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Volume 17, Number 2,
Issue of January 15, 1997
pp. 717-721
Copyright ©1997 Society for Neuroscience
Learning-Dependent Synaptic Modifications in the Cerebellar
Cortex of the Adult Rat Persist for at Least Four Weeks
Jeffrey A. Kleim1, 4,
Kapil Vij4,
David H. Ballard4, and
William T. Greenough1, 2, 3, 4
Departments of 1 Psychology and
2 Cell and Structural Biology, and
3 Neuroscience Program, and 4 Beckman
Institute, University of Illinois, Urbana, Illinois 61801
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Several experiments have demonstrated increased synapse number
within the cerebellar cortex in association with motor skill learning
but not with motor activity alone. The persistence of these synaptic
changes in the absence of continued training was examined in the
present experiment. Adult female rats were randomly allocated to either
an acrobatic condition (AC) or a motor activity condition (MC). The AC
animals were trained to traverse a complex series of obstacles, and
each AC animal was pair-matched with an MC animal that traversed an
obstacle-free runway. These animals were further assigned to one of
three training conditions. Animals in the EARLY condition were trained
for 10 consecutive days before being killed, animals in the DELAY
condition received the same 10 d of training followed by a 28 d period without training, and animals in the CONTINUOUS condition were
trained for the entire 38 d. Unbiased stereological techniques
were used to obtain estimates of the number of synapses per Purkinje
cell within the cerebellar paramedian lobule. Results showed the AC
animals to have significantly more synapses per Purkinje cell than the
MC animals in all three training conditions. There were no differences
in the number of synapses per Purkinje cell among the EARLY, DELAY, and
CONTINUOUS conditions. These data demonstrate that both the motor
skills and the increases in synapse number presumed to support them
persist in the absence of continued training.
Key words:
motor learning;
synaptogenesis;
persistence;
cerebellum;
synaptic plasticity;
rat
INTRODUCTION
Experience can alter neuronal morphology in a
manner that may support memory formation (Greenough and Bailey, 1988 ;
Bailey and Kandel, 1993). A pattern of structural changes resulting
from learning has emerged from studies of differential rearing
conditions and formal training. Rodents reared in complex housing
conditions have thicker visual cortices (Diamond et al., 1964), neurons
with more dendritic material (Volkmar and Greenough, 1972; Globus et al., 1973), and increased cortical synapse/neuron ratios (Turner and
Greenough, 1983; Bhide and Bedi, 1984; Turner and Greenough, 1985).
Similar changes have also been observed after various different behavioral manipulations, including maze training (Greenough et al.,
1979; Chang and Greenough, 1982), sensitization (Bailey and Chen,
1983), and motor skill learning (Greenough et al., 1985; Withers and
Greenough, 1989; Black et al., 1990; Kleim et al., 1994).
If memory is represented in the brain through modifications in
neuronal structure, then these changes should persist for as long as
the encoded experience. The persistence of some of the anatomical
changes described above has been examined in reversal experiments in
which animals are reared in a complex environment followed by a period
of time in standard laboratory cages. These studies have shown that the
increased cortical weight (Katz and Davies, 1984) and dendritic
arborization (Camel et al., 1986) observed in rats reared in a complex
environment tend to persist. Some of the behavioral consequences of
complex housing, such as improved performance on a Hebb-Williams maze,
may also persist (Forgays and Read, 1962). A direct examination of how
termination versus continued training affects the experience-dependent
anatomical and behavioral adaptations within the same experiment has
not been conducted.
Motor learning paradigms provide the opportunity to examine more
specifically the development of a set of behaviors in relation to the
anatomical changes presumed to support them. The cerebellum has been
shown to be involved in motor skill learning: a number of studies have
demonstrated impairments in motor learning and sensory-motor
associations after cerebellar lesions (Lincoln et al., 1982; Hore and
Vilis, 1984; Lavond et al., 1990; Thompson et al., 1990) as well as
alterations in cerebellar physiology in association with learning
(Gilbert and Thach, 1977; Berthier and Moore, 1986; Ojakangas and
Ebner, 1992; Bendre et al., 1995). Recent work has also shown that
animals trained on a complex motor learning task had increased numbers
of synapses per Purkinje cell within the cerebellar cortex (Black et
al., 1990; Federmeier et al., 1994; Kleim et al., 1994) in comparison
to both active and inactive controls. Together these data indicate that
the cerebellum plays a role in motor learning and that changes in
Purkinje cell morphology may underlie skill acquisition/retention.
These results also provide the opportunity to examine how the
learning-dependent anatomical and behavioral changes are affected by
removal from continued training. Here we examine the persistence of the
increased synapse number and the acquired motor skills observed after a brief period of training on a complex motor learning task.
MATERIALS AND METHODS
Behavioral training. Forty-eight 3- to 4-month-old
female, Long-Evans, hooded rats were randomly allocated to either an
acrobatic condition (AC) or a motor activity condition (MC). Animals in the AC group were trained to traverse an elevated obstacle course consisting of ropes, ladders, chains, and parallel bars requiring substantial motor coordination to complete. The time to traverse each
obstacle on each trial was recorded. Although errors were not recorded
in this experiment, previous experiments using similar training
procedures have demonstrated progressive decreases in the number of
errors/trial (see Table 1). Each AC animal was pair-matched with an MC
animal that was forced to traverse a flat, obstacle-free runway equal
in length to the AC task. If the AC animals stopped at any point during
a task, they were immediately given a gentle prod to the hindquarters
by the experimenter. When an AC animal received a prod, an experimenter
would also simultaneously prod the paired MC animal such that both
animals spent equal amounts of time on their respective training
apparati and received comparable amounts of handling. In a previous
study, Black et al. (1990) found that extensive physical activity in
running wheels or on a treadmill had no effect on synaptic numbers, so
the MC group was adopted in this experiment to assess the effects of
handling. Animals from both groups were then further assigned to one of three training conditions. In the EARLY condition (AC,
n = 8; MC, n = 8), rats were trained
for 10 consecutive days before being killed, whereas animals in the
DELAY condition (AC, n = 8; MC, n = 8)
received the same 10 d of training followed by a 28 d period without training. On the last day of the delay period, the animals were
given two trials on the task so that any effects of the delay on task
performance could be examined. Finally, animals in the CONTINUOUS
condition (AC, n = 8; MC, n = 8) were
trained for the entire 38 d before being killed. All animals were
killed within 15 min of their last training session.
Tissue preparation. After training, the animals were
anesthetized with pentobarbital (100 mg/kg) and transcardially perfused with 2% paraformaldehyde/2.5% glutaraldehyde in 0.1 M
phosphate buffer, pH 7.4, and post-fixed overnight at 4°C.
Approximately 10 sagittal (300 µm) sections were taken through one
hemisphere of the paramedian lobule (PML) using a vibratome. The
sections of PML were then washed in cacodylate buffer (0.1 M), post-fixed in 2% osmium tetroxide/1.5% potassium
ferrocyanate in 0.1 M cacodylate buffer for 2 hr, and
stained en block with 2% uranyl acetate for 45 min. The
sections were then gradually dehydrated in alcohol, transferred into
propylene oxide, and embedded in Medcast resin. All tissue samples were
then coded with respect to experimental condition before data analysis.
One animal had to be removed from the anatomical analysis because of
inadequate tissue perfusion.
Stereological methods
The number of synapses per Purkinje cell within the PML was
estimated using quantitative stereological methods. Previous
experiments have shown that experience can lead to an increase in the
volume of neuropil (Rosenzweig et al., 1962; Turner and Greenough,
1985; Black et al., 1990). Because of this volume increase, measures of
synapse density alone may not accurately reflect changes in synapse
number. In conditions of stable neuron number, however, estimates of
synapses per neuron accurately reflect changes in synapse number (Anker
and Cragg, 1974). By obtaining the density of neurons and the density
of synapses per unit volume, the number of synapses per neuron can be
calculated and used to measure changes in synapse number (Turner and
Greenough, 1983; Black et al., 1990).
Purkinje cell density
Eighty serial 1 µm sections were taken through one block of
PML from each animal using a diamond histo-knife (Diatome) and an
ultramicrotome. These sections were mounted on chrom alum
gelatin-coated slides and stained with Toluidine blue. With use of a
computer-assisted microscope and a locally written stereology software
package (Phokus on Stereology), the physical disector (Sterio, 1984)
was used to obtain measures of Purkinje cell density. This method
involves comparing two serial sections, the Reference section and the
Lookup section. Within an unbiased counting frame of a known area, the number of nucleoli (each Purkinje cell having only one) that are present in the Reference section but not the Lookup section
(Q ) are counted. The disector volume of tissue
through which the cells are counted (Vdis) is
given by:
where Aframe is the area of the counting
frame and H is the section thickness multiplied by the
number of sections. The neuronal density
(NvPcell) is then determined by:
This method allows for an accurate estimation of Purkinje cell
density (Black et al., 1990), which is unbiased with respect to cell
size and shape (Sterio, 1984; Pakkenberg and Gundersen, 1988).
Synapse density
After the 1 µm sectioning, a small pyramid was trimmed into
the molecular layer of the cerebellar cortex using a 1 µm Toluidine blue-stained section from that block as a guide. From the pyramid, 20 silver/gray serial sections (~70 nm thick) were taken using a diamond
knife (Diatome) and an ultramicrotome (Reichert Ultracut S). Sections
were collected on Formvar-coated, slotted copper grids and stained with
lead citrate. One micrograph (22,000× print magnification) was taken
from the same position in each section using a JEOL 100C electron
microscope. Synapses were identified by the presence of a postsynaptic
density and at least three vesicles in the presynaptic element (Fig.
1). The physical disector method was again used to
determine synapse density where the number of synapses present in the
Reference section but not the Lookup section were counted
(Q) through a known volume of tissue
(Vdis). The number of synapses per Purkinje cell
was then obtained by dividing the density of synapses per cubic
millimeter by the density of neurons per cubic millimeter. Section
thickness was assumed to be 1 µm for the calculation of Purkinje cell
density and 70 nm for the calculation of synapse density. Although it
is likely that subtle variations in section thickness occur, this
variation was assumed to occur nonsystematically across treatment
conditions. As such, it would merely increase variance somewhat, making
treatment effects more difficult to detect.
Fig. 1.
An electron micrograph showing a typical synapse
(arrow) within the molecular layer of the PML (18,000×
magnification).
[View Larger Version of this Image (140K GIF file)]
RESULTS
Behavioral
A split-plot ANOVA with DAY of training as a within-subject factor
revealed a significant effect of DAY on the mean time/trial/task for AC
animals in the EARLY (F(7,72) = 14.24;
p < 0.001), DELAY (F(7,80) = 23.31; p < 0.001), and CONTINUOUS
(F(7,296) = 32.54; p < 0.001)
conditions with the mean time/trial/task significantly decreasing as
training progressed (Fig. 2). Previous experiments have
shown that this decrease in time reflects a progressive decrease in the
number of foot faults (errors) committed by the animals on each task
(Table 1). Other behavioral changes observed in the AC
animals included a tendency to move on to the next task without
hesitation as well as a reduction in the number of prods during the
performance of each task. In the present experiment, the DELAY animals
had a mean time/trial/task comparable to that of the CONTINUOUS animals
despite the 28 d period without training, indicating that the
skills of these animals persisted in the absence of continued
training.
Fig. 2.
Performance of animals in all three conditions on
the acrobatic task (±SEM). The mean time/trial/task significantly
decreased in all three conditions as training progressed (see
text).
[View Larger Version of this Image (17K GIF file)]
Anatomical
A two-way ANOVA with CONDITION and GROUP as between-subject
factors revealed a significant main effect of GROUP on the number of
synapses per Purkinje cell (F(1,41) = 21.48;
p < 0.01). Subsequent multiple comparisons (Student
Neuman-Keuls, p < 0.05) revealed that the AC animals
had significantly more synapses per Purkinje cell than the MC animals
in the EARLY (Fig. 3A), DELAY (Fig.
3B), and CONTINUOUS (Fig. 3C) conditions. A
significant main effect of group was also found for Purkinje cell
density (F(1,41) = 39.47, p < 0.01). The AC animals had significantly reduced Purkinje cell densities
in comparison to the MC animals in the EARLY and CONTINUOUS conditions
but not in the DELAY condition (Student Neuman-Keuls, p < 0.01) (Table 2). Synapse densities
did not significantly differ between groups in any condition (Table
3).
Fig. 3.
Number of synapses per Purkinje cell (±SEM)
within the PML. Multiple comparisons (*Student-Newman-Keuls,
p < 0.05) showed that the AC animals had
significantly more synapses per Purkinje cell than the MC animals in
the EARLY (A), DELAY (B), and CONTINUOUS (C) conditions.
[View Larger Version of this Image (27K GIF file)]
Table 2.
Purkinje cell density (per
mm3)
| Group |
EARLY |
DELAY |
CONTINUOUS |
|
| AC |
*2054
± (82) (n = 8) |
2122
± (88) (n = 8) |
*1902
± (62) (n = 8) |
| MC |
2449
± (118) (n = 7) |
2392
± (92) (n = 8) |
2535
± (106) (n = 8) |
|
|
Density of Purkinje cells (±SEM) within the paramedian lobule.
Multiple comparisons (
|
|
*
Student-Newman-Keuls; p < 0.05)
showed that the AC animals had significantly lower Purkinje cell
densities than the MC animals in the EARLY and CONTINUOUS conditions.
|
|
Table 3.
Synapse density
(×108/mm3)
| Group |
EARLY |
DELAY |
CONTINUOUS |
|
| AC |
3.88
± (0.25) (n = 8) |
4.14
± (0.31) (n = 8) |
3.62
± (0.22) (n = 8) |
| MC |
3.33
± (0.12) (n = 7) |
3.46
± (0.21) (n = 8) |
3.86
± (0.20) (n = 8) |
|
|
Density of synapses (±SEM) within the molecular layer of the
parmedian lobule. Multiple comparisons (Student-Newman-Keuls; p < 0.05) showed no significant differences between the MC
and AC groups in any condition.
|
|
DISCUSSION
Several experiments have now shown that motor skill acquisition is
associated with increases in synapse number within motor regions of the
brain and that this increase is not attributable to motor activity
(Black et al., 1990; Federmeier et al., 1994; Kleim et al., 1994,
1996a). The results of this experiment show that both the motor skills
and the associated increase in synapse number within the cerebellar
cortex persist for at least 28 d after the cessation of training.
These data are in agreement with previous findings showing that the
increased number of varicosities per sensory neuron associated with
sensitization of the gill withdrawal reflex in Aplysia also
persists for at least 3 weeks (Bailey and Chen, 1989).
The increased dendritic branching associated with
postweaning exposure to complex housing also outlasts the
experience (Camel et al., 1986). Recent work in our laboratory,
however, has shown that the increase in number of synapses per neuron
within the visual cortex of adult rats placed for 1 month in
complex housing conditions decreases to statistical nonsignificance
after a subsequent month in individual cages (Klintsova et al., 1995).
The seemingly more persistent nature of the morphological consequences
of motor skill training may arise from the fact that the skills develop gradually in relatively small increments. This progressive behavioral tuning may be represented in the brain as the gradual refinement of
cerebellar circuitry involving increases in synapse number. Furthermore, the nature of the two tasks is somewhat different. Training on the motor learning task involves the goal-directed acquisition of specific behaviors related to the completion of a task
that remains constant throughout the experience. Rearing in a complex
environment is characterized by a more generalized experience involving
the nonspecific exploration of a continuously changing environment. The
specificity of the experience and the presence of behavioral demand
associated with the motor learning task may account for the difference
in the resilience of the anatomical changes observed in these two
paradigms.
The primary site of plastic change within the cerebellar cortex after
acrobatic training appears to be the parallel fiber to Purkinje cell
synapse (Kleim et al., 1994; Anderson et al., 1996). This alteration
seems to involve the formation of multiple synapses onto existing
parallel fiber varicosities (Federmeier et al., 1994) and is reflected
physiologically as enhanced Purkinje cell responsiveness to parallel
fiber activation (Bendre et al., 1995). Recent work has also
demonstrated an increase in the number of synapses per neuron within
the motor cortex after motor learning and that this increase is
dependent on the amount of training the animals receive (Kleim et al.,
1996a). The persistence of the changes therefore may depend on the
amount of training the animals receive before the delay period. It
would be of interest to examine the permanence of both the motor skills
and the increased synapse number after a shorter initial training
period. It is also interesting to note the striking similarity in the
number of synapses per Purkinje cell within each training condition. Both the AC and MC animals had comparable numbers of synapses per
Purkinje cell across the three training schedules, and these values are
similar to previously obtained estimates (Kleim et al., 1994). These
data suggest that synapse-to-Purkinje cell ratio within the PML is
quite consistent and shows a similarly consistent response to
experience. In addition to the persistent change in synapse number, the
present experiment also suggests that some of the anatomical
consequences of motor skill learning may not persist. The decrease in
Purkinje cell density in the AC EARLY and CONTINUOUS conditions
indicates an increase in the volume of neuropil that has been shown
previously to involve increased vasculature (Isaacs et al., 1992) and
glial volume (Anderson et al., 1994). The AC animals in the DELAY
condition, however, did not maintain the significantly decreased
Purkinje cell density, which suggests that some anatomical correlates
of the experience may not persist. Further examination may provide some
insight into which anatomical changes are associated with the
acquisition and continued performance of motor skill versus those that
are associated with the maintenance of motor skill in the absence of
continued performance.
FOOTNOTES
Received July 11, 1996; revised Oct. 21, 1996; accepted Oct. 24, 1996.
This work was supported by National Institute on Aging Grants AG10154
and MH40631, National Institute of Mental Health Grant MH35321, The
Kiwanis Foundation, the Retirement Research Foundation, and a Natural
Sciences and Engineering Research Council of Canada fellowship. We
thank Amity Carrubba, Jennifer Drew, and Jennifer Kelly for assistance
in training the animals and printing the micrographs, the Beckman
Institute Optical Visualization Facility for use of their stereology
system, and the University of Illinois Center for Electron Microscopy
for the use of their facilities.
Correspondence should be addressed to William T. Greenough, Beckman
Institute, University of Illinois, 405 North Mathews Avenue, Urbana, IL
61801.
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A. J Butler and S. L Wolf
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A. F. Kramer, L. Bherer, S. J. Colcombe, W. Dong, and W. T. Greenough
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J. A. Kleim, T. M. Hogg, P. M. VandenBerg, N. R. Cooper, R. Bruneau, and M. Remple
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L. Collin, A. Usiello, E. Erbs, C. Mathis, and E. Borrelli
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D. B. Katz and J. E. Steinmetz
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S. L. Small, P. Hlustik, D. C. Noll, C. Genovese, and A. Solodkin
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M. P. Mattson, S. L. Chan, and W. Duan
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M.-K. Sun, T. J. Nelson, and D. L. Alkon
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H. T. Chugani
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A. Shimada, C. A. Mason, and M. E. Morrison
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X. Lu, O. Hikosaka, and S. Miyachi
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