Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue8.2000:
MOLECULAR AND CELLULAR HYPOTHESES
ANTIDEPRESSANT ACTION
OF
Regulation of Hippocampal Neurogenesis in Adulthood
Elizabeth Gould, Patima Tanapat, Tracy Rydel, and Nicholas Hastings
A substantial number of new granule neurons are produced in the dentate gyrus in adulthood in a variety of
mammalian species, including humans. Numerous studies
have demonstrated that the production and survival of new
hippocampal neurons can be enhanced or diminished by
hormones and experience. Steroid hormones of the ovaries
and adrenal glands have been shown to modulate the
production of immature neurons by affecting the proliferation of granule cell precursors. Aversive experiences
have been demonstrated to decrease the production of
immature granule cells, whereas enriching experiences,
including learning, have been shown to enhance the
survival of new hippocampal cells. These studies indicate
that adult-generated neurons represent a unique form of
structural plasticity that can be regulated by the environment, and furthermore suggest that new neurons play an
important role in hippocampal function. Biol Psychiatry
2000;48:715–720 © 2000 Society of Biological
Psychiatry
Key Words: Neurogenesis, dentate gyrus, hippocampus,
stress, hormones
Adult Neurogenesis in the Dentate Gyrus
A
dult neurogenesis in the dentate gyrus was first
reported over 30 years ago by Altman and colleagues
(Altman and Das 1965). With [3H]thymidine autoradiography to label proliferating cells and their progeny, it was
shown that new cells are produced in the dentate gyrus of
the adult rat. These new cells were the daughter cells of
progenitors located in the dentate gyrus, primarily on the
border of the granule cell layer (GCL) and hilus (a region
called the subgranular zone [SGZ]). The new cells become
incorporated into the GCL and develop the morphological
characteristics of mature granule neurons (Altman and Das
1965). Sporadic studies over the ensuing three decades
reported additional evidence that new cells become neurons, and the evidence is now compelling. It has been
shown that adult-generated cells produced in the dentate
gyrus of the rat receive synaptic input, extend axons into
the mossy fiber pathway, and express a number of markers
From the Department of Psychology, Princeton University, Princeton, New Jersey.
Address reprint requests to Elizabeth Gould, Princeton University, Department of
Psychology, Green Hall, Princeton NJ 08544.
Received March 21, 2000; revised July 7, 2000; accepted July 28, 2000.
© 2000 Society of Biological Psychiatry
of mature neurons (Cameron et al 1993a, 1993b; Gould
and Tanapat 1997; Gould et al 1999b; Hastings and Gould
1999; Kaplan and Bell 1983; Kaplan and Hinds 1977;
Markakis and Gage 1999; Stanfield and Trice 1988;
Figure 1). The majority of these earlier studies were
carried out in rats. Over the past few years, however,
reports of neurogenesis in adult tree shrews (Tupaia
belangeri), marmosets (Callithrix jacchus), macaques
(Macaca fascicularis and Macaca mulatta), and humans
have demonstrated that adult-generated neurons are a
feature common to the mammalian hippocampus (Eriksson et al 1998; Gould et al 1997, 1998, 1999a; Kornack
and Rakic 1999).
The prolonged period of granule cell genesis in the
dentate gyrus makes it unusually susceptible to experience-dependent structural changes. The proliferation of
progenitor cells and the subsequent developmental events
such as dendritic growth, axon elongation, and synapse
formation represent ongoing structural plasticity that may
be altered by experience. The continual addition of immature neurons could allow restructuring of this area according to the current environment, thus providing important
adaptive plasticity. On the other hand, these ongoing
structural changes might render the dentate gyrus particularly sensitive to environmental perturbations that may
impair hippocampal structure and function.
Studies conducted over the past several years have
identified endocrine, neural, and experiential factors that
regulate the production and survival of late-generated
neurons in this brain region. Although most studies examining the regulation of adult neurogenesis have been
carried out in rats, the limited data available from other
species suggest that the production of new neurons is
affected by the same factors in rodents and primates.
Positive Regulators of Adult-Generated
Neurons
Estrogen
The ovarian hormone estrogen has been shown to stimulate
the production of new granule cells in the adult female rat.
Removal of circulating estrogen by ovariectomy results in a
significant decrease in the proliferation of granule cell precursors. This decrease can be prevented by replacement of
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2000;48:715–720
E. Gould et al
Figure 1. Bromodeoxyuridine (BrdU)–labeled cells in the dentate gyrus of the adult rat. (Left) BrdU-labeled progenitor cells in the
subgranular zone of the adult rat (arrowheads). (Middle) BrdU-labeled cell in the granule cell layer (GCL) of the adult rat (arrowhead).
This cell is colabeled with TOAD-64, a marker of immature neurons, and has the morphological characteristics of a granule cell.
(Right) BrdU-labeled cell (arrowhead) in the GCL of an adult rat that is colabeled with the retrograde tracer fluoro-ruby injected into
the CA3 region, a major target of hippocampal granule cells.
estrogen to ovariectomized rats. Moreover, a natural fluctuation in cell proliferation is observed across the estrous cycle
in the adult rat. During proestrus, a time when estrogen levels
are high, the number of proliferating cells in the dentate gyrus
is maximal, as compared with estrus and diestrus, when
ovarian hormone levels are lower (Tanapat et al 1999). This
natural increase in cell proliferation is most likely responsible
for the gender difference in the proliferation of granule cell
precursors observed in adult rats. Adult female rats produce
more new cells with the characteristics of immature neurons
in the dentate gyrus than do adult male rats; however, many
of these new cells eventually degenerate, such that by several
weeks after mitosis the gender difference favoring females is
no longer detectable (Tanapat et al 1999). These findings
suggest that estrogen induces a transient increase in the
number of immature neurons; however, because the survival
of adult-generated cells appears to be dependent on experience (see below), the persistence of a gender difference in
new neurons for longer periods of time in animals exposed to
nondeprived conditions cannot be ruled out.
The extent to which other gonadal hormones, such as
progesterone and testosterone, affect adult neurogenesis
remains unknown. Moreover, no previous studies have
explored the possibility that periods of dramatic or chronic
changes in gonadal hormones such as puberty, pregnancy,
or aging result in altered granule cell genesis.
Environmental Complexity and Learning
Several studies have shown that environmental complexity
can enhance the number of new neurons in the hippocampus. Barnea and Nottebohm (1994) have demonstrated that
black-capped chickadees that live in the wild maintain
more new hippocampal neurons than those living in
captivity. A similar enhancement in the number of new
hippocampal neurons has been observed in the dentate
gyrus of adult mice and rats living in an enriched environment, as compared with those living under standard
laboratory control conditions (Kempermann et al 1997;
Nilsson et al 1999). There are many variables that differ
between living in the wild and living in captivity and
between living in an enriched environment and under
control conditions in the laboratory, such as social interaction, nutrition, stress, activity levels, and learning opportunities.
Evidence suggests that both learning and physical activity enhance the number of new granule neurons, apparently through different mechanisms. Observations in
black-capped chickadees suggest that certain types of
learning may increase the survival of new cells. For
example, seasonal differences exist in the number of new
hippocampal neurons that correlate with changes in seed
storage and retrieval, behaviors that involve spatial navigation learning (Barnea and Nottebohm 1994). Similarly,
it has been demonstrated that training on a task that
requires the hippocampal formation for acquisition results
in an increase in the number of adult-generated granule
cells (Gould et al 1999b). In untrained laboratory animals,
most adult-generated cells appear to degenerate within 2
weeks of production (Cameron et al 1993a, 1993b; Gould
et al 1999b); however, training on either of two hippocampal-dependent tasks, spatial learning during Morris water
maze training and trace eyeblink conditioning, rescues a
significant proportion of these cells (Ambrogini et al 2000;
Gould et al 1999b). In the Morris water maze task, rats use
extramaze cues to locate a platform submerged in a pool of
water. Rats that learned the location of the hidden platform
Regulation of Hippocampal Neurogenesis
exhibited an increase in the survival of adult-generated
cells, as compared with animals that remained in a pool of
water in the absence of a platform and as compared with
control subjects. A similar increase in the number of new
cells has also been observed using the trace eyeblink
conditioning task. In this paradigm, rats learn to associate
an unconditioned stimulus (US; periorbital shock) and a
conditioned stimulus (CS; white noise) that are separated
in time. Again, as little as 4 days of training resulted in a
greater than twofold increase in the number of new
granule neurons, as compared with rats that were presented with the US and CS in an unpaired condition. This
increase is most likely the result of enhanced cell survival,
as opposed to cell proliferation, for the following three
reasons: 1) learning appears to be effective at increasing
the number of new neurons only when it occurs during the
time of maximal death of newly born cells in laboratory
control subjects (Gould et al 1999b; compare with
Greenough et al 1999; van Praag et al 1999b); 2) the
number of pyknotic or degenerating cells in the SGZ is
diminished following hippocampal-dependent learning,
and bromodeoxyuridine (BrdU)–labeled pyknotic cells
that are observed between 1 and 2 weeks after labeling in
control subjects are completely absent after learning; and
3) the number of BrdU-labeled cells does not increase
when BrdU is administered during the training phase, after
all animals have reached criteria. Although these studies
have shown that certain types of learning increase the
number of newly generated cells by enhancing their
survival, the life span of these cells is not known. Because
the number of cells in the brain does not increase throughout adulthood, these cells, or some comparable population,
must eventually degenerate. The death of newly generated
cells has been observed in the dentate gyrus of laboratory
control animals (Gould et al 1999b); however, given that
cell survival is enhanced by living in a more complex
environment and by learning experiences, these data are
not likely to accurately reflect the timing or magnitude of
such events in animals living in natural conditions.
Another aspect of the enriched environment that has
been shown to enhance the number of new granule cells is
increased physical activity. Providing female mice access
to a running wheel enhances the number of new granule
cells by stimulating the proliferation of granule cell
precursors (van Praag et al 1999a, 1999b).
Negative Regulators of Adult-Generated
Neurons
Deprivation
Whereas they provide important information about the
specific experiences necessary for the production and
survival of new cells, studies demonstrating that environ-
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2000;48:715–720
717
mental enrichment, running, and learning enhance the
number of adult-generated cells as compared with control
subjects (Gould et al 1999b; Kempermann et al 1997;
Nilsson et al 1999; van Praag et al 1999a, 1999b) may also
be a reflection of the abnormal state of laboratory control
animals. Rodents living in the wild experience a more
complex environment, including enhanced activity and
learning opportunities, compared with that of laboratory
animals used in controlled studies. Because standard
laboratory conditions for rodents severely restrict natural
behavior and experience, these animals should be thought
of as living in relative deprivation. The complexity of
natural living may increase the production and extended
survival of more new neurons than what is typically
reported for deprived laboratory control animals. This
possibility should also be considered with regard to adult
neurogenesis in primates. Adult neurogenesis studies carried out in nonhuman primates thus far have only focused
on animals living in laboratory settings (Gould et al 1998,
1999a; Kornack and Rakic 1999). Such conditions involve
dramatic cognitive, motor, and social deprivation relative
to those produced by living in natural settings. The extent
to which laboratory-enriched environments mimic natural
living, in terms of effects on neurogenesis, remains
unknown.
Adrenal Steroids
Adrenal steroids have been shown to inhibit the production of new granule cells throughout life by suppressing
the proliferation of granule cell precursors. Experimental
increases in corticosterone levels diminish the number of
proliferating cells in the dentate gyrus of rat pups during
the stress-hyporesponsive period, when adrenal steroids
are naturally low (Gould et al 1991). Removal of adrenal
steroids after this time stimulates the proliferation of
granule cell precursors and, ultimately, the production of
new granule neurons (Cameron and Gould 1994; Gould et
al 1992). Conversely, treatment of adult rats with corticosterone, the main glucocorticoid of rats, further inhibits the
proliferation of granule cell precursors (Cameron and
Gould 1994). The suppression of granule cell genesis by
adrenal steroids continues throughout adulthood and appears to be responsible for the aging-associated suppression of granule cell genesis. Aged rats and monkeys
exhibit diminished cell proliferation in the dentate gyrus as
well as elevated levels of circulating glucocorticoids
(Gould et al 1999a; Kuhn et al 1996; Sapolsky 1992). A
recent study has shown that removal of adrenal steroids in
aged rats restores high levels of cell proliferation in the
dentate gyrus (Cameron and McKay 1999). The absence
of either type 1 or type 2 adrenal steroid receptors on
granule cell precursors (Cameron et al 1993a, 1993b)
718
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E. Gould et al
suggests that the effects of adrenal steroids on cell proliferation occur indirectly through another factor.
Excitatory Input
The proliferation of granule cell precursors in the dentate
gyrus is also affected by N-methyl-D-aspartate (NMDA)
receptor–mediated excitatory input. In adulthood, treatment with either competitive or noncompetitive NMDA
receptor antagonists increases the number of proliferating
cells in the rodent and tree shrew dentate gyri (Cameron et
al 1995; Gould et al 1997). Conversely, activation of
NMDA receptors inhibits cell proliferation in the dentate
gyrus during adulthood (Cameron et al 1995). The granule
cell population receives a major excitatory input from the
entorhinal cortex via the perforant path. Transmission
across this pathway can involve NMDA receptor activation (Kelsey et al 2000), suggesting that perforant path
input may participate in the suppression of cell proliferation in the dentate gyrus. Consistent with this possibility,
lesion of the entorhinal cortex has an effect on cell
proliferation similar to that of the blockade of NMDA
receptors, to enhance cell proliferation in the dentate gyrus
in adulthood (Cameron et al 1995). These results may
appear to be at variance with studies demonstrating enhancing effects of seizures on hippocampal neurogenesis
(Nakagawa et al 2000; Parent et al 1997); however, most
experimentally induced seizures result in cell death, a
condition known to stimulate granule cell genesis in the
dentate gyrus (Gould and Tanapat 1997). Thus, it is likely
that seizure-induced changes in neurogenesis are the result
of a complex cascade of events, and not merely of changes
in excitatory input. Available evidence suggests that adrenal steroids suppress cell proliferation in the dentate
gyrus by acting through an NMDA receptor–mediated
excitatory pathway (Cameron et al 1998).
Stressful Experience
The suppressive effects of glucocorticoids and NMDA
receptor activation on granule cell genesis in the intact
dentate gyrus suggest that exposure to stress, which
elevates glucocorticoid levels and stimulates hippocampal glutamate release in adulthood (Moghaddam et al
1994; Stein-Behrens et al 1999), naturally inhibits cell
proliferation.
Acute exposure to stress decreases the proliferation of
granule cell precursors in the dentate gyri of adult rats
(Tanapat et al, submitted), tree shrews (Gould et al 1997),
and marmosets (Gould et al 1998). Exposure of adult rats
to predator odor elicits a stress response characterized by
increased adrenal steroid levels (Heale et al 1994; Sgoifo
et al 1996) and a characteristic electrophysiologic response in the dentate gyrus (Heale et al 1994). A single
Figure 2. The number of bromodeoxyuridine (BrdU)–labeled
cells in the dentate gyrus of the adult rat is significantly lower in
subordinate animals, as compared with dominant ones. These
animals lived in a visible burrow system (VBS) for 4 days
(Blanchard et al 1995). Four male and two female animals were
placed into the VBS and videotaped for 10 hours during the dark
phase. Within the first 3 nights, one adult male rat established
himself as the dominant animal, characterized by more time in
the open area and more offensive encounters than the others. All
other male rats were characterized as subordinates. On the last
day, the animals were injected with BrdU and perfused 2 hours
later. *Significant difference from the dominant animal (p ,
.05).
brief exposure to trimethyl thiazoline, a component of fox
feces, rapidly suppresses cell proliferation in the dentate
gyrus (Tanapat et al, submitted). This effect is likely to be
the result of stress-induced increases in glucocorticoids
because rendering animals incapable of an increase in
glucocorticoids (by removing the adrenal glands and
replacing with low-dose corticosterone) prevents the effect
(Tanapat et al, submitted). Similarly, a suppressive effect
of stress on the number of BrdU-labeled cells has been
observed in the dentate gyri of adult rats living as
subordinates in a visible burrow system (Figure 2). Consistent with these findings, nonrodent mammalian species
also show a suppressive effect of stress on hippocampal
cell proliferation. In adult tree shrews, a single exposure to
subordination stress results in a rapid decrease in the
number of new cells produced in the dentate gyri of
stressed animals, as compared with control subjects
(Gould et al 1997). Likewise, studies of marmosets in a
resident intruder paradigm have shown that a single
exposure to social stress results in a rapid decrease in the
number of new cells produced in the dentate gyrus, as
compared with control subjects (Gould et al 1998). The
extent to which other types of stressors have a similar
effect on cell proliferation remains to be determined.
Repeated stress has been shown to produce prolonged
suppression of cell proliferation in the dentate gyri of adult
tree shrews. Twenty-eight days of exposure to a dominant
animal for 1 hour each day results in persistent elevations
Regulation of Hippocampal Neurogenesis
in cortisol levels in adult tree shrews (Fuchs et al 1995)
and a decrease in new cell production in the dentate gyrus,
as well as a decrease in the total GCL volume (Fuchs et al
1997). It is likely that chronic suppression of granule cell
production is at least partially responsible for the changes
in GCL volume, although a causal relationship between
these two changes has yet to be established.
Functional Consequences of Changes in
Adult-Generated Neurons
Although the functional significance of adult-generated
neurons is not known, two lines of evidence suggest that
these new cells play an important role in learning. First,
many new neurons are added to the hippocampus, a brain
region involved in certain types of learning and memory.
Second, regulators of hippocampal neurogenesis in adulthood also alter performance on hippocampal-dependent
learning tasks in a manner that is consistent with a link
between new cells and learning. It is important to note that
functional changes in the number of adult-generated neurons are not likely to be immediately evident. New
neurons require time to differentiate and become integrated into functional circuitry. Thus, it is the period
following changes in cell production that is most likely to
be functionally relevant; however, the fact that adultgenerated cells in the dentate gyrus extend axons into the
CA3 region of the hippocampal formation as early as 4 –10
days following division (Hastings and Gould 1999) suggests that the impact of changes in cell production may be
functionally significant as early as 4 days later. In addition, it is important to note that acute changes in cell
production may not alter hippocampal function. Thus, the
impact of chronic changes in neuron production is more
likely to be of interest because such effects are likely to be
additive.
Chronic exposure to positive regulators of adult neurogenesis, such as estrogen, enriched-environment living,
and running, has been associated with enhanced performance on hippocampal-dependent learning tasks in rodents (Kempermann et al 1997; Luine et al 1997; van
Praag et al 1999a) and other cognitive tasks in humans
(McEwen et al 1997). Conversely, chronic exposure to
negative regulators of adult neurogenesis, such as adrenal
steroids and stress, has been associated with impaired
performance on such tasks (Bodnoff et al 1995; Endo et al
1996; Krugers et al 1997; Luine et al 1994). These
correlations are consistent with the view that adult-generated neurons participate in hippocampal-dependent learning; however, these neuroendocrine and experiential factors also alter other aspects of brain structure and function
that cannot be ruled out as alternative mechanisms for the
changes in hippocampal-dependent learning. Studies de-
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719
signed to examine the behavioral consequences of specific
depletion of new neurons will provide a more direct
approach to this question.
References
Altman J, Das GD (1965): Autoradiographic and histological
evidence of postnatal hippocampal neurogenesis in rats.
J Comp Neurol 124:319 –335.
Ambrogini P, Cuppini R, Cuppini C, Ciaroni S, Cecchini T, Ferri
P, et al (2000): Spatial learning affects immature granule cell
survival in adult rat dentate gyrus. Neurosci Lett 286:21–24.
Barnea A, Nottebohm F (1994): Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees. Proc Natl Acad Sci U S A 91:11217–11221.
Blanchard DC, Spencer RL, Weiss SM, Blanchard RJ, McEwen
B, Sakai RR (1995): Visible burrow system as a model of
chronic social stress: Behavioral and neuroendocrine correlates. Psychoneuroendocrinology 20:117–134.
Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose
GM, Meaney MJ (1995): Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity,
and hippocampal neuropathology in young and mid-aged rats.
J Neurosci 15:61– 69.
Cameron HA, Gould E (1994): Adult neurogenesis is regulated
by adrenal steroids in the dentate gyrus. Neuroscience 61:
203–209.
Cameron HA, McEwen BS, Gould E (1995): Regulation of adult
neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci 15:4687– 4692.
Cameron HA, McKay RD (1999): Restoring production of
hippocampal neurons in old age. Nat Neurosci 2:894 – 897.
Cameron HA, Tanapat P, Gould E (1998): Adrenal steroids and
N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common
pathway. Neuroscience 82:349 –354.
Cameron HA, Woolley CS, Gould E (1993a): Adrenal steroid
receptor immunoreactivity in cells born in the adult rat
dentate gyrus. Brain Res 611:342–346.
Cameron HA, Woolley CS, McEwen BS, Gould E (1993b):
Differentiation of newly born neurons and glia in the dentate
gyrus of the adult rat. Neuroscience 56:337–344.
Endo Y, Nishimura JI, Kimura F (1996): Impairment of maze
learning in rats following long-term glucocorticoid treatments. Neurosci Lett 203:199 –202.
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998): Neurogenesis in the
adult human hippocampus. Nat Med 4:1313–1317.
Fuchs E, Flugge G, McEwen BS, Tanapat P, Gould E (1997):
Chronic subordination stress inhibits neurogenesis and decreases the volume of the granule cell layer. Soc Neurosci
23:317.
Fuchs E, Uno H, Flugge G (1995): Chronic psychosocial stress
induces morphological alterations in hippocampal pyramidal
neurons of the tree shrew. Brain Res 673:275–282.
Gould E, Cameron HA, Daniels DC, Woolley CS, McEwen BS
(1992): Adrenal hormones suppress cell division in the adult
rat dentate gyrus. J Neurosci 12:3642–3650.
720
BIOL PSYCHIATRY
2000;48:715–720
Gould E, McEwen BS, Tanapat P, Galea LAM, Fuchs E (1997):
Neurogenesis in the dentate gyrus of the adult tree shrew is
regulated by psychosocial stress and NMDA receptor activation. J Neurosci 17:2492–2498.
Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E
(1999a): Hippocampal neurogenesis in adult Old World
primates. Proc Natl Acad Sci U S A 96:5263–5267.
Gould E, Tanapat P (1997): Lesion-induced proliferation of
neuronal progenitors in the dentate gyrus of the adult rat.
Neuroscience 80:427– 436.
Gould E, Tanapat P, Beylin A, Reeves AJ, Shors TJ (1999b):
Hippocampal-dependent learning enhances the survival of
granule neurons generated in the dentate gyrus of adult rats.
Nat Neurosci 2:260 –265.
Gould E, Tanapat P, Hastings NB, Shors TJ (1999c): Neurogenesis in adulthood: A possible role in learning. Trends Cogn
Sci 3:186 –192.
Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E (1998):
Proliferation of granule cell precursors in the dentate gyrus of
adult monkeys is diminished by stress. Proc Natl Acad Sci
U S A 95:3168 –3171.
Gould E, Woolley CS, Cameron HA, Daniels DC, McEwen BS
(1991): Adrenal steroids regulate postnatal development of
the rat dentate gyrus: II. Effects of glucocorticoids and
mineralocorticoids on cell birth. J Comp Neurol 313:486 –
493.
Greenough WT, Cohen NJ, Juraska JM (1999): New neurons in
old brains: Learning to survive? Nat Neurosci 2:203–205.
Hastings NB, Gould E (1999): Rapid extension of axons into the
CA3 region by adult-generated granule cells. J Comp Neurol
413:146 –154.
Heale VR, Vanderwolf CH, Kavaliers M (1994): Components of
weasel and fox odors elicit fast wave bursts in the dentate
gyrus of rats. Behav Brain Res 63:159 –165.
Kaplan MS, Bell DH (1983): Neuronal proliferation in the
9-month-old rodent-radioautographic study of granule cells in
the hippocampus. Exp Brain Res 52:1–5.
Kaplan MS, Hinds JW (1977): Neurogenesis in the adult rat:
Electron microscopic analysis of light radioautographs. Science 197:1092–1094.
Kelsey JE, Sanderson KL, Frye CA (2000): Perforant path
stimulation in rats produces seizures, loss of hippocampal
neurons, and a deficit in spatial mapping which are reduced
by prior MK-801. Behav Brain Res 107:59 – 69.
Kempermann G, Kuhn HG, Gage FH (1997): More hippocampal
neurons in adult mice living in an enriched environment.
Nature 386:493– 495.
Kornack DR, Rakic P (1999): Continuation of neurogenesis in
the hippocampus of the adult macaque monkey. Proc Natl
Acad Sci U S A 96:5768 –7573.
Krugers HJ, Douma BR, Andringa G, Bohus B, Korf J, Luiten
PG (1997): Exposure to chronic psychosocial stress and
corticosterone in the rat: Effects on spatial discrimination
learning and hippocampal protein kinase Cgamma immunoreactivity. Hippocampus 7:427– 436.
Kuhn HG, Dickinson-Anson H, Gage FH (1996): Neurogenesis
in the dentate gyrus of the adult rat: Age-related decrease of
neuronal progenitor proliferation. J Neurosci 16:2027–2033.
Luine V, Villegas M, Martinez C, McEwen BS (1994): Repeated
E. Gould et al
stress causes reversible impairments of spatial memory performance. Brain Res 639:167–170.
Luine VN, Richards ST, Wu VY, Beck KD (1998): Estradiol
enhances learning and memory in a spatial memory task and
effects levels of monoaminergic neurotransmitters. Horm
Behav 34:149 –162.
Markakis EA, Gage FH (1999): Adult-generated neurons in the
dentate gyrus send axonal projections to field CA3 and are
surrounded by synaptic vesicles. J Comp Neurol 406:449 –
460.
McEwen BS, Alves SE, Bulloch K, Weiland NG (1997): Ovarian
steroids and the brain: Implications for cognition and aging.
Neurology 48:S8 –S15.
Moghaddam B, Bolinao ML, Stein-Behrens B, Sapolsky R
(1994): Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res 655:251–254.
Nakagawa E, Aimi Y, Yasuhara O, Tooyama I, Shimada M,
McGeer PL, Kimura H (2000): Enhancement of progenitor
cell division in the dentate gyrus triggered by initial limbic
seizures in rat models of epilepsy. Epilepsia 41:10 –18.
Nilsson M, Perfilieva E, Johansson U, Orwar O, Eriksson PS
(1999): Enriched environment increases neurogenesis in the
adult rat dentate gyrus and improves spatial memory. J Neurobiol 39:569 –578.
Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS,
Lowenstein DH (1997): Dentate granule cell neurogenesis is
increased by seizures and contributes to aberrant network
reorganization in the adult rat hippocampus. J Neurosci
17:3727–3738.
Sapolsky RM. (1992): Do glucocorticoid concentrations rise with
age in the rat? Neurobiol Aging 13:171–174.
Sgoifo A, de Boer SF, Haller J, Koolhaas JM (1996): Individual
differences in plasma catecholamine and corticosterone stress
responses of wild-type rats: Relationship with aggression.
Physiol Behav 60:1403–1407.
Stanfield BB, Trice JE (1988): Evidence that granule cells
generated in the dentate gyrus of adult rats extend axonal
projections. Exp Brain Res 72:399 – 406.
Stein-Behrens BA, Lin WJ, Sapolsky RM (1999): Physiological
elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63:596 – 602.
Tanapat P, Galea LA, Gould E (1998): Stress inhibits the
proliferation of granule cell precursors in the developing
dentate gyrus. Int J Dev Neurosci 16:235–239.
Tanapat P, Hastings N, Reeves AJ, Gould E (1999): Estrogen
stimulates a transient increase in the number of new neurons
in the dentate gyrus of the adult female rat. J Neurosci
19:5792–5801.
Tanapat P, Hastings NB, Rydel T, Gould E (submitted): Exposure to predator odor inhibits hippocampal cell proliferation
via adrenal steroids.
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999a):
Running enhances neurogenesis, learning, and long-term
potentiation in mice. Proc Natl Acad Sci U S A 96:13427–
13431.
van Praag H, Kempermann G, Gage FH (1999b): Running
increases cell proliferation and neurogenesis in the adult
mouse dentate gyrus. Nat Neurosci 2:266 –270.
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Regulation of Hippocampal Neurogenesis in Adulthood
Elizabeth Gould, Patima Tanapat, Tracy Rydel, and Nicholas Hastings
A substantial number of new granule neurons are produced in the dentate gyrus in adulthood in a variety of
mammalian species, including humans. Numerous studies
have demonstrated that the production and survival of new
hippocampal neurons can be enhanced or diminished by
hormones and experience. Steroid hormones of the ovaries
and adrenal glands have been shown to modulate the
production of immature neurons by affecting the proliferation of granule cell precursors. Aversive experiences
have been demonstrated to decrease the production of
immature granule cells, whereas enriching experiences,
including learning, have been shown to enhance the
survival of new hippocampal cells. These studies indicate
that adult-generated neurons represent a unique form of
structural plasticity that can be regulated by the environment, and furthermore suggest that new neurons play an
important role in hippocampal function. Biol Psychiatry
2000;48:715–720 © 2000 Society of Biological
Psychiatry
Key Words: Neurogenesis, dentate gyrus, hippocampus,
stress, hormones
Adult Neurogenesis in the Dentate Gyrus
A
dult neurogenesis in the dentate gyrus was first
reported over 30 years ago by Altman and colleagues
(Altman and Das 1965). With [3H]thymidine autoradiography to label proliferating cells and their progeny, it was
shown that new cells are produced in the dentate gyrus of
the adult rat. These new cells were the daughter cells of
progenitors located in the dentate gyrus, primarily on the
border of the granule cell layer (GCL) and hilus (a region
called the subgranular zone [SGZ]). The new cells become
incorporated into the GCL and develop the morphological
characteristics of mature granule neurons (Altman and Das
1965). Sporadic studies over the ensuing three decades
reported additional evidence that new cells become neurons, and the evidence is now compelling. It has been
shown that adult-generated cells produced in the dentate
gyrus of the rat receive synaptic input, extend axons into
the mossy fiber pathway, and express a number of markers
From the Department of Psychology, Princeton University, Princeton, New Jersey.
Address reprint requests to Elizabeth Gould, Princeton University, Department of
Psychology, Green Hall, Princeton NJ 08544.
Received March 21, 2000; revised July 7, 2000; accepted July 28, 2000.
© 2000 Society of Biological Psychiatry
of mature neurons (Cameron et al 1993a, 1993b; Gould
and Tanapat 1997; Gould et al 1999b; Hastings and Gould
1999; Kaplan and Bell 1983; Kaplan and Hinds 1977;
Markakis and Gage 1999; Stanfield and Trice 1988;
Figure 1). The majority of these earlier studies were
carried out in rats. Over the past few years, however,
reports of neurogenesis in adult tree shrews (Tupaia
belangeri), marmosets (Callithrix jacchus), macaques
(Macaca fascicularis and Macaca mulatta), and humans
have demonstrated that adult-generated neurons are a
feature common to the mammalian hippocampus (Eriksson et al 1998; Gould et al 1997, 1998, 1999a; Kornack
and Rakic 1999).
The prolonged period of granule cell genesis in the
dentate gyrus makes it unusually susceptible to experience-dependent structural changes. The proliferation of
progenitor cells and the subsequent developmental events
such as dendritic growth, axon elongation, and synapse
formation represent ongoing structural plasticity that may
be altered by experience. The continual addition of immature neurons could allow restructuring of this area according to the current environment, thus providing important
adaptive plasticity. On the other hand, these ongoing
structural changes might render the dentate gyrus particularly sensitive to environmental perturbations that may
impair hippocampal structure and function.
Studies conducted over the past several years have
identified endocrine, neural, and experiential factors that
regulate the production and survival of late-generated
neurons in this brain region. Although most studies examining the regulation of adult neurogenesis have been
carried out in rats, the limited data available from other
species suggest that the production of new neurons is
affected by the same factors in rodents and primates.
Positive Regulators of Adult-Generated
Neurons
Estrogen
The ovarian hormone estrogen has been shown to stimulate
the production of new granule cells in the adult female rat.
Removal of circulating estrogen by ovariectomy results in a
significant decrease in the proliferation of granule cell precursors. This decrease can be prevented by replacement of
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E. Gould et al
Figure 1. Bromodeoxyuridine (BrdU)–labeled cells in the dentate gyrus of the adult rat. (Left) BrdU-labeled progenitor cells in the
subgranular zone of the adult rat (arrowheads). (Middle) BrdU-labeled cell in the granule cell layer (GCL) of the adult rat (arrowhead).
This cell is colabeled with TOAD-64, a marker of immature neurons, and has the morphological characteristics of a granule cell.
(Right) BrdU-labeled cell (arrowhead) in the GCL of an adult rat that is colabeled with the retrograde tracer fluoro-ruby injected into
the CA3 region, a major target of hippocampal granule cells.
estrogen to ovariectomized rats. Moreover, a natural fluctuation in cell proliferation is observed across the estrous cycle
in the adult rat. During proestrus, a time when estrogen levels
are high, the number of proliferating cells in the dentate gyrus
is maximal, as compared with estrus and diestrus, when
ovarian hormone levels are lower (Tanapat et al 1999). This
natural increase in cell proliferation is most likely responsible
for the gender difference in the proliferation of granule cell
precursors observed in adult rats. Adult female rats produce
more new cells with the characteristics of immature neurons
in the dentate gyrus than do adult male rats; however, many
of these new cells eventually degenerate, such that by several
weeks after mitosis the gender difference favoring females is
no longer detectable (Tanapat et al 1999). These findings
suggest that estrogen induces a transient increase in the
number of immature neurons; however, because the survival
of adult-generated cells appears to be dependent on experience (see below), the persistence of a gender difference in
new neurons for longer periods of time in animals exposed to
nondeprived conditions cannot be ruled out.
The extent to which other gonadal hormones, such as
progesterone and testosterone, affect adult neurogenesis
remains unknown. Moreover, no previous studies have
explored the possibility that periods of dramatic or chronic
changes in gonadal hormones such as puberty, pregnancy,
or aging result in altered granule cell genesis.
Environmental Complexity and Learning
Several studies have shown that environmental complexity
can enhance the number of new neurons in the hippocampus. Barnea and Nottebohm (1994) have demonstrated that
black-capped chickadees that live in the wild maintain
more new hippocampal neurons than those living in
captivity. A similar enhancement in the number of new
hippocampal neurons has been observed in the dentate
gyrus of adult mice and rats living in an enriched environment, as compared with those living under standard
laboratory control conditions (Kempermann et al 1997;
Nilsson et al 1999). There are many variables that differ
between living in the wild and living in captivity and
between living in an enriched environment and under
control conditions in the laboratory, such as social interaction, nutrition, stress, activity levels, and learning opportunities.
Evidence suggests that both learning and physical activity enhance the number of new granule neurons, apparently through different mechanisms. Observations in
black-capped chickadees suggest that certain types of
learning may increase the survival of new cells. For
example, seasonal differences exist in the number of new
hippocampal neurons that correlate with changes in seed
storage and retrieval, behaviors that involve spatial navigation learning (Barnea and Nottebohm 1994). Similarly,
it has been demonstrated that training on a task that
requires the hippocampal formation for acquisition results
in an increase in the number of adult-generated granule
cells (Gould et al 1999b). In untrained laboratory animals,
most adult-generated cells appear to degenerate within 2
weeks of production (Cameron et al 1993a, 1993b; Gould
et al 1999b); however, training on either of two hippocampal-dependent tasks, spatial learning during Morris water
maze training and trace eyeblink conditioning, rescues a
significant proportion of these cells (Ambrogini et al 2000;
Gould et al 1999b). In the Morris water maze task, rats use
extramaze cues to locate a platform submerged in a pool of
water. Rats that learned the location of the hidden platform
Regulation of Hippocampal Neurogenesis
exhibited an increase in the survival of adult-generated
cells, as compared with animals that remained in a pool of
water in the absence of a platform and as compared with
control subjects. A similar increase in the number of new
cells has also been observed using the trace eyeblink
conditioning task. In this paradigm, rats learn to associate
an unconditioned stimulus (US; periorbital shock) and a
conditioned stimulus (CS; white noise) that are separated
in time. Again, as little as 4 days of training resulted in a
greater than twofold increase in the number of new
granule neurons, as compared with rats that were presented with the US and CS in an unpaired condition. This
increase is most likely the result of enhanced cell survival,
as opposed to cell proliferation, for the following three
reasons: 1) learning appears to be effective at increasing
the number of new neurons only when it occurs during the
time of maximal death of newly born cells in laboratory
control subjects (Gould et al 1999b; compare with
Greenough et al 1999; van Praag et al 1999b); 2) the
number of pyknotic or degenerating cells in the SGZ is
diminished following hippocampal-dependent learning,
and bromodeoxyuridine (BrdU)–labeled pyknotic cells
that are observed between 1 and 2 weeks after labeling in
control subjects are completely absent after learning; and
3) the number of BrdU-labeled cells does not increase
when BrdU is administered during the training phase, after
all animals have reached criteria. Although these studies
have shown that certain types of learning increase the
number of newly generated cells by enhancing their
survival, the life span of these cells is not known. Because
the number of cells in the brain does not increase throughout adulthood, these cells, or some comparable population,
must eventually degenerate. The death of newly generated
cells has been observed in the dentate gyrus of laboratory
control animals (Gould et al 1999b); however, given that
cell survival is enhanced by living in a more complex
environment and by learning experiences, these data are
not likely to accurately reflect the timing or magnitude of
such events in animals living in natural conditions.
Another aspect of the enriched environment that has
been shown to enhance the number of new granule cells is
increased physical activity. Providing female mice access
to a running wheel enhances the number of new granule
cells by stimulating the proliferation of granule cell
precursors (van Praag et al 1999a, 1999b).
Negative Regulators of Adult-Generated
Neurons
Deprivation
Whereas they provide important information about the
specific experiences necessary for the production and
survival of new cells, studies demonstrating that environ-
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2000;48:715–720
717
mental enrichment, running, and learning enhance the
number of adult-generated cells as compared with control
subjects (Gould et al 1999b; Kempermann et al 1997;
Nilsson et al 1999; van Praag et al 1999a, 1999b) may also
be a reflection of the abnormal state of laboratory control
animals. Rodents living in the wild experience a more
complex environment, including enhanced activity and
learning opportunities, compared with that of laboratory
animals used in controlled studies. Because standard
laboratory conditions for rodents severely restrict natural
behavior and experience, these animals should be thought
of as living in relative deprivation. The complexity of
natural living may increase the production and extended
survival of more new neurons than what is typically
reported for deprived laboratory control animals. This
possibility should also be considered with regard to adult
neurogenesis in primates. Adult neurogenesis studies carried out in nonhuman primates thus far have only focused
on animals living in laboratory settings (Gould et al 1998,
1999a; Kornack and Rakic 1999). Such conditions involve
dramatic cognitive, motor, and social deprivation relative
to those produced by living in natural settings. The extent
to which laboratory-enriched environments mimic natural
living, in terms of effects on neurogenesis, remains
unknown.
Adrenal Steroids
Adrenal steroids have been shown to inhibit the production of new granule cells throughout life by suppressing
the proliferation of granule cell precursors. Experimental
increases in corticosterone levels diminish the number of
proliferating cells in the dentate gyrus of rat pups during
the stress-hyporesponsive period, when adrenal steroids
are naturally low (Gould et al 1991). Removal of adrenal
steroids after this time stimulates the proliferation of
granule cell precursors and, ultimately, the production of
new granule neurons (Cameron and Gould 1994; Gould et
al 1992). Conversely, treatment of adult rats with corticosterone, the main glucocorticoid of rats, further inhibits the
proliferation of granule cell precursors (Cameron and
Gould 1994). The suppression of granule cell genesis by
adrenal steroids continues throughout adulthood and appears to be responsible for the aging-associated suppression of granule cell genesis. Aged rats and monkeys
exhibit diminished cell proliferation in the dentate gyrus as
well as elevated levels of circulating glucocorticoids
(Gould et al 1999a; Kuhn et al 1996; Sapolsky 1992). A
recent study has shown that removal of adrenal steroids in
aged rats restores high levels of cell proliferation in the
dentate gyrus (Cameron and McKay 1999). The absence
of either type 1 or type 2 adrenal steroid receptors on
granule cell precursors (Cameron et al 1993a, 1993b)
718
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E. Gould et al
suggests that the effects of adrenal steroids on cell proliferation occur indirectly through another factor.
Excitatory Input
The proliferation of granule cell precursors in the dentate
gyrus is also affected by N-methyl-D-aspartate (NMDA)
receptor–mediated excitatory input. In adulthood, treatment with either competitive or noncompetitive NMDA
receptor antagonists increases the number of proliferating
cells in the rodent and tree shrew dentate gyri (Cameron et
al 1995; Gould et al 1997). Conversely, activation of
NMDA receptors inhibits cell proliferation in the dentate
gyrus during adulthood (Cameron et al 1995). The granule
cell population receives a major excitatory input from the
entorhinal cortex via the perforant path. Transmission
across this pathway can involve NMDA receptor activation (Kelsey et al 2000), suggesting that perforant path
input may participate in the suppression of cell proliferation in the dentate gyrus. Consistent with this possibility,
lesion of the entorhinal cortex has an effect on cell
proliferation similar to that of the blockade of NMDA
receptors, to enhance cell proliferation in the dentate gyrus
in adulthood (Cameron et al 1995). These results may
appear to be at variance with studies demonstrating enhancing effects of seizures on hippocampal neurogenesis
(Nakagawa et al 2000; Parent et al 1997); however, most
experimentally induced seizures result in cell death, a
condition known to stimulate granule cell genesis in the
dentate gyrus (Gould and Tanapat 1997). Thus, it is likely
that seizure-induced changes in neurogenesis are the result
of a complex cascade of events, and not merely of changes
in excitatory input. Available evidence suggests that adrenal steroids suppress cell proliferation in the dentate
gyrus by acting through an NMDA receptor–mediated
excitatory pathway (Cameron et al 1998).
Stressful Experience
The suppressive effects of glucocorticoids and NMDA
receptor activation on granule cell genesis in the intact
dentate gyrus suggest that exposure to stress, which
elevates glucocorticoid levels and stimulates hippocampal glutamate release in adulthood (Moghaddam et al
1994; Stein-Behrens et al 1999), naturally inhibits cell
proliferation.
Acute exposure to stress decreases the proliferation of
granule cell precursors in the dentate gyri of adult rats
(Tanapat et al, submitted), tree shrews (Gould et al 1997),
and marmosets (Gould et al 1998). Exposure of adult rats
to predator odor elicits a stress response characterized by
increased adrenal steroid levels (Heale et al 1994; Sgoifo
et al 1996) and a characteristic electrophysiologic response in the dentate gyrus (Heale et al 1994). A single
Figure 2. The number of bromodeoxyuridine (BrdU)–labeled
cells in the dentate gyrus of the adult rat is significantly lower in
subordinate animals, as compared with dominant ones. These
animals lived in a visible burrow system (VBS) for 4 days
(Blanchard et al 1995). Four male and two female animals were
placed into the VBS and videotaped for 10 hours during the dark
phase. Within the first 3 nights, one adult male rat established
himself as the dominant animal, characterized by more time in
the open area and more offensive encounters than the others. All
other male rats were characterized as subordinates. On the last
day, the animals were injected with BrdU and perfused 2 hours
later. *Significant difference from the dominant animal (p ,
.05).
brief exposure to trimethyl thiazoline, a component of fox
feces, rapidly suppresses cell proliferation in the dentate
gyrus (Tanapat et al, submitted). This effect is likely to be
the result of stress-induced increases in glucocorticoids
because rendering animals incapable of an increase in
glucocorticoids (by removing the adrenal glands and
replacing with low-dose corticosterone) prevents the effect
(Tanapat et al, submitted). Similarly, a suppressive effect
of stress on the number of BrdU-labeled cells has been
observed in the dentate gyri of adult rats living as
subordinates in a visible burrow system (Figure 2). Consistent with these findings, nonrodent mammalian species
also show a suppressive effect of stress on hippocampal
cell proliferation. In adult tree shrews, a single exposure to
subordination stress results in a rapid decrease in the
number of new cells produced in the dentate gyri of
stressed animals, as compared with control subjects
(Gould et al 1997). Likewise, studies of marmosets in a
resident intruder paradigm have shown that a single
exposure to social stress results in a rapid decrease in the
number of new cells produced in the dentate gyrus, as
compared with control subjects (Gould et al 1998). The
extent to which other types of stressors have a similar
effect on cell proliferation remains to be determined.
Repeated stress has been shown to produce prolonged
suppression of cell proliferation in the dentate gyri of adult
tree shrews. Twenty-eight days of exposure to a dominant
animal for 1 hour each day results in persistent elevations
Regulation of Hippocampal Neurogenesis
in cortisol levels in adult tree shrews (Fuchs et al 1995)
and a decrease in new cell production in the dentate gyrus,
as well as a decrease in the total GCL volume (Fuchs et al
1997). It is likely that chronic suppression of granule cell
production is at least partially responsible for the changes
in GCL volume, although a causal relationship between
these two changes has yet to be established.
Functional Consequences of Changes in
Adult-Generated Neurons
Although the functional significance of adult-generated
neurons is not known, two lines of evidence suggest that
these new cells play an important role in learning. First,
many new neurons are added to the hippocampus, a brain
region involved in certain types of learning and memory.
Second, regulators of hippocampal neurogenesis in adulthood also alter performance on hippocampal-dependent
learning tasks in a manner that is consistent with a link
between new cells and learning. It is important to note that
functional changes in the number of adult-generated neurons are not likely to be immediately evident. New
neurons require time to differentiate and become integrated into functional circuitry. Thus, it is the period
following changes in cell production that is most likely to
be functionally relevant; however, the fact that adultgenerated cells in the dentate gyrus extend axons into the
CA3 region of the hippocampal formation as early as 4 –10
days following division (Hastings and Gould 1999) suggests that the impact of changes in cell production may be
functionally significant as early as 4 days later. In addition, it is important to note that acute changes in cell
production may not alter hippocampal function. Thus, the
impact of chronic changes in neuron production is more
likely to be of interest because such effects are likely to be
additive.
Chronic exposure to positive regulators of adult neurogenesis, such as estrogen, enriched-environment living,
and running, has been associated with enhanced performance on hippocampal-dependent learning tasks in rodents (Kempermann et al 1997; Luine et al 1997; van
Praag et al 1999a) and other cognitive tasks in humans
(McEwen et al 1997). Conversely, chronic exposure to
negative regulators of adult neurogenesis, such as adrenal
steroids and stress, has been associated with impaired
performance on such tasks (Bodnoff et al 1995; Endo et al
1996; Krugers et al 1997; Luine et al 1994). These
correlations are consistent with the view that adult-generated neurons participate in hippocampal-dependent learning; however, these neuroendocrine and experiential factors also alter other aspects of brain structure and function
that cannot be ruled out as alternative mechanisms for the
changes in hippocampal-dependent learning. Studies de-
BIOL PSYCHIATRY
2000;48:715–720
719
signed to examine the behavioral consequences of specific
depletion of new neurons will provide a more direct
approach to this question.
References
Altman J, Das GD (1965): Autoradiographic and histological
evidence of postnatal hippocampal neurogenesis in rats.
J Comp Neurol 124:319 –335.
Ambrogini P, Cuppini R, Cuppini C, Ciaroni S, Cecchini T, Ferri
P, et al (2000): Spatial learning affects immature granule cell
survival in adult rat dentate gyrus. Neurosci Lett 286:21–24.
Barnea A, Nottebohm F (1994): Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees. Proc Natl Acad Sci U S A 91:11217–11221.
Blanchard DC, Spencer RL, Weiss SM, Blanchard RJ, McEwen
B, Sakai RR (1995): Visible burrow system as a model of
chronic social stress: Behavioral and neuroendocrine correlates. Psychoneuroendocrinology 20:117–134.
Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose
GM, Meaney MJ (1995): Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity,
and hippocampal neuropathology in young and mid-aged rats.
J Neurosci 15:61– 69.
Cameron HA, Gould E (1994): Adult neurogenesis is regulated
by adrenal steroids in the dentate gyrus. Neuroscience 61:
203–209.
Cameron HA, McEwen BS, Gould E (1995): Regulation of adult
neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci 15:4687– 4692.
Cameron HA, McKay RD (1999): Restoring production of
hippocampal neurons in old age. Nat Neurosci 2:894 – 897.
Cameron HA, Tanapat P, Gould E (1998): Adrenal steroids and
N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common
pathway. Neuroscience 82:349 –354.
Cameron HA, Woolley CS, Gould E (1993a): Adrenal steroid
receptor immunoreactivity in cells born in the adult rat
dentate gyrus. Brain Res 611:342–346.
Cameron HA, Woolley CS, McEwen BS, Gould E (1993b):
Differentiation of newly born neurons and glia in the dentate
gyrus of the adult rat. Neuroscience 56:337–344.
Endo Y, Nishimura JI, Kimura F (1996): Impairment of maze
learning in rats following long-term glucocorticoid treatments. Neurosci Lett 203:199 –202.
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998): Neurogenesis in the
adult human hippocampus. Nat Med 4:1313–1317.
Fuchs E, Flugge G, McEwen BS, Tanapat P, Gould E (1997):
Chronic subordination stress inhibits neurogenesis and decreases the volume of the granule cell layer. Soc Neurosci
23:317.
Fuchs E, Uno H, Flugge G (1995): Chronic psychosocial stress
induces morphological alterations in hippocampal pyramidal
neurons of the tree shrew. Brain Res 673:275–282.
Gould E, Cameron HA, Daniels DC, Woolley CS, McEwen BS
(1992): Adrenal hormones suppress cell division in the adult
rat dentate gyrus. J Neurosci 12:3642–3650.
720
BIOL PSYCHIATRY
2000;48:715–720
Gould E, McEwen BS, Tanapat P, Galea LAM, Fuchs E (1997):
Neurogenesis in the dentate gyrus of the adult tree shrew is
regulated by psychosocial stress and NMDA receptor activation. J Neurosci 17:2492–2498.
Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E
(1999a): Hippocampal neurogenesis in adult Old World
primates. Proc Natl Acad Sci U S A 96:5263–5267.
Gould E, Tanapat P (1997): Lesion-induced proliferation of
neuronal progenitors in the dentate gyrus of the adult rat.
Neuroscience 80:427– 436.
Gould E, Tanapat P, Beylin A, Reeves AJ, Shors TJ (1999b):
Hippocampal-dependent learning enhances the survival of
granule neurons generated in the dentate gyrus of adult rats.
Nat Neurosci 2:260 –265.
Gould E, Tanapat P, Hastings NB, Shors TJ (1999c): Neurogenesis in adulthood: A possible role in learning. Trends Cogn
Sci 3:186 –192.
Gould E, Tanapat P, McEwen BS, Flugge G, Fuchs E (1998):
Proliferation of granule cell precursors in the dentate gyrus of
adult monkeys is diminished by stress. Proc Natl Acad Sci
U S A 95:3168 –3171.
Gould E, Woolley CS, Cameron HA, Daniels DC, McEwen BS
(1991): Adrenal steroids regulate postnatal development of
the rat dentate gyrus: II. Effects of glucocorticoids and
mineralocorticoids on cell birth. J Comp Neurol 313:486 –
493.
Greenough WT, Cohen NJ, Juraska JM (1999): New neurons in
old brains: Learning to survive? Nat Neurosci 2:203–205.
Hastings NB, Gould E (1999): Rapid extension of axons into the
CA3 region by adult-generated granule cells. J Comp Neurol
413:146 –154.
Heale VR, Vanderwolf CH, Kavaliers M (1994): Components of
weasel and fox odors elicit fast wave bursts in the dentate
gyrus of rats. Behav Brain Res 63:159 –165.
Kaplan MS, Bell DH (1983): Neuronal proliferation in the
9-month-old rodent-radioautographic study of granule cells in
the hippocampus. Exp Brain Res 52:1–5.
Kaplan MS, Hinds JW (1977): Neurogenesis in the adult rat:
Electron microscopic analysis of light radioautographs. Science 197:1092–1094.
Kelsey JE, Sanderson KL, Frye CA (2000): Perforant path
stimulation in rats produces seizures, loss of hippocampal
neurons, and a deficit in spatial mapping which are reduced
by prior MK-801. Behav Brain Res 107:59 – 69.
Kempermann G, Kuhn HG, Gage FH (1997): More hippocampal
neurons in adult mice living in an enriched environment.
Nature 386:493– 495.
Kornack DR, Rakic P (1999): Continuation of neurogenesis in
the hippocampus of the adult macaque monkey. Proc Natl
Acad Sci U S A 96:5768 –7573.
Krugers HJ, Douma BR, Andringa G, Bohus B, Korf J, Luiten
PG (1997): Exposure to chronic psychosocial stress and
corticosterone in the rat: Effects on spatial discrimination
learning and hippocampal protein kinase Cgamma immunoreactivity. Hippocampus 7:427– 436.
Kuhn HG, Dickinson-Anson H, Gage FH (1996): Neurogenesis
in the dentate gyrus of the adult rat: Age-related decrease of
neuronal progenitor proliferation. J Neurosci 16:2027–2033.
Luine V, Villegas M, Martinez C, McEwen BS (1994): Repeated
E. Gould et al
stress causes reversible impairments of spatial memory performance. Brain Res 639:167–170.
Luine VN, Richards ST, Wu VY, Beck KD (1998): Estradiol
enhances learning and memory in a spatial memory task and
effects levels of monoaminergic neurotransmitters. Horm
Behav 34:149 –162.
Markakis EA, Gage FH (1999): Adult-generated neurons in the
dentate gyrus send axonal projections to field CA3 and are
surrounded by synaptic vesicles. J Comp Neurol 406:449 –
460.
McEwen BS, Alves SE, Bulloch K, Weiland NG (1997): Ovarian
steroids and the brain: Implications for cognition and aging.
Neurology 48:S8 –S15.
Moghaddam B, Bolinao ML, Stein-Behrens B, Sapolsky R
(1994): Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res 655:251–254.
Nakagawa E, Aimi Y, Yasuhara O, Tooyama I, Shimada M,
McGeer PL, Kimura H (2000): Enhancement of progenitor
cell division in the dentate gyrus triggered by initial limbic
seizures in rat models of epilepsy. Epilepsia 41:10 –18.
Nilsson M, Perfilieva E, Johansson U, Orwar O, Eriksson PS
(1999): Enriched environment increases neurogenesis in the
adult rat dentate gyrus and improves spatial memory. J Neurobiol 39:569 –578.
Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS,
Lowenstein DH (1997): Dentate granule cell neurogenesis is
increased by seizures and contributes to aberrant network
reorganization in the adult rat hippocampus. J Neurosci
17:3727–3738.
Sapolsky RM. (1992): Do glucocorticoid concentrations rise with
age in the rat? Neurobiol Aging 13:171–174.
Sgoifo A, de Boer SF, Haller J, Koolhaas JM (1996): Individual
differences in plasma catecholamine and corticosterone stress
responses of wild-type rats: Relationship with aggression.
Physiol Behav 60:1403–1407.
Stanfield BB, Trice JE (1988): Evidence that granule cells
generated in the dentate gyrus of adult rats extend axonal
projections. Exp Brain Res 72:399 – 406.
Stein-Behrens BA, Lin WJ, Sapolsky RM (1999): Physiological
elevations of glucocorticoids potentiate glutamate accumulation in the hippocampus. J Neurochem 63:596 – 602.
Tanapat P, Galea LA, Gould E (1998): Stress inhibits the
proliferation of granule cell precursors in the developing
dentate gyrus. Int J Dev Neurosci 16:235–239.
Tanapat P, Hastings N, Reeves AJ, Gould E (1999): Estrogen
stimulates a transient increase in the number of new neurons
in the dentate gyrus of the adult female rat. J Neurosci
19:5792–5801.
Tanapat P, Hastings NB, Rydel T, Gould E (submitted): Exposure to predator odor inhibits hippocampal cell proliferation
via adrenal steroids.
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999a):
Running enhances neurogenesis, learning, and long-term
potentiation in mice. Proc Natl Acad Sci U S A 96:13427–
13431.
van Praag H, Kempermann G, Gage FH (1999b): Running
increases cell proliferation and neurogenesis in the adult
mouse dentate gyrus. Nat Neurosci 2:266 –270.