Nature Neuroscience
2, 260 - 265 (1999)
doi:10.1038/6365
Learning enhances adult neurogenesis in the hippocampal formationElizabeth Gould1, Anna Beylin1, Patima Tanapat1, Alison Reeves1
& Tracey J. Shors21 Department of Psychology, Princeton University,
Princeton, New Jersey 08544, USA 2 Department of Psychology & Center for Neuroscience,
Rutgers University, Piscataway, New Jersey
08854, USA
Correspondence should be addressed to Elizabeth Gould goulde@princeton.eduThousands of hippocampal neurons are born in adulthood, suggesting that
new cells could be important for hippocampal function. To determine whether
hippocampus-dependent learning affects adult-generated neurons, we examined
the fate of new cells labeled with the thymidine analog bromodeoxyuridine
following specific behavioral tasks. Here we report that the number of adult-generated
neurons doubles in the rat dentate gyrus in response to training on associative
learning tasks that require the hippocampus. In contrast, training on associative
learning tasks that do not require the hippocampus did not alter the number
of new cells. These findings indicate that adult-generated hippocampal neurons
are specifically affected by, and potentially involved in, associative memory
formation.The involvement of the hippocampal formation in learning has been recognized
for decades1,
2, but the cellular mechanisms underlying this
association remain enigmatic. The hippocampal formation produces new neurons
throughout adulthood in many vertebrates, from birds to primates3,
4,
5,
6,
7,
8;
however, although the number of neurons produced is high, the function of
these cells is unknown. One possibility is that these new cells are important
in hippocampus-dependent learning, a view consistent with reports that generalized
environmental complexity enhances the number of new hippocampal neurons in
adult birds and mice3,
6. However, previous studies have not
explored the possibility that hippocampus-dependent learning specifically
alters the fate of adult-generated hippocampal neurons.
To determine whether associative learning affects adult-generated hippocampal
neurons, we examined the fate of new cells labeled with the thymidine analog
bromodeoxyuridine (BrdU) in adult rats after a number of different behavioral
manipulations. We used two different hippocampus-dependent tasks (classical
conditioning of the eyeblink response using a trace protocol9,
10,
11,
12
and spatial navigation learning in a Morris water maze13) and
two hippocampus-independent learning tasks (classical eyeblink conditioning
using a delay protocol9 and cue training in a Morris water maze13).
RESULTS
In the classical conditioning protocol, all of the animals that received
paired training reached the criteria of 60% conditioned responses (CRs) to
the conditioned stimulus (CS) by the end of training. None of the unpaired
animals reached criteria. Rats exposed to paired training increased their
CRs over 800 trials, whereas rats exposed to unpaired training did not (
F7,133 = 12.61, p < 0.0001). Of rats exposed to paired
training, there was no overall significant difference in percent CRs between
the trace and delay protocols (F1,19 = 4.24, p =
0.05). By the last day of training, levels of performance were indistinguishable
between groups exposed to trace and delay conditioning. In the maze task,
there was no difference in latency between animals trained with a visible
platform versus a submerged platform over the course of training (F
1,10 = 2.88, p = 0.12). As expected, the rats showed a decrease
in latency over trials (p < 0.01).
Our previous [3H]thymidine-autoradiographic study demonstrated
that the number of new cells in the dentate gyrus of adult control rats increases
between two hours and one week after DNA synthesis, and then declines dramatically
by two weeks after labeling5. Similar results were obtained
for the number of BrdU labeled cells in the dentate gyrus of control rats
at different survival times following BrdU injection (2096.0  61.2
at 2 hours after BrdU injection, 3874.5 121.0 at 24 hours after BrdU
injection, 5882.8 170.8 at 1 week after BrdU injection and 2130.0
175.1 at two weeks after BrdU injection; F3,11
= 146.35, p = 0.0001). It is likely that the decrease in labeled cells
observed between one week and two weeks following DNA synthesis is due to
cell death as opposed to label dilution, because the number of silver grains
per labeled cell does not decrease between these time points after [
3H]thymidine injection5, and BrdU-labeled pyknotic or
degenerating cells are observed in the dentate gyrus between these time points
after BrdU injection (E.G., unpublished data).
To determine whether learning alters the survival of new cells in the dentate
gyrus, we engaged animals in behavioral tasks during the time when the numbers
of new cells normally diminish. In animals that received BrdU one week before
training, learning either of the hippocampus-dependent tasks dramatically
increased the number of BrdU-labeled cells in the dentate gyrus compared to
naive controls (F2,15 = 137.40, p = 0.0001 for trace
conditioning; F3,20 = 266.40, p = 0.0001 for maze
training) when the brains were examined 24 hours after the last day of training
(Fig. 1a, b, e and f). This difference
seems to be specific to the dentate gyrus because learning did not affect
the number of BrdU-labeled cells in the subventricular zone, a region lining
the wall of the lateral ventricles that produces new cells in adulthood14 (in the trace-conditioning experiment, 4820.6 271.5 for
naive controls, 4993.8 214.7 for trace-paired stimuli, 5323.7
212.7 for trace-unpaired stimuli, F2,15 = 0.09, p
= 0.3598; in the water-maze experiment, 4668.2 382.2 for naive controls,
4949.2 412.8 for place-trained rats; 5359.0 756.2 for cue-trained
rats; 5066.2 539.5 for swim-stress rats, F3,20
= 0.279, p = 0.8538). After hippocampus-dependent learning, the majority
of new hippocampal cells were located in the granule cell layer and expressed
a marker of immature granule neurons, Turned-on-after-division, a 64-kD protein
(TOAD-64) or a marker of mature granule neurons, the calcium-binding protein
calbindin, but not an astroglial marker, glial fibrillary acidic protein (GFAP; Fig. 2a−d). When
examined one week after the end of training (three weeks after BrdU injection),
the number of BrdU labeled cells in the dentate gyrus remained elevated in
the hippocampus-dependent learning groups, but the percentage of BrdU labeled
cells that expressed cell-specific markers did not differ between any of the
groups. When examined 1 week after the end of training, that is, approximately
3 weeks after BrdU injection,  57% of BrdU labeled cells expressed TOAD-64
(F3,20 = 0.311, p = 0.8169), 11% of BrdU-labeled
cells expressed GFAP (F3,20 = 0.572, p = 0.6402),
and 71% of BrdU-labeled cells expressed calbindin (F3,20
= 0.572, p = 0.6402). No differences were observed in the volume
of the granule cell layer with any training (in the trace-conditioning experiment,
3.08 0.37 mm3 for naive controls, 3.25 0.51
mm3 for trace-paired animals, 3.21 0.38 mm
3 for trace-unpaired animals, F2,15 = 0.043,
p = 0.958; in the water-maze experiment, 3.20 0.19 mm
3 for naive controls, 3.19 0.23 mm3 for place-trained
rats, 3.11 0.23 mm3 for cue-trained rats, 2.95
0.24 mm3 for swim-stress rats, F3,20 = 0.302;
p = 0.8236).
 | | |
| | |
Exposure to similar environmental conditions and production of the same
number and types of motor responses in the absence of overt learned responses
had no effect on the number of BrdU-labeled cells in the dentate gyrus. Specifically,
exposure to the same number of eyeblink-conditioning stimuli presented in
an explicitly unpaired manner using either trace (trace unpaired) or delay
(delay unpaired) stimulus parameters did not affect the number of BrdU-labeled
cells compared to naive controls (Fig. 1a−d). Similarly, rats exposed to the water maze for the
same amount of time as the place-trained group but without a platform exhibited
no difference in the number of BrdU-labeled cells compared to naive controls
(Fig. 1e and f).
Training on associative learning tasks that do not require the hippocampus
was similarly ineffective at altering the number of BrdU-labeled cells. Rats
trained on a Cue Test in the water maze did not exhibit more neurons after
training than naive controls (Fig. 1e and f). Similarly, acquisition of the conditioned response
during delay eyeblink conditioning did not result in more new neurons after
training (Fig. 1c and d;
F2,12 = 1.889, p = 0.1936).
It is likely that the increased number of BrdU-labeled cells in the dentate
gyrus following hippocampus-dependent learning is, at least in part, the result
of enhanced cell survival, because significant differences among groups in
the number of pyknotic, or degenerating cells were observed in the subgranular
zone. The presence of degenerating cells in the subgranular zone, the region
of cell proliferation in the dentate gyrus, in control rats, has been reported
previously15. Animals exposed to either of the hippocampus-dependent
tasks (trace-eyeblink conditioning or place learning in a water maze) showed
fewer pyknotic cells than all other groups (in the trace-conditioning experiment,
220.0 41.9 for naive control, 81.8 24.3 for trace-paired
animals, 214.8 46.5 for trace-unpaired animals, F3,15
= 12.339, p = 0.0007; in the water-maze experiment, 208.7
30.9 for naive controls, 50.0 8.4 for the place-trained group, 222.0
48.1 for the cue-trained group, 236.0 34.2 for the swim-stress
group, F3,20 = 16.527, p = 0.0001). BrdU-labeled pyknotic
cells were observed occasionally in the subgranular zone, but these profiles
were relatively rare (0−36 per dentate gyrus), and labeled cells were
never observed in the dentate gyrus after hippocampus-dependent learning.
To assess whether training alters the rate of cell proliferation, additional
groups of animals received BrdU during, rather than before, training on the
trace eyeblink protocol. In this experiment, the number of new cells produced
in the dentate gyrus did not differ between conditioned animals and naive
controls (Fig. 1g and h;
F2,13 = 0.011, p = 0.9892). No BrdU-labeled pyknotic
cells were observed in the dentate gyrus of animals in any group injected
with BrdU 24 hours before perfusion.
DISCUSSION
These results demonstrate a direct association between hippocampus-dependent
learning and neurons generated in the adult hippocampal formation. Types of
learning that depend on the hippocampus, including trace eyeblink conditioning
and spatial water-maze training, increased the number of newly generated neurons
in the dentate gyrus of the hippocampal region. Conversely, learning that
does not require the hippocampus, including delay-eyeblink conditioning and
cue-maze training, did not alter the numbers of new granule neurons compared
to naive controls. It should be noted that animals that learned tasks not
requiring the hippocampus and those in the various control groups, including
naive controls and those exposed to the same stimuli but without explicit
learning, did maintain a significant number of new neurons. Because all of
these conditions are likely to involve some form of learning, the possibility
that a basal number of new neurons, that is, the control number, is maintained
by learning of an unspecified nature can not be ruled out. However, because
exposure to both delay-eyeblink conditioning and cue-maze training are known
to activate, but not require, the hippocampal formation16,
17,
these results suggest that for learning to further enhance the number of new
hippocampal neurons, the animal must be engaged in a task for which this brain
region is essential.
It is likely that the changes we observed in the number of BrdU-labeled
cells are primarily the result of hippocampus-dependent learning enhancing
the survival of new granule cells, as opposed to the proliferation of granule-cell
precursors, for the following reasons. First, hippocampus-dependent learning
increased the number of cells produced before, but not during, training. Second,
hippocampus-dependent training enhanced the number of BrdU-labeled cells in
the dentate gyrus during the time when the number of new cells is known to
diminish in laboratory controls. The number of new cells in the dentate gyrus
increases between 2 hours and 1 week after DNA synthesis and then declines
dramatically by the two week time point (our results and 5). This decrease in labeled cells is most likely the result
of cell death, and not label dilution from continual cell proliferation, because
no decrease in the number of silver grains per labeled cell was observed between
one and two weeks after [3H]thymidine injection in our previous
study5. Third, hippocampus-dependent learning decreased the
number of pyknotic cells in the subgranular zone of the dentate gyrus compared
to controls. Although we cannot rule out the possibility that hippocampus-dependent
learning had some effect on cell proliferation, available evidence strongly
suggests that the increased number of BrdU-labeled cells we observed is the
result of enhanced survival. Consistent with our results, previous studies
have reported that environmental complexity increases the number of adult-generated
hippocampal neurons in birds and mice, presumably by enhancing cell survival3,
6. Studies3 of black-capped chickadees demonstrated
a naturally occurring seasonal fluctuation in hippocampal neurogenesis that
correlates positively with engagement in spatial learning behaviors, that
is, seed storage and retrieval. However, several variables, including stress,
social interaction, nutrition and learning opportunities, differ between captivity
versus wild living in the case of birds, and between standard laboratory cage
housing versus 'enriched environment' conditions in the case of mice. Our
results demonstrate that it is hippocampus-dependent learning, but not experience
in the absence of explicit learning or learning that does not require the
hippocampus, that enhances the number of adult-generated neurons.
Another study in this issue reports that water-maze training in mice does
not alter the number of new neurons in the dentate gyrus34.
In that study, animals were injected with BrdU during place training. These
results are essentially consistent with ours in that we also did not observe
an enhanced number of labeled cells in the dentate gyrus of animals injected
with BrdU during training. Rather, we observed an enhanced survival of those
cells that were generated before training. Rescue of adult-generated cells
by certain types of learning may occur only during a specific 'sensitive period'
following the production of a new cell. The results of our study suggest some
new cells require this type of input for survival between 1 and 2 weeks after
mitosis, a time when adult-generated granule cells appear to be forming connections
with the CA3 region (N.B. Hastings and E. Gould, unpublished data). Hippocampus-dependent
learning may facilitate the integration of adult-generated cells into existing
circuitry and insure their survival.
Our previous studies have identified factors that alter the production
of new granule neurons by affecting the proliferation of granule cell precursors.
We have shown that adrenal steroids suppress the proliferation of granule
cell progenitors by activating an NMDA-receptor-dependent excitatory pathway18,
19. Additionally, stressful experiences, known to increase levels
of adrenal steroids and hippocampal glutamate release20, also
diminish the proliferation of granule cell precursors in the dentate gyrus
of adult tree shrews and marmoset monkeys7,
8. Although the
experiments in the present report were not designed to assess the effects
of stress on cell proliferation, the effects of stress on the survival of
adult-generated cells were considered in the spatial learning study. In this
case, animals exposed to swim stress, that is, those that were in the water
for the same duration as the place-learning animals, showed no change in the
number of BrdU-labeled cells in the dentate gyrus. These results suggest that
stress does not alter the survival of recently produced neurons, a finding
consistent with our previous data showing that adrenal steroids are only necessary
for the maintenance of mature, and not immature, granule neurons in the adult
dentate gyrus21. Because time is required for new cells to become
integrated into functional circuitry, it is unlikely that acute stress, which
affects cell proliferation and not survival, would have an immediate impact
on hippocampal function via this mechanism. However, continually diminished
production of new cells resulting from chronic stress or corticosterone treatment
may contribute to performance decrements in hippocampus-dependent tasks under
some conditions22,
23.
There are many theories of hippocampal function, including the assertion
that the hippocampus is necessary for acquiring associations between discontiguous
events, either temporal or spatial24, or for the acquisition
of declarative as opposed to procedural memories25. In addition
to acquisition, studies have provided evidence that the hippocampus has a
transient role in memory25. Our results suggest that learning
about space (spatial navigation learning) and time (trace classical conditioning)
under relatively specific conditions has a trophic effect on adult-generated
hippocampal neurons. The direct relationship between hippocampus-dependent
learning and the survival of adult-generated hippocampal neurons suggests
a function for these new neurons in certain types of learning. The immature
status of adult-generated hippocampal cells may make them uniquely qualified
to form synaptic connections rapidly and to participate in the transient storage
of information.
METHODS
Adult male Sprague Dawley rats (300−350 g) from the Princeton University
animal colony were injected with BrdU (200mg/kg) and trained on either a classical-conditioning
task or a maze-learning task one week later (n = 5−6 for each
group). Previous studies have shown that under normal laboratory conditions,
the number of new cells in the dentate gyrus declines significantly between
one and two weeks after DNA synthesis5. To test the possibility
that training would alter the survival of new cells, we trained animals between
one and two weeks after BrdU injection. The rats were perfused transcardially
with 4.0% paraformaldehyde in 0.1 M phosphate buffer 24 hours or 7 days after
the last day of training. To determine whether learning affects cell proliferation,
we injected rats with BrdU during training and after learning criterion had
been reached, and perfused them 24 hours later.
Classical conditioning.
For classical conditioning,
the rats were anesthetized and implanted with four subcutaneous electrodes
around the eyelid26,
27. For animals injected with BrdU before
training, electrode implantation occurred three days after BrdU injection.
For those injected with BrdU during training, electrode implantation occurred
one week before BrdU injection. Two electrodes delivered the unconditioned
stimulus (US) and two recorded eyelid electromyographic (EMG) responses. Rats
were acclimated to the conditioning apparatus for one hour, and spontaneous
blink rate was recorded. Twenty-four hours later, rats were exposed to paired
or unpaired stimuli using a trace protocol, or paired or unpaired stimuli
using a delay protocol (200 trials per day for 4 consecutive days). During
trace conditioning, a 83-dB, 250-ms burst of white noise (CS) was separated
from a 100-ms, 0.7-mA periorbital shock (US) by a 500-ms trace interval. The
intertrial interval (ITI) was 20 10 s. Trace eyeblink conditioning
using these parameters is hippocampus dependent; that is, acquisition of this
task is prevented by hippocampal lesions (A. Beylin, A. Talk, C. Ghandi, L.
Matzel and T.J. Shors, unpublished data). During unpaired training, rats received
the same number of CS and US exposures, but in an explicitly unpaired manner.
The maximum EMG response occurring during a 250-ms prestimulus baseline recording
period was added to four times its standard deviation. Responses that exceeded
that value and had a width of at least three ms were considered eyeblinks.
Eyeblinks were considered conditioned responses (CRs) if they occurred at
least 250 ms after CS onset. In the unpaired-trace protocol, eyeblinks were
counted if they occurred 250 ms after CS onset. Three groups of animals were
trained for trace-paired or trace-unpaired protocols or were naive controls.
Two groups that received BrdU one week before the start of training were perfused
at either 24 h (n = 6 per group) or 7 days after the end of training
(n = 6 per group). One group that received BrdU during training, after
learning criterion had been reached, was perfused 24 hours later (n
= 5−6 per group).
During delay conditioning, a 320-ms, 83-dB CS coterminated with an 80-ms,
0.7-mA US. In this protocol, eyeblinks were considered CRs if they occurred
at least 80 ms after CS onset. During unpaired training, rats received the
same number of CS and US exposures except in an explicitly unpaired manner.
In the unpaired-delay protocol, eyeblinks were counted if they occurred at
least 80 ms after CS onset. These animals, in addition to a separate group
of naive control animals, were perfused 24 hours after the last day of training
(n = 5−6 per group). Delay eyeblink conditioning is not hippocampus
dependent; hippocampal lesions do not impair this type of learning in rabbits
or rats28 (A. Beylin, A. Talk, C. Ghandi, L. Matzel and T.J.
Shors, unpublished data).
Morris water-maze training.
For maze training29,
30, groups of rats were trained on a cue test using a visible
platform, on a place test using a submerged platform or in a swim-stress condition
in which each rat was time-yoked to a place-test-trained rat. Acquisition
of the place test, but not the cue test, is disrupted by hippocampal lesions13. The water maze (175  75 cm) was filled with room-temperature
water and nontoxic white paint. Prominent posters and objects surrounded the
maze. Rats were exposed to 4 trials per day for 4 days with an ITI of 60 s.
During cue testing, the platform was visible and randomly moved to one of
four quadrants on each trial. During place testing, the platform was submerged
in the same quadrant on all trials. For both the cue and place tasks, the
rat was randomly placed into a quadrant facing the maze wall. Latency to reach
the platform was timed, and swim path was videotaped. The rat remained on
the platform for 30 s. Additional animals were time-yoked to rats in the place
test; these rats were placed in the maze for the same amount of time but without
a platform. The ITI for these animals was 90 s (total time that rats trained
with the cue and place tests were allowed to remain on the platform added
to the 60 s ITI). This experiment was done twice—once with animals perfused
7 days after the last day of training (n = 6 per group) and once with
animals perfused 24 h after the last day of training (n = 6 per group).
Histological procedures.
Brains of all rats were processed
immunohistochemically for combined BrdU and markers of several cell types,
including TOAD-64, a marker of immature neurons31, GFAP, a marker
of astroglia5, and calbindin, a marker of mature granule neurons6, using peroxidase or fluorescent methods. For stereological analysis,
coronal sections (40  m) were cut throughout the entire hippocampal function
with an oscillating tissue slicer. The sections were mounted onto slides and
incubated in H2O2, rinsed, permeabilized with trypsin,
denatured in 2 N HCl, rinsed and incubated with normal horse serum and mouse
monoclonal antibody against BrdU (Novocastra, Newcastle upon Tyne, UK, 1:250).
The sections were rinsed in PBS and reacted immunohistochemically using a
Vectastain ABC Elite kit with nickel-enhanced diaminobenzidine (DAB). The
sections were then rinsed and incubated in a second primary antibody: anti-GFAP
(Santa Cruz Biotechnology, Santa Cruz, California; 1:5000), anti-TOAD 64 (gift
of Susan Hockfield 1:10,000) or anti-calbindin (Chemicon, Temecula, California
1:750). Following several rinses, the sections were reacted immunohistochemically,
omitting nickel from the DAB solution, and then counterstained for Nissl with
cresyl violet and coverslipped with Permount. For immunofluorescence, the
sections were processed for BrdU labeling as described above but with anti-mouse
CY-3 (Sigma, 1:300) followed by incubation in anti-TOAD-64, anti-GFAP or anti-calbindin.
These latter antigens were visualized with either goat anti-rabbit-Alexa 488
(Molecular Probes, Eugene, Oregon, 1: 1000 for TOAD-64 and calbindin) or biotinylated
rabbit anti-goat (Vector, Burlingame, California, 1:200) followed by avidin-CY2
(Amersham Pharmacia, Piscataway, New Jersey, 1:1000). The sections were dried,
counterstained with the DNA dye Hoechst 44323 and coverslipped under PBS and
glycerol. Control sections were processed as described above with omission
of the primary antisera.
Stereological analysis of the number of BrdU-labeled cells was done on
peroxidase-stained tissue on coded slides using a modified version of the
optical fractionator method32. BrdU-labeled cells on every twelfth
section throughout the dentate gyrus were counted, omitting cells in the outermost
plane of focus to avoid counting cell caps. The same stereological methods
were used for counting the number of degenerating or pyknotic cells in the
subgranular zone. Pyknotic cells were defined by darkly stained, condensed
spherical chromatin, lack of a nuclear membrane and pale or absent cytoplasm15. BrdU-labeled pyknotic cells were also counted, although these
profiles were rare. The volume of the granule cell layer was determined for
each animal using Cavalieri's principle33. For purposes of comparison,
we also examined the number of BrdU-labeled cells in the subventricular zone
(SVZ), a region lining the wall of the lateral ventricles and known to produce
cells in adulthood14. For this analysis, we counted the number
of BrdU-labeled cells in the SVZ present on coronal sections throughout the
dentate gyrus (every twelfth section throughout the entire hippocampal region).
This analysis includes a substantial part of the SVZ but excludes the anterior
portion. For double labeling, the percentage of BrdU-labeled cells that expressed
TOAD-64, calbindin or GFAP was determined by counts of labeled cells on a
minimum of six sections throughout the dentate gyrus using an Olympus BX-60
fluorescent microscope. A minimum of 50 labeled cells were examined for each
animal. Immunofluorescent double-labeled cells were verified using a Zeiss
Axiovert confocal laser scanning microscope (510LSM). For statistical analysis,
ANOVA was followed by Neuman Keuls post hoc comparisons.
Received 26 October 1998; Accepted 27 January 1999
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Acknowledgments
We thank Charles Gross for comments on the manuscript and Joseph Goodhouse
for assistance with confocal imaging. This work was supported by MH52423,
MH59970 and IBN9511027.
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