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The Journal of Neuroscience, January 15, 2003, 23(2):659-665
Associative Memory Formation Increases the Observation of
Dendritic Spines in the Hippocampus
Benedetta
Leuner,
Jacqueline
Falduto, and
Tracey J.
Shors
Department of Psychology and Center for Collaborative Neuroscience,
Rutgers University, Piscataway, New Jersey 08854
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ABSTRACT |
Dendritic spines are sources of synaptic contact that can be
altered by experience and, as such, may be involved in memories for
that experience. Here we tested whether the acquisition of new memories
is associated with changes in the density of dendritic spines. Adult
male rats were trained using the trace eyeblink conditioning paradigm,
an associative learning task that requires the hippocampus for
acquisition. Additional groups were exposed to the same number of
stimuli presented in an explicitly unpaired manner or were naive.
Twenty-four hours later, the density of dendritic spines was measured
using Golgi impregnation. Trace conditioning was associated with an
increase in the density of dendritic spines on the pyramidal cells of
area CA1 of the hippocampus, an effect that was prevented by blocking
acquisition of the learned response with a competitive NMDA
receptor antagonist. Training with delay conditioning, a similar task
that does not require the hippocampus, also produced an increase in
spine density. The learning-induced increase in dendritic spine density
was specific to basal dendrites of pyramidal cells in the CA1 region of
the hippocampus. Changes did not occur on their apical dendrites or on
cells in the dentate gyrus or somatosensory cortex. These results suggest that the formation and expression of associative memories increase the availability of dendritic spines and the potential for
synaptic contact.
Key words:
eyeblink conditioning; synaptic plasticity; basal
dendrites; synaptogenesis; NMDA; learning
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Introduction |
The mechanisms by which memories are
acquired and stored in the mammalian brain are assumed to involve
modifications in synaptic plasticity (Ramon y Cajal, 1893 ). The most
extensively examined region in which plastic events are thought to
occur is the hippocampal formation, a brain region involved in the
acquisition of some types of learning (Solomon et al., 1986; Clark and
Squire, 1998; Riedel et al., 1999) as well as possessing a remarkable
degree of plasticity. Although there are many instances of changes in hippocampal synaptic neurotransmission in response to learning (McNaughton and Morris, 1987; Power et al., 1997), there are few examples of learning-induced changes in structural plasticity that
involve either the production of new synapses or a reorganization of
existing synapses (Bailey and Kandel, 1993; Moser, 1999). Dendritic spines, small protrusions on the shaft of dendrites in the mammalian brain, represent a means whereby new contacts between cells can be
established and existing contacts strengthened. As such, it has long
been suggested that dendritic spines are involved in the formation of
new memories. Also, because most spines are the location of excitatory
synapses in the hippocampus, an increase in their number could
translate into a significant increase in excitatory neurotransmission
(Andersen et al., 1966; Harris and Kater, 1994), which is often
considered an integral step in memory formation.
Although there are reports that environmental experience can affect
dendritic spines, especially in cortical regions (Anderson et al.,
1996; Kleim et al., 1996; Knafo et al., 2001), evidence distinguishing
training-induced effects on dendritic spines from learning itself does
not exist. Training on a hippocampal-dependent task of spatial maze
learning has been associated with a transient increase in dendritic
spine density (O'Malley et al., 2000), although others did not observe
a change (Rusakov et al., 1997). There is also indirect evidence
associating spines with learning; exposure to a complex
spatial environment enhanced spines and, in a separate group of
animals, enhanced performance in the water maze (Moser et al., 1994).
Training on another hippocampus-dependent task (Solomon et al., 1986;
Moyer et al., 1990; Beylin et al., 2001), trace eyeblink conditioning,
was associated with changes in synaptic structure, but spine number was
not assessed (Geinisman et al., 2000, 2001).
Trace conditioning is an associative learning task in which two stimuli
are separated in time. Here we tested whether the acquisition of trace
memories alters the density of dendritic spines in the hippocampus
using Golgi impregnation. After demonstrating that trace conditioning
increased the density of dendritic spines on basal dendrites of CA1
pyramidal neurons, relative to training with unpaired stimuli, we
evaluated whether this effect was a result of learning itself. Early
acquisition of the classically conditioned eyeblink response is
dependent on activation of the NMDA type of glutamate receptor
(Servatius and Shors, 1996; Thompson and Disterhoft, 1997). Thus, in
the second experiment, the NMDA receptor antagonist was
administered to determine whether changes in spine density are evident
after the blockade of learning. In the third and final experiment, we
evaluated whether learning an association that is not dependent on the
hippocampus, but engages its activity, would affect dendritic spine
density in hippocampal cell regions.
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Materials and Methods |
Experiment 1: the effects of trace conditioning on
spine density
Subjects and surgical procedures. Adult male Sprague
Dawley rats (300-400 gm; 2-3 months of age) were purchased from
Zivic-Miller Laboratories (Zelienople, PA) and maintained in the
Department of Psychology at Rutgers University. Rats were individually
housed, had ad libitum access to laboratory chow and water,
and were maintained on a 12 hr light/dark cycle. Rats were acclimated
to the colony room for at least 1 week before surgery. They were
anesthetized with sodium pentobarbital anesthesia (45 mg/kg)
supplemented by isoflurane inhalant and fitted with headstages attached
to four electrodes: two recorded electromyographic (EMG) activity for determination of the eyeblink, and two delivered the periorbital stimulation to elicit the eyeblink reflex (Servatius and Shors, 1996).
Electrodes consisted of silver wire implanted subcutaneously to emerge
through and around the eyelid. One end of the wires was deinsulated,
and the other was attached through gold pins to a strip connector that
served as a headstage. The headstage was surrounded by a plastic cap
and secured to the skull with acrylic. A recovery period of at least
5 d occurred before behavioral testing.
Classical eyeblink conditioning. Headstages were connected
to a cable that allowed free movement within the conditioning chamber. Rats were acclimated to the conditioning apparatus for 1 hr.
Twenty-four hours later, rats were returned to the conditioning
apparatus and spontaneous eyeblinks were recorded. To detect any
sensitized response before training, responses to 10 white-noise
stimuli [250 msec; 83 dB; intertrial interval (ITI) of 25 ± 5 sec] before training were also recorded. Eyeblinks during the
first 100 msec of the white noise were recorded. Rats were then exposed
to 300 trials of trace conditioning with paired stimuli
(n = 9) or unpaired training (n = 8).
During trace conditioning, an 83 dB, 250 msec burst of white-noise
conditioned stimulus (CS) was separated from a 100 msec, 0.7 mA
periorbital shock unconditioned stimulus (US) by a 500 msec trace
interval (see Fig. 1A). These stimulus parameters produce learning that is dependent on an intact hippocampus in rats
(Beylin et al., 2001). Each block of trace conditioning consisted of
100 trials with every 10 trial sequence composed of one CS-alone presentation, four paired presentations of the CS and US, one US-alone
presentation, and another four paired presentations of the CS
and US. The ITI was 25 ± 5 sec. During unpaired training, rats
received the same number of CS and US exposures presented in an
explicitly unpaired manner. The ITI was 10 ± 3 sec. To detect the
occurrence of an eyeblink, the maximum EMG response occurring during a
250 msec prestimulus baseline recording period was added to four times
its SD. Responses that exceeded that value and were >3 msec
were considered eyeblinks. During trace conditioning, eyeblinks were
considered conditioned responses (CRs) if they began 500 msec before US
onset. In the unpaired protocol, eyeblinks were recorded during the
same time interval as paired training. Eyeblink performance was
computed as a percentage of CRs to the CS. Twenty-four hours later,
rats that underwent trace conditioning with paired or unpaired stimuli
were killed with a group of naive animals (n = 8) that
did not receive stimulus exposure. Blood samples were collected via
cardiac puncture before perfusion for the radioimmunoassay of
corticosterone (CORT). Previous studies have demonstrated that paired
and unpaired training elevates CORT levels (Shors et al., 1992), a
factor that has been implicated in regulating changes in dendritic
morphology in the hippocampus (Woolley et al., 1990; Shors et al.,
2001).
Golgi method. Rats were deeply anesthetized with an overdose
of sodium pentobarbital and transcardially perfused with 120 ml of
4.0% paraformaldehyde in 0.1 M phosphate buffer
and 1.5% picric acid (v/v). Brains were postfixed and stored overnight in the same solution. After postfixation, a modified version of the
single-section Golgi impregnation procedure was used to process brains
(Gabbott and Somogyi, 1984; Woolley and Gould, 1994; Shors et al.,
2001). Serial coronal sections (150 µm) were cut on an oscillating
tissue slicer in a bath of 3.0% potassium dichromate in distilled
water. The sections were incubated overnight at room temperature in
individual wells containing 3.0% potassium dichromate. The following
day, the sections were rinsed and mounted onto ungelatinized slides, a
coverslip was glued over the sections at the four corners, and the
slide assembly was placed in a Coplin jar containing 1.5% silver
nitrate in distilled water. After 48 hr, the slide assemblies were
dismantled and the sections removed from the slides. The sections were
rinsed in distilled water, dehydrated in ethanol, cleared in xylenes,
and mounted onto ungelatinized glass slides. Slides were coverslipped
with Permount and allowed to dry before quantitative analysis.
Spine density analysis. Spine density analysis was conducted
blind to experimental condition. For CA1 pyramidal neurons, spine density was measured on apical dendrites of stratum radiatum and basal
dendrites of stratum oriens. Quantitative analysis was conducted on
tissue stained dark with Golgi impregnation that was uniform throughout
the section. Six Golgi-impregnated pyramidal neurons discernible from
nearby impregnated cells were selected. These neurons were located
within the CA1 region of the dorsal hippocampal formation and were
required to have no breaks in staining along its dendrites. Measurement
occurred at least 50 µm away from the soma for apical dendrites and
30 µm for basal dendrites on secondary and tertiary branches. Five
segments between 10 and 20 µm in length and in the same plane of
focus were chosen. In some cases, the segments were from the same
branch. Counting required focusing in and out with the fine adjustment
of the microscope (Nikon Eclipse E400; Nikon, Tokyo, Japan)
using 1000× magnification and oil immersion. Only spines that
were distinct from the dendritic branch were counted. Spine density was
calculated by dividing the number of spines on a segment by the length
of the segment and was expressed as the number of spines per 10 µm of
dendrite. Densities of spines on five segments of a cell were averaged
for a cell mean, and the six cells from each animal were averaged for
an animal mean. Spine density values using this method are
underestimates, because spines protruding either above or beneath the
dendritic shaft are not accounted for (Woolley and Gould, 1994).
Measurement of dendritic length. Dendritic length
measurements were conducted on a subset of animals (n = 5 per group). To be selected for analysis, three isolated and
thoroughly impregnated CA1 pyramidal neurons were chosen from each
animal. Images of each cell were taken with a CCD camera mounted to the
microscope at 400× magnification. From this image, three secondary and
three tertiary dendrites were traced, and the length was measured using Scion Image software (Scion Corporation, Frederick, MD). The mean length of secondary and tertiary dendrites for each cell was
calculated, and the cells were averaged for an animal mean.
Radioimmunoassay of corticosterone. As indicated, cardiac
blood was collected before perfusion. Samples were added immediately to
test tubes containing 0.1 ml of heparin and centrifuged at 3000 rpm for 20 min. Plasma aliquots were stored at  20°C and thawed before analysis. Circulating levels of CORT were measured using
a solid phase radioimmunoassay system (Coat-A-Count; Diagnostic Products, Los Angeles, CA). The assay sensitivity was 5.7 ng/ml.
Experiment 2: the effects of associative learning on spine density
To determine whether the effect of trace conditioning on spine
density was sensitive to learning itself or whether it was simply the
product of training, rats were injected intraperitoneally with
the NMDA receptor antagonist
(±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphoric acid (CPP) (10 mg/kg; Sigma, St. Louis, MO) or saline vehicle 1 hr before training. As
before, rats were exposed to 300 trials of trace conditioning or
unpaired training (n = 6-9 animals/group) and killed
24 hr later for Golgi impregnation. To confirm that NMDA receptor
blockade did indeed prevent learning, separate groups were injected
with saline (n = 7) or CPP (n = 5) and
exposed to 300 trials of trace conditioning. Twenty-four hours later
and in the absence of the drug, these groups were exposed to 300 additional trials of training.
Experiment 3: the effects of trace versus delay conditioning on
spine density
Rats were exposed to 300 trials of conditioning using a trace
(n = 6), unpaired (n = 5), or delay
(n = 6) paradigm to determine whether the effect of
conditioning on spines was specific to hippocampal-dependent learning.
In delay conditioning, an 850 msec, 83 dB CS overlapped and
coterminated with a 100 msec, 0.7 mA US (see Fig.
1B). These stimulus parameters do not require an
intact hippocampus for learning (Beylin et al., 2001). As in the
previous experiments, rats were killed 24 hr after training, and the
tissue was processed for Golgi impregnation. In this experiment, we
extended the observation of dendritic spines on CA1 pyramidal cells to
include granule cells of the dentate gyrus, as well as basal spines on
pyramidal cells of the somatosensory cortex. For analysis of granule
cells, three neurons located in the dorsal blade of the dentate gyrus were selected. For the analysis of cortical neurons, three neurons located in the somatosensory trunk regions and parietal association cortices (3.3-3.8 mm posterior to bregma; 2-3 mm lateral) (Paxinos and Watson, 1986) were chosen. Both the dentate gyrus and the cortical
neurons selected for analysis were required to be uniformly impregnated
and easily distinguished from neighboring cells. For each cell, five
segments 10-20 µm in length in the same plane of focus were chosen,
and counting began at least 25 µm away from the soma on secondary and
tertiary dendritic branches.
Statistical analysis. Repeated-measures ANOVA was
conducted to evaluate eyeblink performance. The animal means for the
density of spines and length of CA1 pyramidal cell apical and basal
dendrites, spine density on neurons of the cortex and dentate gyrus,
and CORT levels were analyzed using ANOVA. To evaluate group
differences, post hoc analysis using the Newman-Keuls test
was applied to significant main effects and interactions.
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Results |
Trace conditioning increases dendritic spine density
The group of rats exposed to paired stimuli during trace
conditioning (Fig. 1A)
emitted more CRs over 300 trials than rats exposed to the same number
of unpaired stimuli (F(2,30) = 4.64; p < 0.05) (Fig.
2A). Twenty-four hours
after the training experience, the group exposed to paired stimuli
possessed a greater density of spines on the basal dendrites of
pyramidal cells in area CA1 of the hippocampus compared with the group
exposed to the same number of unpaired stimuli or naive controls
(F(2,18) = 11.47; p < 0.005) (Fig. 2B). The group exposed to trace
conditioning had ~27% more spines than the group exposed to unpaired
stimuli (p < 0.005) and ~39% more than the
naive controls (p < 0.005) (Fig.
3). The spine density on basal dendrites
was not different between animals exposed to unpaired stimuli versus
those left in their home cage (naive) (p = 0.26). Thus, exposure to the conditioning stimuli themselves or the
context associated with the training procedures did not increase spine
density, suggesting that the training-induced increase in spine density
is not an artifact of stimulus exposure or production of the
unconditioned motor response.
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Figure 1.
Schematic diagram of trace
(A) and delay (B)
conditioning procedures. In trace conditioning, there is a temporal gap
(trace) between the CS offset and US onset. In delay
conditioning, the CS overlaps and coterminates with the US. Bold
lines represent the interval during which an eyeblink was
considered a CR.
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Figure 2.
Trace conditioning increases dendritic spine
density in area CA1 of the hippocampus. A, Animals that
underwent trace conditioning with paired stimuli exhibited more CRs
than animals trained with unpaired stimuli. The mean density of
dendritic spines on basal (B) and apical
(C) dendrites of CA1 pyramidal cells of the
hippocampus. Trace conditioning increased the density of spines on
basal but not apical dendrites. The asterisk indicates a
significant difference. Error bars indicate SEM.
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Figure 3.
Golgi impregnation of pyramidal cells in area CA1
of the hippocampus. A, Photomicrograph (200×
magnification) of a Golgi-impregnated CA1 pyramidal cell illustrating
the apical and basal dendrites. B, C, Representative
basal dendritic segments (1000× magnification) from animals exposed to
trace conditioning with paired (B) versus
unpaired (C) stimuli. Scale bar, 1 µm.
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To further characterize the change in spine density on basal dendrites,
we examined their distribution in the different groups (Moser et al.,
1997) (Fig. 4). All segments from all
cells within a group were sorted according to the number of spines that
were observed and expressed as the percentage of the total number of segments (180 trace-paired segments, 210 trace-unpaired segments, and 240 naive segments). Although the distributions are similar among
groups, there are a greater number of segments with high spine density
and fewer segments with low spine density from animals exposed to trace
conditioning. In contrast, the groups exposed to unpaired stimuli and
those left in their home cage have a greater number of segments with
low numbers. A Pearson correlation revealed no significant relationship
between the number of CRs in individual animals exposed to paired
training and the number of spines on their dendrites
(p = 0.71).
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Figure 4.
Distribution of spine densities on basal
dendrites. Segments within groups of naive animals
(A) and those exposed to unpaired
(B) and paired (C) stimuli
were sorted according to spine number and expressed as the percentage
of the total number of segments.
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There was no effect of trace conditioning on spines located on
the apical dendrites of CA1 pyramidal cells
(F(2,19) = 2.53; p = 0.11) (Fig. 2C). In addition, there was no effect of
training on the length of secondary or tertiary branches of apical and basal dendrites, suggesting that training did not induce an expansion or retraction of the dendrite (Table 1).
Finally, exposure to paired versus unpaired training did not
differentially affect CORT levels (paired, 214.91 ± 21.14 ng/ml;
unpaired, 221.20 ± 27.70 ng/ml; naive, 245.53 ± 24.87 ng/ml) (F(2,22) = 0.43;
p = 0.65). Note that these levels were obtained from
blood drawn 24 hr after training. Therefore, differing levels of
glucocorticoids at the time the animals were perfused did not
mediate the training-induced changes in spine density. In addition,
changes in glucocorticoid levels during training are not likely
to mediate this effect, because previous studies have shown that
exposure to both paired and unpaired training elevates corticosterone
levels to a similar degree (Shors et al., 1992).
NMDA receptor antagonism prevents learning and the
increase in spine density
Administration of the NMDA receptor antagonist CPP did not
affect the spontaneous blink rate
(F(1,27) = 0.08; p = 0.78) or responding to a white-noise stimulus before training
(F(1,27) = 0.54; p = 0.47). There was a significant three-way interaction between injection
with CPP versus saline, exposure to paired versus unpaired stimuli, and
trials of training (F(2,54) = 6.43;
p < 0.005); only saline-injected animals exposed to
paired stimuli acquired the CR (p < 0.05) (Fig.
5A). There was also an
interaction between injection with CPP versus saline and exposure to
paired versus unpaired training on the spine density of basal dendrites in area CA1 (F(1,23) = 6.50;
p < 0.05) (Fig. 5B). The density of spines
in those that were injected with saline and exposed to paired training
was greater than in those injected with saline and exposed to unpaired
training (p < 0.05). However, spine density in
those injected with CPP before training did not differ between those
exposed to paired and those exposed to unpaired stimuli (p > 0.05). Thus, the training-induced increase
in spine density did not occur in those that did not emit CRs. There
was no effect of training (F(1,22) = 0.13; p = 0.72) or drug administration (F(1,22) = 3.89; p = 0.06), nor was there an interaction between training and drug
administration (F(1,22) = 1.48;
p = 0.24) on the spine density of apical dendrites.
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Figure 5.
NMDA receptor antagonism prevents learning
and the increase in spine density. A, Animals
injected with the NMDA receptor antagonist CPP displayed significantly
fewer CRs than saline-injected animals. B, Mean density
of spines on basal dendrites of CA1 pyramidal cells of the hippocampus.
Blocking acquisition of the learned response with the NMDA receptor
antagonist CPP prevented the training-induced increase in spine density
on basal dendrites. C, An additional group of
animals injected with CPP also did not acquire the trace-conditioned
response relative to saline-injected controls. Twenty-four hours later
and in the absence of the antagonist (as noted by the
dashedline), these animals acquired the CR and displayed
no evidence of residual learning. The asterisk indicates a
significant difference. Error bars indicate SEM.
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To verify that exposure to the NMDA receptor antagonist did
prevent learning, additional groups of animals were injected with CPP
before training, trained, and then trained again in the absence of the
antagonist. During exposure to the first 300 trials, those injected
with CPP emitted fewer CRs (<10%) than the group injected with saline
(F(1,10) = 19.98; p < 0.005). On exposure to 300 additional trials, their response rate did
not differ from those injected with saline and exposed to the first 300 trials of training (p = 0.13) (Fig.
5C). Thus, there was no evidence of residual learning in
animals injected with CPP and trained, further suggesting that the
increase in spine density after trace conditioning is a result of
learning and not performance or exposure to the training conditions.
Hippocampal-independent learning also increases spine density
Groups of rats that underwent trace (Fig. 1A)
and delay (Fig. 1B) conditioning emitted more CRs
than those exposed to unpaired stimuli
(F(2,13) = 29.58; p < 0.005) (Fig. 6A). Those
exposed to delay conditioning emitted more CRs than those exposed to
trace conditioning, as reported previously (p < 0.005) (Beylin et al., 2001). Training on both conditioning tasks
increased the spine density on basal dendrites in area CA1
(F(2,11) = 7.11; p < 0.01) (Fig. 6B) compared with animals exposed to
unpaired stimuli (p < 0.05). Neither trace nor
delay conditioning altered the density of spines on apical dendrites
(F(2,9) = 0.42; p = 0.67). In addition, there was no effect of trace or delay conditioning
on the spine density of pyramidal cells in the somatosensory cortex
(F(2,11) = 0.53; p = 0.60) (Fig. 6C) or granule cells of the dentate gyrus (F(2,12) = 0.19; p = 0.83) (Fig. 6D).
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Figure 6.
Trace and delay conditioning increase dendritic
spine density in the hippocampus. A, Animals that
underwent delay or trace conditioning exhibited significantly more
conditioned responses than animals trained with unpaired stimuli.
B-D, The mean density of spines on basal dendrites of
CA1 pyramidal cells (B), pyramidal cells of the
cortex (C), and granule cells of the dentate
gyrus (D). Both trace and delay conditioning
increased the density of spines in area CA1 but not in the dentate
gyrus or cortex. Significant differences are noted with
asterisks. Error bars indicate SEM.
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Discussion |
It has long been postulated that dendritic spines are an
anatomical substrate involved in memory formation or storage (Ramon y
Cajal, 1893). However, there are no reports of a direct and persistent
effect of learning itself on dendritic spines in the hippocampus, a
brain region critically involved in some types of learning and memory
processes (Solomon et al., 1986; Clark and Squire, 1998). From our
initial experiment, we present data indicating that associative
learning enhances dendritic spine density by ~20% on hippocampal
pyramidal cells of area CA1. Although these data suggest that learning
increases spine density in the hippocampus, they are inconclusive,
because other aspects of the training experience could alter their
numbers. Therefore, in a second experiment, we prevented acquisition of
the learned response by administering a competitive NMDA receptor
antagonist before training (Servatius and Shors, 1996; Thompson and
Disterhoft, 1997). Animals that were injected with saline and
trace-conditioned possessed a greater density of dendritic spines in
area CA1 compared with those exposed to unpaired stimuli, whereas those
that were injected with the antagonist did not emit CRs and showed no
increase in spine density. To verify that no learning occurred in those that were injected with the NMDA receptor antagonist, a similar group
was injected with the antagonist and underwent additional training in
the absence of the drug. There was no evidence of residual learning in
this group. Thus, the training-induced increase in spine density
appears to be specific to learning the association between the CS and
the US. Because the increase was observed only in those exposed to the
paired stimuli and not in those exposed to explicitly unpaired stimuli,
it appears to be specific to learning a positive association between
the two conditioning stimuli. To our knowledge, these results are the
first demonstration that changes in spine density occur as a result of
learning and not a result of training per se.
In a final experiment, we determined that the learning-induced
increase in spine density was not specific to
hippocampal-dependent learning but was also evident in animals trained
on the hippocampal-independent task of delay conditioning. This is
perhaps not surprising, because the hippocampus must process stimulus
information before any knowledge of the task requirements. Also, it has
been demonstrated that neuronal activity in CA1 pyramidal cells
increases during the performance of both trace and delay tasks (Berger
et al., 1980). In vitro studies have attributed the enhanced
excitability to a reduction in the afterhyperpolarization and enhanced
synaptic responsiveness of CA1 pyramidal neurons (Disterhoft et al.,
1986; LoTurco et al., 1988; Moyer et al., 1996). Such heightened
activity of hippocampal pyramidal cells could influence the formation
or extension of dendritic spines. Indeed, changes in activity have been
associated with alterations in synaptic structure on Purkinje cells
after classical eyeblink conditioning (Anderson et al., 1999). Other
studies indicate that tetanic stimulation enhances the de
novo appearance of dendritic spines, at least in vitro (Engert and Bonhoeffer, 1999; Maletic-Savatic et al., 1999).
Furthermore, exposure to both trace and delay conditioning increases
other measures of synaptic plasticity in area CA1 of the hippocampus, such as the binding affinity of AMPA receptors (Tocco et al., 1992).
Note that the hippocampus is more engaged in delay conditioning than
was previously thought. Using the parameters of the present experiments, animals with hippocampal lesions can acquire the delay
response (Schmaltz and Theios, 1972; Solomon et al., 1986; Beylin et
al., 2001), but they are impaired under more difficult training
parameters (a very long interstimulus interval) (Clark and Squire,
1998; Beylin et al., 2001). Moreover, animals with hippocampal lesions
that have already acquired the association under the typical delay
conditions rapidly acquire the learned response using a trace paradigm
(Beylin et al., 2001). Thus, once the association has been established,
the hippocampus is no longer necessary for learning or expressing the
trace memory. The present data suggest that the initial acquisition of
these associations affects the density of dendritic spines regardless
of whether the hippocampus is necessary.
The length of branches on apical and basal dendrites did not change as
a function of training, suggesting that the learning-induced increase
in spine density was not attributable to expansion or shrinkage of the
dendritic tree. The learning-induced increase in spine density was also
regionally specific to area CA1 and not the dentate gyrus. Moreover,
the effects were located on basal and not apical dendrites.
Interestingly, others have found that experiences such as environmental
enrichment and stimulus exposure increase spine density on basal and
not apical dendrites; these experiences were associated with enhanced
spatial learning ability (Moser et al., 1994, 1997). Basal dendrites
receive more contralateral input than apical dendrites (Swanson
et al., 1978; Ishizuka et al., 1990; Li et al., 1994; Amaral and
Witter, 1995), as well as fewer inhibitory inputs from interneurons
(Toth and Freund, 1992). There are also physiological differences
between these regions, at least to the extent that the magnitude of
long-term potentiation is greater in basal dendrites (Kaibara and
Leung, 1993). Together, these data suggest that basal dendrites in CA1 have a high capacity for synaptic plasticity. An examination of the
distribution of the spine densities on the basal dendrites demonstrates
additional specificity. There are a greater number of segments with
high spine density and fewer segments with low spine density in the
trace-conditioned group, whereas the unpaired and naive groups show the
opposite pattern of results. It should be noted that we examined
dendritic spines 24 hr after training; therefore, changes in spine
density could occur in other cell regions at earlier or later time
points and at different stages in the learning process.
Dendritic spines are the primary source of synaptic contact in the
mammalian brain. We cannot verify that the learning-related increase in
spine density translates into an increase in synaptic contact, but such
a consequence is likely. Others have reported increases in
synaptogenesis after training (Wenzel et al., 1980; Van Reempts et al.,
1992; Stewart and Rusakov, 1995; Ramirez-Amaya et al., 1999; Kleim et
al., 2002) and similarly, use-dependent measures of synaptic plasticity
such as long-term potentiation are associated with changes in
hippocampal synapse number and/or structure (Desmond and Levy, 1986;
Geinisman, 2000; Yuste and Bonhoeffer, 2001). More recently, it was
reported that trace conditioning did not alter the number of axospinous
synapses in the hippocampus but did increase the number of multiple
synapse boutons, a condition under which one presynaptic bouton
synapses with two or more dendritic spines (Geinisman et al., 2001).
This effect was evident on apical dendrites, but basal dendrites
were not examined. The present findings concur, because we also did not
observe an increase in spine number on apical dendrites after learning.
It has been proposed that existing spines may relocate from
nonactivated boutons and synapse with those activated by conditioning,
at least on apical dendrites (Geinisman et al., 2001).
These data indicate that an increase in spine density accompanies
associative memory formation. They do not indicate that an increase is
necessary for learning to occur, especially because their presence was
enhanced after delay conditioning, which under the present training
conditions does not require the hippocampus (Beylin et al., 2001). The
increase in spine density does not appear to be a result of enhanced
arousal or the stress of training. In previous studies, we found
that exposure to an acute stressful event (30 brief intermittent tail
shocks) also increased spine density in area CA1 of the hippocampus,
but the effect was less localized and less evident on basal
dendrites (Shors et al., 2001). In the present experiment, levels of
the stress hormone corticosterone were not elevated at the time of
tissue preparation (24 hr after training), but would have been elevated
equally during exposure to paired versus unpaired stimuli (Shors et
al., 1992). Because only exposure to paired training was associated
with an increase in the presence of spines, these data are consistent
with learning-related phenomena.
Dendritic spines exist on most excitatory neurons in the hippocampal
formation as well as in cortical structures (Harris and Kater, 1994).
Although identified over 100 years ago, their functional significance
remains unknown. The present results indicate that they are affected by
the formation of simple associative memories and are thus consistent
with a long-held belief that these spines are sensitive to new
experience and memories for experience.
| |
FOOTNOTES |
Received Sept. 3, 2002; revised Oct. 31, 2002; accepted Nov. 1, 2002.
This work was supported by National Institute of Mental Health (NIMH)
Grant R01-59970, National Science Foundation Grant IBN0217403, and by
the National Alliance for Research on Schizophrenia and Depression
(T.J.S.). B.L. was supported by NIMH National Research Service Award
MH63568. We thank L. D. Matzel and C. R. Gallistel for
comments on this manuscript.
Correspondence should be addressed to Tracey J. Shors, Rutgers
University, Department of Psychology, 152 Frelinghuysen Road, Piscataway, NJ 08854. E-mail: shors{at}rci.rutgers.edu.
| |
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TOP
ABSTRACT
Introduction
Memory
