(Stroke. 1997;28:623-631.)
© 1997 American Heart Association, Inc.
Articles |
Studies on the Influence of Enriched-Environment Housing Combined With Systemic Administration of an 
2-Adrenergic Antagonist on Spatial Learning and Hyperactivity After Global Ischemia in Rats
From the A.I. Virtanen Institute (K.P., J. Sirviö, J.K., P.R.) and the Department of Neuroscience and Neurology (R.M., P.R.), University of Kuopio; Orion Corporation, Orion Pharma, Turku (A.H.); and the Department of Neurology and University Hospital of Kuopio (J. Sivenius), Finland.
Correspondence to Kirsi Puurunen, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, SF-70211 Kuopio, Finland. E-mail kpuurune{at}keula.uku.fi.
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Abstract |
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Background and Purpose The purpose of this study was to determine whether an enriched housing environment and/or systemic administration of the
2-adrenergic receptor antagonist
atipamezole facilitate the rate of spatial learning after global
ischemia in rats. Methods Carotid arteries were closed for 20 minutes after permanent cauterization of vertebral arteries on the previous day. Enriched-environment housing and drug/saline treatment were begun 3 days after ischemia. For rehabilitation, housing in an enriched environment was combined with exploration in a labyrinth. Behavioral tests (the open-arena test and water-maze learning set task) were performed after 1-week periods of drug/saline treatment three times. In addition, the open-arena test was performed to evaluate the baseline level of animals 2 days after the induction of ischemia and at the end of the experiment, when the water-maze task was assessed in another room.
Results Rats housed in an enriched environment after ischemia showed better acquisition of the water-maze learning set task after 1 week of housing. The influence of atipamezole treatment on this parameter did not reach statistical significance. In the open-arena test, ischemic animals were slightly hyperactive; however, this symptom was eliminated by housing in an enriched environment.
Conclusions The present data suggest that housing in an enriched environment facilitates the rate of spatial learning in rats with global ischemia. Rehabilitation also alleviated the hyperactivity observed in ischemic animals.
Key Words: cerebral ischemia, global • hippocampus • memory • rehabilitation • rats
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Introduction |
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The development of efficient neurological rehabilitation programs requires an understanding of the neural mechanisms underlying the recovery of brain function; thus, there is extensive research examining plasticity after brain damage.1 2 3 4 A beneficial effect of housing in an enriched environment on recovery from lesions of the cerebral cortex is a common finding, but enriched-environment housing facilitates recovery from many different kinds of brain damage, such as hippocampal lesions; septal, amygdala, hypothalamic, and dorsolateral thalamic lesions; and neurotoxic lesions (for review, see Reference 11 ). Enriched-environment housing is reported to modify neuron size, dendritic branching and spine density, number of synapses per neuron, size of synaptic contact and plate perforations, and the percentage of total tissue volume (for review, see Reference 55 ).
In addition to the beneficial effects obtained with
enriched-environment housing, there are dramatic effects of drug
administration on functional recovery after brain injury. Amphetamine,
a psychostimulant that is an indirect dopaminergic
agonist,6 7 8 9 10 11 12 13 14 15 16 is perhaps the best-documented agent with the
capacity to enhance recovery in animal studies. On the other hand,
haloperidol, a dopaminergic antagonist,8 10 12
diazepam,17 a 
-aminobutyric acid mimetic, and
phenytoin18 may interfere with recovery as measured by a
variety of specific behavioral tests in rats or cats.
The beneficial effect of amphetamine is dependent on simultaneous
symptom-relevant experience and drug administration.10 11
This effect is thought to result from activation of the noradrenergic
system. For example, the intraventricular administration of
norepinephrine, but not dopamine19 or
serotonin,20 facilitates recovery after injury to the
sensorimotor cortex. In addition, norepinephrine is involved in
cortical plasticity (eg, ocular dominance and long-term
potentiation).21 22 Therefore, it is of particular
interest that preliminary data suggest that 1-adrenergic
receptor antagonists may be detrimental to recovery.19 23
The 2-adrenergic autoreceptors regulate the firing of
noradrenergic neurons and the release of norepinephrine; thus,
2-adrenergic receptor antagonists (eg, yohimbine and
idazoxan), which increase the release of norepinephrine, may enhance
recovery after specific cortical lesions,13 24 and
2-adrenergic receptor agonists (eg, clonidine) may be
detrimental.24 25
There are many studies examining the influences of enriched-environment
housing and drug treatment on recovery of function after cortical and
hippocampal lesions; however, there are only a few studies that have
examined these influences on recovery of function after brain
ischemia. In a recent study of focal ischemia, rats
housed in an enriched environment had a significantly better functional
outcome than rats housed in individual cages.26 It is not
yet known, however, whether housing in an enriched environment
facilitates recovery from global brain ischemia. Therefore, in
the present study the effectiveness of enriched-environment housing
combined with cognitive exercise on the behavioral outcome was tested
in a four-vessel ischemic model in rats. This setting was
designed to resemble the ideal clinical situation in the treatment of
patients with stroke. In addition, the effects of a specific
2-adrenergic antagonist, atipamezole, on rehabilitation
in this model were evaluated. The water-maze task was used to assess
spatial learning and memory, and motor activity in an open arena was
also investigated.
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Materials and Methods |
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Global Ischemia Model
The experimental procedure was approved by the local ethics committee. The timetable of the experiment is represented in Fig 1
. Global ischemia was induced using a slightly
modified version of the four-vessel occlusion model by Pulsinelli and
Brierley.27 Male Wistar rats (HsdBrl:WH [Hannover
origin]; National Laboratory Animal Centre, Kuopio) (260 to 400
g) were anesthetized with a mixture of sodium pentobarbital (9.72
mg/mL) and chloral hydrate (10 mg/mL) administered 2 mL/kg
intraperitoneally, and their vertebral arteries were exposed and closed
permanently by cauterization. The next day, anesthesia was induced with
3% halothane in 30% O2/70% N2O and then
lowered to 0.5% halothane to maintain a surgical depth of anesthesia.
The carotid arteries were exposed, and anesthesia was stopped before
closing the arteries with clips for 20 minutes. Sham-operated animals
underwent the surgical procedure without artery occlusions.
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The rectal temperature was monitored and maintained at 37°C using a heating pad (Harvard Homeothermic Blanket Control Unit, 50-7061). After both surgeries, the animals were placed in an incubator (AGA Incubator MK 440, AGA Medical AB) (30°C) until they recovered. After vertebral artery occlusion, the animals were housed individually in standard cages (53x32.5x20 cm). Baseline activity level was determined using the open-arena test 2 days after induction of ischemia. Housing in an enriched environment combined with exploration in a labyrinth (subsequently the term "training" will be used for this combination) and drug treatment were initiated on day 3 after ischemia induction. The ischemic animals were divided into groups: (1) ischemia+atipamezole+training (ATI+train), (2) ischemia+atipamezole (ATI), (3) ischemia+saline+training (NaCl+train), and (4) ischemia+saline (NaCl). Group 5 consisted of sham-operated controls. The animals had free access to food and water during the entire experimental procedure.
Drug Treatment
Atipamezole
(4-[2-ethyl-2,3-dihydro-1H-inden-2-yl]-1H-imidazole; Orion
Corporation, Orion Pharma) is a relatively novel and highly selective
and specific 2-adrenoceptor
antagonist.28 29 In receptor-binding studies, atipamezole
is reported to have approximately 100 times greater affinity for
2-adrenoceptors and an
2/1-selectivity ratio over 100 times
greater than that of either idazoxan or yohimbine. In studies with
isolated organs, atipamezole is a more potent
2-adrenoceptor antagonist and has a relative
2/1-blocking ratio approximately 200
times greater than that of idazoxan.29 Atipamezole has an
almost equal affinity for the different 2-adrenoceptor
subtypes.30 Atipamezole penetrates rapidly into the
brain31 and causes a dose-dependent increase in the
release of central norepinephrine and serotonin.28
Atipamezole was dissolved in 0.9% saline and was administered (0.5
mg/kg SC) once a day beginning on the third day after ischemia.
Administration continued in three periods of 7 days, with 2-day breaks
between each drug-treatment period. Because atipamezole may interfere
with water-maze test behavior,32 there was a washout
period after each drug-treatment period before behavioral testing.
Control groups were injected with 0.9% saline (2 mL/kg SC).
Training
Enriched Environment
The enriched environment consisted of two cages (61x46x46 cm)
that were connected by a short tunnel and ladders. One of the walls was
constructed of bars, and the cages contained tunnels, shelves, a small
running wheel, and different kinds of manipulable objects (eg, glass
balls, jars, wooden objects) that were changed every week. The rats
were housed in the enriched environment in groups of 6 to 7 animals.
The other animals were housed individually in standard cages.
Labyrinth
Thirty minutes after atipamezole/saline administration, the
enriched-environment groups also were placed into the labyrinth
(127x127 cm with 37-cm walls) for 30 minutes. The purpose of the
labyrinth exposure was to enhance the spontaneous activity of the rats
by allowing them to explore a complex environment and to practice
spatial memory.
Behavioral Tests
Open-Arena Test
The open-arena test was performed in the same room as the first
series of water-maze tests. The apparatus was placed on the rim of the
water maze. Each rat was placed in the middle of a black painted square
(110x110 cm, 30-cm walls) and was monitored for 15 minutes by a
black-and-white video camera (Ikegami) connected to a computer
(IBM-compatible PC) through an image analyzer (HVS image) in 3-minute
sessions that were interrupted by a 25-second break, during which the
computer loaded the next program. The computer system registered the
distance traveled, and the experimenter observed the number of rearings
(rearing up on hind legs), number of fecal boli, and time spent
grooming.
Water-Maze Test
To assess spatial learning, a modified version of the Morris
water-maze task was used. The water-maze apparatus has been previously
described in detail.33 The pool was divided into four
quadrants of equal surface area. The starting locations were called
north, south, east, and west and were located arbitrarily at equal
distances on the pool rim. The platform was located in the middle of
the quadrant, except in the north-west quadrant where the center of the
platform was 22 cm from the north-south axis and 20 cm from the pool
rim. The swim paths were monitored by a video camera linked to a
computer through an image analyzer (see open-arena test). The rats had
6 trials on each test day. If the rat failed to find the hidden
platform within 70 seconds, it was placed on the platform. The animal
was allowed to remain on the platform for 10 seconds and rest for
either 30 seconds (after trials 1, 2, 4, and 5) or 1 minute (after
trial 3). The first, third, fourth, and sixth trials of the day were
started from one of the points located farthest from the platform. The
start point was changed after each trial, and the platform was changed
to a different quadrant each day: south-west, north-east, north-west,
south-east, south-west, north-west, north-east, and south-west. Testing
was performed for 2 days after each of the three treatment periods.
After the last 2 water-maze test days, the animals were tested in
another room to evaluate their performance in a new environment. The
water-maze testing was performed in a black pool filled with clear
water. The invisibility of the platform has been verified
previously.34 Escape latency (time to reach the platform)
and length of the path the animal swam to find the platform were used
to assess the acquisition of the water-maze task. Swimming speed (path
length/escape latency) was used to assess the motor activity of rats in
this task. The shorter the latency to find the platform, the better the
memory for its location was considered to be.
Histology
At the end of the experiment, the rats were anesthetized with
the mixture previously described and perfused transcardially with
saline (2 minutes) and then with 4% paraformaldehyde (400 mL). The
brains were removed and postfixed for 6 hours. The hippocampal area was
cut into 50-µm sections and stained with cresyl fast violet. The
semiquantitative analysis of neuronal damage in the CA subfields of
each hemisphere was done by determining the grade of pyramidal cell
loss. The neuronal damage was scored in the same manner as in the study
by Block and Pulsinelli35 : score of 1, 0% to 10%; score
of 2, 10% to 50%; and score of 3, 50% to 100% loss of pyramidal
cells. The assessment was done in a blinded manner on coded slides from
different levels of the dorsal hippocampus.
Statistics
The water-maze data, escape latency, path length, and swimming
speed (path length/escape latency) were analyzed using ANOVA for
repeated measures. The open-arena data, path length, numbers of
rearings and fecal boli, and time spent grooming of the first test day
were analyzed by one-way ANOVA with Scheffé's post hoc test to
determine whether there were differences between groups in the baseline
levels, and the data of the next three tests were analyzed by ANOVA for
repeated measures.
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Water-Maze Test
Swimming speed did not differ between the groups; thus, escape latency was used to express the rate of acquisition of the water-maze task. When assessed during the first and second days of testing, swimming speed did not differ between groups (F[4,44]=0.34, P>.1; data not shown), but a significant overall group effect was found in escape latency (F[4,44]=2.85, P<.05) as shown in Fig 2
. The NaCl group had longer escape
latencies than sham-operated rats (F[1,18]=5.41, P<.05).
The ATI group had longer escape latencies than sham-operated rats
(F[1,18]=6.16, P<.05), and they did not differ from the
NaCl group (F[1,18]=0.05, P>.1). The escape latencies of
the NaCl+train group did not differ from those of the sham-operated
rats (F[1,18]=0.06, P>.1), but they were not
significantly shorter than those of the NaCl group (F[1,18]=2.56,
P>.1). The difference between the ATI+train group and the
NaCl group approached significance (F[1,17]=3.86, P=.066),
and the performance of the former did not differ from that of
sham-operated rats (F[1,17]=0.76, P>.1). There was a
significant difference between the ATI+train and ATI groups
(F[1,17]=4.55, P<.05).
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When the effects of training and atipamezole treatment were analyzed among the four ischemic groups during the first and second days of testing, the effect of training was significant (F[1,35]=6.76, P<.02), whereas the effect of atipamezole treatment was not significant (F[1,35]=0.02, P>.1), and the interaction between those effects was not significant (F[1,35]=0.05, P>.1).
When assessed during the third and fourth testing days, the overall
group effect in escape latency was not significant (F[4,44]=0.07,
P>.1; Fig 3). The swimming speed did not
differ between groups (F[4,44]=0.24, P>.1; data not
shown).
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When assessed during the fifth and sixth testing days, a significant
overall group effect was found in escape latency (F[4,44]=4.28,
P=.005; Fig 4). The swimming speed did not
differ between groups (F[4,44]=0.62, P>.1; data not
shown). The ATI group had longer escape latencies than sham-operated
rats (F[1,18]=12.78, P=.002). There was a significant
difference between ATI+train and ATI groups (F[1,17]=9.04,
P<.01). There was no difference between NaCl+train and NaCl
groups (F[1,18]=0.56, P>.1). Although there was a slight
difference in the escape latencies between NaCl and sham-operated rats
(F[1,18]=3.25, P=.09), the analysis of swim paths
indicated that the ischemic animals learned to locate the
platform and to navigate directly to it (Fig 4).
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When assessed during the seventh and eighth testing days in a novel
environment, a significant overall group effect was found on escape
latency (F[4,44]=2.51, P=.05; Fig 4
). The swimming speed
did not differ among groups (F[4,44]=0.77, P>.1; data not
shown). The ATI+train and ATI groups had longer escape latencies than
sham-operated rats (F[1,17]=5.23, P<.05, and
F[1,18]=9.94, P<.01, respectively). The NaCl+train and
NaCl groups did not differ from sham-operated rats (F[1,18]=3.05,
P=.1, and F[1,18]=0.43, P>.1,
respectively).
Open-Arena Test
One-way ANOVA with Scheffé's post hoc test was used to
examine differences between groups at the start level, which was
measured in the open-arena test 2 days after global ischemia
was induced (ie, before drug treatment and training had begun). None of
the groups differed significantly (P>.05) in the path
length, number of rearings, or number of fecal boli, even though the
group destined to be ATI+train had a slightly longer path length than
the other groups. Sham-operated animals spent the most time grooming,
however; there was a significant difference in the baseline activity
level between the sham group and the NaCl+train and ATI groups.
When the next three open-arena tests were assessed using ANOVA for
repeated measures, a significant overall group effect was found in the
path length (F[4,44]=9.48, P<.001) and in the number of
rearings (F[4,44]=7.46, P<.001), as well as in the time
spent grooming (F[4,44]=6.25, P<.001), but there were no
significant differences between groups in the number of fecal boli
(F[4,44]=0.22, P>.1). These four open-arena parameters
are represented in Fig 5.
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The path lengths of the NaCl group were significantly longer than those of the sham group (F[1,17]=5.03, P<.05). Training decreased the path length; there was a significant difference between NaCl+train and NaCl groups (F[1,18]=21.94, P<.001). The activities of the ATI and NaCl groups were very similar, and there was no difference in path length between these groups (F[1,18]=0.09, P>.1). The difference in the path length between the ATI+train and NaCl+train groups, however, approached significance (F[1,17]=4.05, P=.06). This tendency was probably due to a higher baseline level in the ATI+train group.
The rats in the NaCl group also made more rearings than the sham-operated group (F[1,18]=4.32, P=.05). Again, training decreased the number of rearings, and there was a significant difference between the NaCl+train and NaCl groups (F[1,18]=18.84, P<.001) in the number of rearings. There was no significant difference between the ATI and NaCl groups (F[1,18]=0.76, P>.1) or ATI+train and NaCl+train groups (F[1,17]=2.11, P>.1) in the number of rearings.
There was no significant difference in the time spent grooming between the NaCl group and sham group (F[1,18]=0.15, P>.1), whereas the NaCl+train group spent more time grooming than the NaCl group (F[1,18]=5.05, P<.05). There was no significant difference between the ATI and NaCl groups (F[1,18]=0.90, P>.1) or the ATI+train and NaCl+train groups (F[1,17]=0.34, P>.1).
Histological Analysis
One rat from the ATI+train group was excluded because of
unilateral hippocampal damage. The other groups consisted of 10 animals
each. All rats from the ischemic groups, except 1 from the NaCl
group and another from the NaCl+train group, had a damage score of 3
bilaterally. The two exceptional animals had a damage score of 2 in one
and a score of 3 in the other hemisphere in the CA1 field of the
hippocampus. Cell loss in the hippocampal CA1 field was usually nearly
complete. Some animals also had cell death in the most distal and
proximal parts of CA3, ie, in CA3 next to CA2 and in CA3c inside the
hilus. There were also three rats that had damage in all parts of CA3
hippocampal areas, one of them unilaterally. Loss of the hilar neurons
was also commonly observed in the dentate gyrus. Examples of anterior
hippocampal sections stained with cresyl fast violet from all groups
are shown in Fig 6.
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Discussion |
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This is the first time that an enriched-environment setting has been evaluated in animals with global forebrain ischemia. The major finding of the present study was that enriched-environment housing combined with cognitive exercise enhanced the performance of rats with global ischemia in the water-maze and open-arena tests. Animals that received training learned to find the hidden platform more rapidly than animals living in standard cages, and they also demonstrated less exploratory activity in the open-arena test.
In the open-arena test, ischemia resulted in hyperactivity, as indicated by the increased locomotor activity and number of rearings. Hippocampal lesions have been found to increase locomotor activity in the open field,36 37 which is in line with many studies that report hyperactivity after global ischemia in gerbils. Activity level has been used as a behavioral test in ischemic drug studies38 and as a predictor of CA1 damage.39 Hyperactivity can result from deficits in adaptive responses to novelty versus familiarity and behavioral inhibition.40 The hippocampus and its output area, the subiculum, send projections to the nucleus accumbens, which is thought to be important in the sensorimotor control.41 According to the present results, hyperactivity lasted for up to 4 weeks. Ischemia did not significantly affect the number of fecal boli, which is an index of emotional reactivity.42
Training diminished hyperactivity, as indicated by the reduced locomotor activity and the reduced number of rearings of ischemic rats in the open-arena test. Consequently, the time spent grooming was increased. The results of some studies suggest that social isolation induces hyperactivity in rats in a novel environment.43 The present result may not be simply a consequence of isolation of the animals because sham-operated animals did not show a marked change in behavior, and in this experiment individually housed rats were in standard cages and were handled daily when given saline/drug injections. In addition, the rats underwent an intensive testing procedure.
It has been suggested that hyperactivity after global ischemia in gerbils may represent an impaired ability to form spatial maps.44 There is extensive evidence indicating that a deficit in spatial learning and memory, especially in working memory, is induced by hippocampal damage (eg, see References 45 and 4645 46 ). Global ischemia is known to impair acquisition of the water-maze task,47 48 although not all results are consistent (see Reference 4949 ), probably because of the different kinds of experimental procedures used in global ischemia models and in water-maze paradigms. There is also a correlation between the magnitude of dorsal hippocampal lesions and spatial learning impairment, with a threshold at about 20% of the total hippocampal volume.45 In global ischemia studies, Olsen et al48 reported impaired water-maze performance if there was total neuronal loss of the CA1 in the anterior-dorsal hippocampus, but rats with partial damage of the CA1 region did not have significant impairment. Nunn et al50 did not find a significant correlation, however, between cell loss in CA1 and spatial learning when rats with submaximal cell loss of the CA1 field after global ischemia were included. The results of the present study, in which the platform location was changed each day, are consistent with previous findings that global ischemia impairs performance of a learning set version of the water maze,51 52 53 54 although in the present study the impairment in the water-maze task was short-lasting. Behavior in the water-maze learning set task appears to be more sensitive to global ischemia damage, and a learning impairment in this kind of task is evident when only half of the CA1 area is damaged.51 54 In the present study, there was no spatial learning deficit induced by global ischemia when the animals were tested in another room. In a previous study, rats with 15-minute four-vessel occlusion were impaired also when tested in a new pool.55 On the other hand, ischemic rats that attained the level of sham-operated animals after training in a radial-arm maze learned the spatial memory task equally as well as sham-operated rats when the task was performed in a new room56 ; thus, this finding indicates that the rats recovered the previously impaired spatial learning ability.
In the present study, the ischemic rats eventually learned to find the platform, even though anatomic examination of brain tissue confirmed that there was extensive damage in the hippocampus, especially in the CA1 field. Training resulted in a different rate of learning among ischemic animals. Importantly, the acquisition of a learning set task was faster in rats that were trained. The structural or functional substrates for this novel finding on the facilitating influence of training in global ischemia were not addressed in this study, however. Recently, Whishaw et al57 suggested that if rats with fimbria fornix lesions can learn the location of the platform in relation to ambient cues, this ability must be mediated by extrahippocampal structures. This may explain the recovery in the present experiment. It is possible that the animals with ischemia did not learn spatial mapping by distant cues but that they adopted a kind of taxon strategy, which is effective for the learning set version of the water-maze task. Learning this kind of strategy may be dependent on the extrahippocampal brain areas involved in motor learning, such as the frontal cortex and striatum. Previously, housing in an enriched environment combined with open-field testing was found to affect metabolism in the nucleus accumbens and the subiculum, which are connected. Lesions of the nucleus accumbens slightly impair acquisition of the water-maze task.58 Analysis of swim paths, however, does not support the use of a taxonomic strategy by ischemic rats, since the rats learned to swim rather directly toward the correct location. In addition, on the next day the rats initially mapped the position of the platform relevant to its previous location, which also suggests that they did not see the platform in our clear-water, black-pool water-maze apparatus.
There is some previous data indicating a role for norepinephrine in the
facilitation of functional recovery.24 59 60 Nakai et
al61 suggest that central noradrenergic neurons may be
equipped with transmitter-specific repair mechanisms throughout their
life. Norepinephrine may facilitate the excitability of neurons, which
is a prerequisite for synaptic plasticity. Atipamezole is a selective
2-adrenergic antagonist29 that increases
the turnover of norepinephrine and also increases dopamine and
serotonin turnover in rat brain.28 It is interesting to
note that atipamezole (300 µg/kg) enhances the excitability of
granular neurons to stimulation of the perforant path (M.
Pitkänen, R. Pussinen, A. Ylinen, P.J. Haapalinna, Riekkinen, Sr,
J. Sirviö, unpublished data, 1996). However, atipamezole
treatment did not significantly improve the rate of spatial learning in
ischemic rats when combined with training.
Atipamezole treatment impaired water-maze performance in the ischemic rats that were housed in standard cages. It is possible that the washout period between atipamezole treatment and water-maze testing was too short, especially since the drug was administered subchronically. It is known that pretraining administration of atipamezole (at doses of 300 µg/kg or higher) interferes with the acquisition of the water-maze task.32 The reasons for this are not clear, but the impairment may be related to the fact that the water-maze task is rather stressful. This may mask any potential facilitatory effects of atipamezole treatment.
The major finding of the present study was that enriched-environment housing combined with cognitive exercise enhanced performance of rats with global ischemia in the water-maze and open-arena tests. The result is consistent with previous studies using a focal ischemia model and various behavioral tests.26 62 It may be that the enriched environment stimulates brain plasticity, resulting in the improved performance.63 64 65 An enriched environment can increase cortical thickness and protein content, dendritic branching, number of dendritic spines, and the size of the synaptic contact area.66 67 The extent to which environmental enrichment after brain damage facilitates compensatory mechanisms rather than true recovery is difficult to establish.1 2 66 67 68 There is no correlation between infarct size and improved motor function in rats housed in an enriched environment.62 Thus, the environment may significantly alter the functional outcome of ischemia without reducing the infarct size.
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Acknowledgments |
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This study was supported by the Academy of Finland. We wish to thank Katariina Sivenius, BMed, for her excellent technical assistance. We thank also Dr Ewen MacDonald, DPharm, for revising the language of the manuscript. We are also grateful to the personnel of the National Laboratory Animal Center and Technical Center.
Received July 22, 1996; revision received October 24, 1996; accepted December 13, 1996.
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