECS or drug treatment, as described in Figure 2. The
results are the mean ± SEM number of BrdU-positive cells in
hippocampus (n = 8 per group). ECS,
Electroconvulsive shock; TCP, tranylcypromine.
*p < 0.05 significantly different from vehicle
control (F(3,28) = 7.05;
p < 0.05).
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Next, the time course for antidepressant regulation of BrdU labeling
was examined. Administration of fluoxetine for 1 or 5 d did not
significantly affect the number of BrdU-positive cells compared with
control (Fig. 4). After 14 or 28 d
of fluoxetine treatment, a significant increase in BrdU-positive cells
was seen compared with vehicle-treated controls and 1 or 5 d of
treatment. This indicates that chronic, but not acute, antidepressant
treatment increases BrdU labeling in the hippocampus, which is
consistent with the time course for the therapeutic action of
antidepressants (Duman et al., 1997).
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Figure 4.
Chronic, but not acute, fluoxetine administration
increases BrdU labeling in the adult hippocampus. Rats were
administered fluoxetine for 1, 5, 14, or 28 d and were then given
BrdU for analysis of cell proliferation, as described in Figure
1. The results are the mean ± SEM number of BrdU-positive cells
in hippocampus at each time point (n = 8 per
group). *p < 0.05 significantly different from
vehicle control (F(4,35) = 4.35;
p < 0.05).
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To determine whether upregulation of the number of BrdU-labeled cells
is specific to antidepressants, the influence of a nonantidepressant psychotropic drug was examined. Chronic administration of a clinically relevant dose of haloperidol, an antipsychotic agent, did not significantly influence the number of BrdU-labeled cells in dentate gyrus (vehicle, 4117 ± 259; haloperidol, 3788 ± 238 BrdU-labeled cells; mean ± SEM; n = 6 per group).
This indicates that the increase in BrdU-positive cells may be specific
to antidepressants. In addition, we have found that chronic
administration of morphine decreases granule cell proliferation, an
effect opposite to that of antidepressant treatment (Eisch et al.,
2000).
Chronic antidepressant treatment increases cell proliferation
To specifically isolate the effect of antidepressant treatment on
cell proliferation, rats were administered ECS (10 d) or fluoxetine (14 d), given a single injection of BrdU, and killed 2 hr later. At
this time point, both ECS and fluoxetine treatment significantly
increased the number of BrdU-positive cells relative to the respective
controls (vehicle, 3610 ± 330; fluoxetine, 4350 ± 420; ECS,
5780 ± 720; F(2,18) = 6.89;
p < 0.05). These results indicate that antidepressant
treatment increases the proliferation of hippocampal cells.
In all of the animals killed at either 2 or 24 hr after BrdU injection,
the BrdU-positive cells in the hilus and dentate gyrus were found in
clusters (Fig. 5A-C), with
irregularly shaped nuclei and diffuse patterns of BrdU staining. This
is representative of immature cells undergoing division (Kuhn et al.,
1996; Parent et al., 1997). The number of cells per cluster was not
affected by ECS or chemical antidepressant treatments. In addition, in all animals killed at 2 hr, a cell undergoing mitosis was seen. The
existence of these mitotic figures (Fig. 5B,C) indicates
that the BrdU is labeling newly born cells and not labeling cells that are undergoing DNA repair. Taken together, these results demonstrate that chronic antidepressant administration increases the number of
BrdU-positive cells in the adult hippocampus and that the increase in
labeling can be attributed to an increase in cell proliferation.
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Figure 5.
Representative photomicrographs of proliferating
and mature BrdU-labeled cells. A-C, Photomicrographs of
labeled cells 2 hr after BrdU injection (1000×). At this time point
proliferating cells are localized to the SGZ and often appear in
clusters. The cell clusters in A and B
contain multiple progenitor cells. Mitotic figures (B,
C, indicated by arrow) were also evident
in sections from every animal. D, E,
Photomicrographs of labeled cells 4 weeks after BrdU injection
(1000×). At this time point mature cells are found throughout the
granule cell layer and appear ovoid or round, similar to surrounding
granule cells. The characteristics of the new and mature cells from
control and antidepressant-treated sections were not different. Only
the number of proliferating cells was significantly increased by
antidepressant treatment.
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In a separate experiment, we examined the influence of antidepressant
treatment on cell proliferation when BrdU is administered without a
drug washout period. Fluoxetine was administered for 14 d and then
BrdU was administered 2 hr after the last fluoxetine treatment. This
paradigm also significantly increased the number of BrdU-positive cells
(vehicle, 4962 ± 398; fluoxetine, 6740 ± 498 BrdU-labeled
cells per dentate gyrus; mean ± SEM; n = 8 per
group; p < 0.05). The magnitude of this increase was
similar to that observed when BrdU was administered 4 d after the
last fluoxetine treatment (Fig. 3). These results indicate that
fluoxetine increases proliferation within hours after the last
treatment and that this effect is sustained for at least 4 d.
Alternatively, this data provides evidence that that the increase in
BrdU-labeled cells is not a rebound effect that occurs during the
4 d allowed for the washout period.
To determine whether the antidepressant-induced upregulation of cell
proliferation is specific to the hippocampus, another brain region
known to contain progenitor cells in adulthood, the subventricular zone
of the lateral ventricle (Kuhn et al., 1996), was examined. Chronic ECS
or fluoxetine treatment did not influence the number of BrdU-labeled
cells per section of this brain region (data not shown;
p > 0.05). In addition to demonstrating that antidepressants specifically increase cell proliferation in the hippocampus, these results also suggest that antidepressant
administration does not have a general effect on the amount of BrdU
entering the brain or the incorporation of BrdU into the DNA of
proliferating cells.
Antidepressant treatment increases neurogenesis
Newly born cells in the hippocampus can have several fates: some
cells die, whereas others survive and differentiate into mature neurons
or glia. To examine the influence of antidepressant treatment on cell
fate, the number and phenotype of the BrdU-positive cells was
determined 28 d after BrdU administration, a time at which the
cells have matured.
At this time the number of BrdU-positive cells was significantly
increased in the animals treated with chronic ECS or fluoxetine compared with vehicle control (Fig. 6).
This indicates that the proliferating cells induced by antidepressant
treatment are still surviving 28 d later. The mature cells were
found throughout the dentate gyrus, had normal granule cell morphology,
and appeared ovoid or round with uniform BrdU staining throughout the
nucleus (Fig. 5D,E). No clusters of mature cells were found
at this time. The absolute number of BrdU-positive cells in all groups
was lower relative to the 24 hr time, in agreement with previous
studies demonstrating a decline in total cell number 2 weeks after BrdU administration (Gould et al., 1999a).
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Figure 6.
The number of BrdU-positive cells is increased 4 weeks after chronic antidepressant treatment. Rats received BrdU
injections 4 d after the last ECS (10 d) or fluoxetine (14 d)
treatment and were killed 4 weeks later. The results are the mean ± SEM number of BrdU-positive cells (n = 7 per
group). *p < 0.05 significantly different from
vehicle control (F(2,18) = 5.8;
p < 0.01).
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Using markers for mature neurons, NSE or NeuN, and astrocytes
GFAP, the phenotype of the BrdU-positive cells was determined by
triple immunofluorescent labeling (Fig.
7). Confocal microscopy, using z-plane
sections to confirm colocalization for each cell, revealed that the
majority of BrdU-positive cells were neuronal (75%) and not glial
(13%) in both the control and antidepressant-treated groups. The
remaining 12% of cells were not labeled with either a neuronal or
glial marker; these cells may represent a phenotype not labeled here,
or they may be cells located deeper in the tissue section and therefore
not accessible to the antibodies used. They may also represent
quiescent undifferentiated cells (Eriksson et al., 1998; van Praag et
al., 1999b). These data indicate that the antidepressants do not affect
the differentiation of cells into neurons or glia.
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Figure 7.
Triple labeling confirms that BrdU-positive cells
mature into neurons. Rats received BrdU injections 4 d after the
last ECS treatment and were killed 4 weeks later. A representative
confocal laser-scanning image (66×) of a section from a
fluoxetine-treated rat that has been triple-labeled with BrdU
(A, green; BrdU-positive cells indicated by
arrows), GFAP (B, blue), and NeuN
(C, red). The merged image (D)
demonstrates cells that are double-labeled in the GCL for BrdU and NeuN
but not GFAP.
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In a separate experiment, the influence of antidepressant treatment on
the survival of cells that have already been born in the hippocampus
was determined. In this experiment, we administered BrdU 1 d
before initiating chronic fluoxetine treatment (14 d). Twenty-eight
days after the BrdU administration (14 d after the last fluoxetine
injection), there was no difference in the number of BrdU-positive
cells in the hippocampus (control, 2764 ± 320; fluoxetine,
2808 ± 348 BrdU-labeled cells; mean ± SEM;
n = 6). The survival rate of the newly born cells in
the hippocampus is approximately the same in both the vehicle and
fluoxetine-treated groups (~50% of BrdU-labeled cells in each group
survives at this time point). This indicates that chronic
antidepressant treatment does not directly affect the rate of
maturation and survival of BrdU-positive cells in the hippocampus.
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DISCUSSION |
The results of this study demonstrate that chronic antidepressant
administration increases neurogenesis in the dentate gyrus of the adult
rat hippocampus. Upregulation of neurogenesis is observed in response
to administration of different classes of antidepressants, indicating
that increased neurogenesis may be a common action of antidepressant
treatment. In addition, increased BrdU labeling is observed after
chronic (14 or 28 d), but not short-term (1 or 5 d)
antidepressant treatment. These findings indicate that the time course
for the upregulation of BrdU labeling is consistent with the time delay
required for the therapeutic action of antidepressants (Duman et al.,
1997).
In contrast, chronic administration of the non-antidepressant
psychotropic drug haloperidol, does not increase BrdU labeling in
hippocampal granule cells. In addition, we have recently demonstrated that morphine, another non-antidepressant psychotropic drug, decreases BrdU labeling of granule cells (Eisch et al., 2000). These findings indicate that the upregulation of hippocampal BrdU labeling may be
pharmacologically selective to the chemical antidepressant drugs. The
lack of effect of haloperidol in this study differs from two previous
studies, one reporting an increase (Dawirs et al., 1998), and one
reporting a decrease (Backhouse et al., 1982) in cell proliferation.
However, there are several differences between the current and these
previous reports, including dose and time course of drug treatment,
species and age of test animals, and the BrdU labeling protocol. One or
more of these variables could account for the difference in our
results. In the current study, the dose and time of haloperidol
treatment were consistent with the therapeutic treatment regimen
(Nibuya et al., 1995), in contrast to the two previous studies. Using
this relevant treatment paradigm and the same BrdU labeling protocol
that was used for the antidepressant studies, haloperidol does not
increase BrdU labeling.
Regulation of neurogenesis could occur at several different stages,
including cell proliferation, differentiation, and survival. We
demonstrate that 2 hr after BrdU administration, antidepressant treatment significantly increased the number of BrdU-labeled cells compared with the saline control group. This indicates that
antidepressant treatment increases cell proliferation. To examine the
effect of antidepressants on survival of labeled cells, BrdU was
administered before the start of antidepressant treatment, and the
number of labeled cells was determined 4 weeks later. Under these
conditions, the survival of the BrdU-labeled cells can be determined
independent of the influence of antidepressant treatment on cell
proliferation. In this experiment, the number of BrdU-labeled cells in
the treatment group was not different from the control group,
indicating that antidepressants do not influence cell survival.
The differentiation of labeled cells was determined 4 weeks after
antidepressant or saline treatment by colocalization of neuronal and
glial phenotypic markers in BrdU-labeled cells. At this time point,
there is a significant increase in the number of BrdU-labeled cells
relative to controls. This increase is a result of the upregulation of
cell proliferation by antidepressant treatment. The majority (75%) of
the surviving BrdU-positive cells express a neuronal marker (i.e., NeuN
or NSE) and have physical characteristics of healthy, viable neurons. A
much smaller number (13%) of cells express a glial marker (GFAP). The
remaining 12% of cells were not labeled with either cell marker and
may represent another phenotype or quiescent undifferentiated cells.
This ratio of labeled neurons and glia is similar to that reported in
previous studies (Eriksson et al., 1998; van Praag et al., 1999b), and was not significantly influenced by antidepressant treatment. This is
consistent with our finding that antidepressant treatment increases the
proliferation, but not survival, of labeled hippocampal cells. Once the
cells are induced to proliferate by antidepressant treatment, their
survival and differentiation rates are identical to animals treated
with vehicle. The result is a net increase in the number of neurons
produced, or neurogenesis, in antidepressant-treated animals compared
with vehicle controls.
It is not currently known whether the mature BrdU-positive neurons seen
in this study are functional in vivo. However, new neurons
in the granule cell layer in hippocampus have been demonstrated to send
axons to the CA3 pyramidal cell layer, the appropriate projection area
for granule cells (Markakis and Gage, 1999). Mature BrdU-labeled cells
in the granule cell layer are also surrounded by synaptic vesicles,
indicating that they receive synaptic inputs. Learning and memory tasks
that are dependent on the hippocampus result in an upregulation of
neurogenesis (Gould et al., 1999a; van Praag et al., 1999b). In
addition, increased neurogenesis in response to voluntary running has
recently been correlated with an increase in granule cell long-term
potentiation, a cellular model of learning and memory (van Praag et
al., 1999a). Taken together, these studies demonstrate that newly
formed cells differentiate into mature neurons that integrate into the
existing hippocampal circuitry and may increase the functional capacity
of this brain structure.
The mechanisms underlying the regulation of hippocampal neurogenesis
are being actively investigated. Interestingly, both the cAMP cascade
and BDNF, which we have found to be upregulated by antidepressant
treatment (Nibuya et al., 1995, 1996; Thome et al., 2000), have been
shown to play a role in the regulation of neurogenesis. Activation of
the cAMP pathway or incubation with BDNF is reported to increase
neuronal differentiation and neurite outgrowth of progenitor cells
in vitro (Palmer et al., 1997; Takahashi et al., 1998). In
addition, intraventricular infusion of BDNF is reported to increase
neurogenesis in the adult olfactory bulb (Zigova et al., 1998). Yet
another possibility is insulin-like growth factor (IGF-1), a
growth-promoting peptide hormone that has neurotrophic properties.
IGF-1 increases proliferation and survival of neurons in adult rat
(Aberg et al., 2000), although antidepressant regulation of this factor
has not been demonstrated. Studies are currently underway to examine
the role of the cAMP response element-binding protein and BDNF,
as well as other factors, in the upregulation of cell proliferation in
response to antidepressant treatment.
In addition to a potential role for these second messenger and
neurotrophic factor systems, preliminary studies demonstrate that
direct activation of the serotonin-1A (5HT1A)
receptor can induce neurogenesis (Jacobs et al., 1998). This group has
also demonstrated in a preliminary study that chronic fluoxetine
treatment increases proliferation of granule cells (Jacobs and Fornal,
1999). Because chronic antidepressant treatment is reported to increase 5HT1A function (Duman, 1998; Haddjeri et al.,
1998), it is possible that antidepressant treatment may increase
neurogenesis in part by activation of the 5HT1A receptor.
Recently, two studies have demonstrated that there is a decrease in
neuronal and glial density in the prefrontal cortex of postmortem
brains of patients with major depression (Ongur et al., 1998; Rajkowska
et al., 1999). Although the current study has centered on the
hippocampus, given the recent report that neurogenesis also occurs in
the adult prefrontal cortex (Gould et al., 1999b), it is possible that
the effects of antidepressants on neurogenesis may extend to cortical
areas as well as hippocampal regions. This possibility must be
addressed in future studies.
An increase in the number and function of hippocampal granule cells
could represent an important adaptive response to antidepressant agents. This effect would be in opposition to the downregulation of
neurogenesis, as well as atrophy of hippocampal neurons, which occurs
in response to stress. A reversal of stress-induced hippocampal neuronal atrophy has been demonstrated in animals (Watanabe et al.,
1992a,b), and more recently it has been demonstrated in humans that a
reversal of hippocampal atrophy occurs after treatment for Cushing's
disease (Starkman et al., 1999). It is possible that
antidepressant-induced upregulation of neurogenesis would oppose the
reduction of hippocampal function and volume that has been reported in
patients suffering from depression and other stress-related disorders
(Sapolsky, 1996; Sheline et al., 1996). Future studies will be required
to determine whether antidepressants increase neurogenesis in humans
and to determine whether this effect is involved in the therapeutic
response to these agents.
| |
FOOTNOTES |
Received July 17, 2000; revised Sept. 13, 2000; accepted Sept. 22, 2000.
This work is supported by United States Public Health Service Grants
MH45481, MH53199, and 2 PO1 MH25642, and by a Veterans Administration
(VA) National Center Grant for post-traumatic stress disorder,
VA Medical Center.
Correspondence should be addressed to Dr. Ronald S. Duman, 34 Park
Street, New Haven, CT 06508. E-mail: ronald.duman{at}yale.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
