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Stroke. 1997;28:1225-1232

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(Stroke. 1997;28:1225-1232.)
© 1997 American Heart Association, Inc.

Articles

Neural Grafting to Experimental Neocortical Infarcts Improves Behavioral Outcome and Reduces Thalamic Atrophy in Rats Housed in Enriched but Not in Standard Environments

Bengt Mattsson; Jens Christian Sørensen, MD, PhD; Jens Zimmer, MD, PhD; Barbro B. Johansson, MD, PhD

From the Laboratory for Experimental Neurology, Wallenberg Neuroscience Center, Lund University Hospital (Sweden) (B.M., B.B.J.), and Department of Anatomy and Cytology, Institute of Medical Biology, Odense University (Denmark) (J.C.S., J.Z.).

Correspondence to Barbro B. Johansson, MD, PhD, Laboratory for Experimental Neurology, Wallenberg Neuroscience Center, Lund University Hospital, S-221 85 Lund, Sweden. E-mail Barbro.Johansson{at}neurol.lu.se


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
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Background and Purpose The purpose of this study was to evaluate whether grafting of fetal neocortical tissue 1 week after focal brain ischemia improved behavioral outcome and reduced secondary thalamic atrophy.

Methods One week after distal ligation of the right middle cerebral artery in spontaneously hypertensive male rats, blocks of fetal neocortex (embryonic day 17) were homografted to rats housed in standard or enriched environments. Control infarcted nongrafted rats were housed in the enriched environment. Behavioral outcome was repeatedly tested until the rats were killed 20 weeks after the ligation. Ten days earlier, a mixture of 2% Fluoro-Gold and 10% biotinylated dextran amine was injected into the transplants for retrograde and anterograde tracing of graft-host connections.

Results Grafted and nongrafted rats with enriched housing performed significantly better than grafted rats with standard housing on a rotating pole and a prehensile traction test. Grafted "enriched" rats were moreover significantly better than grafted "standard" rats and nongrafted enriched rats in a rotation test and a postural and locomotor tail position test. In the latter test, nongrafted enriched rats performed significantly better than grafted standard rats. The lesion-induced atrophy in posterior thalamus with its major sensorimotor cortex relay nuclei was significantly reduced in grafted enriched rats compared with nongrafted enriched rats. Afferent and efferent graft-host connections were identified in both grafted groups. Graft volumes did not differ.

Conclusions Neural grafting enhanced functional outcome and reduced thalamic atrophy only when combined with housing in enriched environments.


Key Words: brain tissue transplantation • hypertension • middle cerebral artery occlusion • rats • stroke outcome


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
In adult rats, fetal neocortical tissue can survive grafting to surgical cavities in motor cortex1 2 3 and to the infarcted area after middle cerebral artery (MCA) occlusion.4 5 Grafts in the infarcted area receive afferent connections from ipsilateral and contralateral cortex, the thalamus, and several other host brain subcortical nuclei.6 Sensory stimulation of the rat vibrissae can enhance the metabolic activity in grafts, indicating that such connections can be functionally relevant.7 Whereas projections of transplant fibers to the host brain have not been convincingly demonstrated for cell suspension grafts,8 transplant connections to the surrounding host cortex, thalamus, and striatum are clearly seen after implantation of blocks of frontal neocortical tissue to the infarct cavity 3 weeks after MCA occlusion.9

In neonatal rats, fetal cortical transplants can ameliorate thalamic atrophy ipsilateral to frontal cortex lesions.10 11 A similar effect has thus far not been described in adult rats, in which neocortical grafting 3 weeks after a distal MCA occlusion did not reduce thalamic atrophy in transplanted compared with nontransplanted rats.12 Although transplantation 3 weeks after an MCA occlusion may allow extensive survival,13 thalamic atrophy is already substantial at that time. Earlier transplantation may therefore be more appropriate to interfere with secondary thalamic atrophy. Because the very first days after an arterial occlusion may not be optimal for graft survival,3 13 14 we chose to transplant 1 week after the MCA occlusion. The aim of the present study was to evaluate whether blocks of fetal neocortical tissue grafted 1 week after an MCA occlusion were more effective in ameliorating thalamic atrophy and improving the functional outcome than housing the lesioned rats in an enriched environment alone, as demonstrated in an earlier study.12


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Surgery
The experimental protocol was approved by the local Ethics Committee for Animal Research. Thirty-two adult male spontaneously hypertensive rats were anesthetized with methohexital 50 mg/kg IP, and the right MCA was ligated with a 10-0 monofilament nylon thread distal to the origin of the striatal branches. The craniotomy was closed with bone wax, and the skin was sutured. To keep the operation time as short as possible and to avoid problems in the behavioral tests, the animals were not intubated and no catheters were inserted for blood pressure and blood gas control. The day after the operation, 24 of the rats were transferred to enriched environment cages (820x610x450 mm) furnished with horizontal and inclined boards and equipped with various items, such as a chain, a swing board, and wooden blocks. Twice a week the space between the boards was changed, and some objects were replaced with new ones. Eight transplanted rats were kept in standard laboratory cages (550x350x200 mm) with 4 rats in each.

One week after the MCA occlusion, the rats were anesthetized with methohexital and placed in a Kopf stereotaxic apparatus. Through a skull incision and with the use of a trephine drill, a craniotomy was performed over the lateral aspect of the right hemisphere just caudal to the coronal suture. The infarct cavity was exposed when the resulting bone plate was removed. Blocks of fetal neocortical tissue were dissected from rat fetuses (embryonic day 17) removed from pregnant females of the same strain anesthetized with sodium pentobarbital (100 mg/kg). The dissection of fetal frontoparietal cortex and implantation into the infarct cavities followed routine procedures.12 15 After careful removal of the meninges from the donor tissue, two pieces (2 to 3 mm2) of fetal neocortex, one from each hemisphere, were aspirated into a glass cannula fixed to the needle of a 50-µL Hamilton syringe. The tissue blocks were implanted into the infarct cavity in 12 of the rats housed in the enriched environment and in all 8 rats housed in standard cages. In the 12 lesioned control rats housed in the enriched environment, the transplantation cannula was inserted into the cavity, but vehicle only, containing glucose 0.6% and NaCl 0.9%, was deposited. The bone plate was then put in place, the skin was sutured, and the rats were returned to their respective cages.

Behavioral Tests
Functional outcome was tested repeatedly during the postoperative months with tests evaluating prehensile traction, sensorimotor integration, balance on an inclined plane, circling behavior in rotometer bowls, and ability to traverse a rotating pole, as well as a new score for postural and locomotor tail position. Furthermore, spatial navigation was tested in a water maze. The time points for the different tests are shown in Fig 1Down.



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  		Figure 1. Experimental design. MCA indicates middle cerebral artery.

The prehensile traction test evaluated muscle strength and equilibrium when the rat's forepaws were placed on a rope (scored as follows: 0=hangs on 0 to 2 seconds; 1=hangs on 3 to 4 seconds; 2=hangs on 5 seconds, no third limb up to rope; and 3=hangs on 5 seconds and brings rear limb up to rope). The total time the rats could hang on the rope was also recorded.16 17

For the sensorimotor integration test, the animals were placed on an elevated 15-cm-wide circular platform, and the fur was touched with a ballpoint pen at seven regions on each side of the body. For each region the extent of orientation was rated on a scale from 0 to 4 (0=no head orientation toward touch; 4=precise localization of the head and biting of pen).18

The inclined plane consisted of two rectangular plywood boards connected by a hinge allowing adjustment of the inclination. A rubber mat was fixed to the surface of the moveable board. The maximum angle of the inclination at which the rat could maintain its position was recorded.12

The amphetamine-induced circling behavior was tested in automated rotometer bowls.19 20 D-Amphetamine (1 mg/kg) was given intraperitoneally immediately before the test. The turning behavior was monitored over 90 minutes, and a motor asymmetry score was calculated as counterclockwise minus clockwise turns.

Coordination and integration of movement were tested on a rotating pole.21 The pole, 45 mm in diameter and 1.5 m in length, rotated alternately to the left or to the right with three or 10 turns per minute. Scoring was as follows: 0=the rat falls down; 1=the rat is unable to traverse the pole but does not fall down; 2=the rat falls down while attempting to cross the pole; 3=the rat jumps with both hind limbs together, apparently supporting the weak hind limb with the opposite strong limb; 4=the affected hind limb is used for less than 50% of the steps; 5=the rat crosses the pole with a few foot slips; and 6=the rat crosses the pole with no foot slips.

Because of the observation that the position of the tail varied markedly between individual rats when they traversed the pole, we designed a rat tail test, taking into consideration not only the postural and locomotor tail position but also the position of the body in relation to the pole. The performance of every rat was documented on video. Scoring was as follows: 1=tail hangs down and rat drags itself along the pole if at all able to cross; 2=tail winds around the pole and rat clings firmly to the pole while walking; 3=tail touches the pole and body is close to the pole while rat is walking; 4=tail is directed to the left (opposite the infarct) but does not touch the pole; and 5=tail is kept in midline, not touching the pole, and body is kept high above the pole.

Spatial navigation abilities were evaluated with the use of a Morris water maze.22 The maze consisted of a circular tank (120 cm in diameter and 45 cm deep) filled with room temperature water that was rendered opaque by the addition of powdered milk. The maze was located in a corner of a room with many external cues that were visible from within the pool and therefore available for orientation of the rats. To escape from swimming, the rats could climb a platform placed in one of the quadrants but hidden with its surface 2 cm below the water level. The rats were trained in the water maze for eight trials a day over 5 consecutive days. On each trial the rat was placed at one of the four starting positions and given 60 seconds to find the submerged platform and climb onto it. After 15 seconds of rest on the platform, the rat was placed at the next randomly predetermined starting point. The latency and the distance the rat swam to find the hidden platform and the swim speed were recorded by a computer-based video tracking system (Paul Fray Ltd). After the last trial on the fifth day, the platform was removed and the rat placed at one of the starting positions and allowed to swim freely for 60 seconds. During this period the swim path was plotted, and the time spent in each of the quadrants was recorded by the computer together with the number of crossings over concentric annuli with their center at the site where the platform would have been.

Tracer Injections, Perfusion, and Histology
The rats were anesthetized with methohexital 50 mg/kg IP for stereotaxic injections of neuronal tracers 18.5 weeks after grafting. The craniotomy was reopened, and 0.2 µL of a mixture composed of 10% biotinylated dextran amine (molecular weight, 10 000) and 2% Fluoro-Gold in distilled water was slowly injected into the presumed transplant. The rats were thereafter returned to their respective cages, leaving time for active transport of the tracers. Ten days later the rats were anesthetized with methohexital 50 mg/kg IP and transcardially perfused for 5 minutes with a solution of 4% paraformaldehyde and 0.1% glutaraldehyde in 0.15 mol/L Sørensen phosphate buffer (pH 7.4). The brains were then removed and soaked in a solution of 20% sucrose in Sørensen phosphate buffer. On the following day, when the brains had sunk as a result of tissue penetration by the cryoprotective sucrose, they were frozen in gaseous carbon dioxide and stored at -20°C until sectioning. The frozen brains were sectioned on a cryostat into four parallel series of 40-µm-thick coronal sections. Three series were collected on gelatin-coated slides, one of which was stained with toluidine blue for general cell staining and volumetric analysis of infarct size and thalamic atrophy. Another series was stained for acetylcholine esterase (AChE) according to the protocol of Hedreen et al23 to visualize ingrowing AChE-positive, host cholinergic fibers. The third series was left unstained, dehydrated, and mounted with Entellan (Merck 7960) for fluorescence microscopic analysis of Fluoro-Gold–labeled transplant and host neurons with fiber projections to the transplant injection sites. The fourth series was collected as free-floating sections in a cryoprotective solution containing polyethylene glycol and subsequently histochemically stained as previously described9 for biotinylated dextran amine–containing neurons and efferent graft to host brain connections.

Volumetric Estimates
The size of each cortical hemisphere was calculated by measuring the cross-sectional area on 15 toluidine blue–stained sections, approximately 1 mm apart, starting from anterior coordinate +3.7 mm in relation to bregma.24 The infarct volumes were calculated from the cross-sectional areas and the distance between the sections according to the Cavalieri principle,25 and the tissue loss was calculated as the difference between the intact hemisphere and the lesioned or lesioned and grafted cortex. The graft volumes were measured separately (see below) and not included in these measurements.

Using the same procedure,25 we estimated the thalamic volume from 15 cross-sectional areas of sections stained for AChE between anterior coordinates -0.92 and -4.16 in relation to bregma. The graft volume was determined in a similar manner from area measurements of every toluidine blue–stained section.

The image analyzing system used for the volume determinations consisted of a light board with constant light (Northern Light model B90, Imaging Research Inc), a video camera (CCD72, Dage MTI) fitted with a Nikon lens (f 55 mm), a digitizing unit attached to the video camera (Dage MTI), and a Macintosh IIsi computer equipped with a video card (Image Grabber, Neotech Ltd). The software Image Grabber 2.03 (Neotech Ltd) was used to capture the digitized images. For further processing we used Image/MG 1.44b (National Institutes of Health).

Statistical Analysis
Data from tests based on scoring systems are presented as median values with 25% upper and lower percentiles. The Kruskal-Wallis nonparametric ANOVA with a multiple comparison post hoc test at the 95% significance level was used for determination of differences between the groups. One-way parametric ANOVA with Scheffé's post hoc procedure at the 95% significance level was used to determine group differences in weight, infarct, and graft volumes and degrees on the inclined plane. The values are presented as mean±SD unless otherwise stated.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
There was no difference in weight between the groups; the increases in weight from preoperative values were 266±4 to 343±17 g, 262±4 to 346±13 g, and 262±8 to 347±18 g in lesioned but not transplanted rats, transplanted rats in a standard environment, and transplanted rats in an enriched environment, respectively. One control rat had no infarct, and one was found dead in its cage 4 days before the end of the experiment. Two transplanted rats in the standard environment and one rat in the enriched environment were excluded because they had no grafts. One transplanted rat in the enriched environment developed a skin abscess overlying the transplant and was given an overdose of anesthetics. The final analysis was accordingly based on 10 grafted and 10 nongrafted rats housed in an enriched environment and 6 grafted rats housed in a standard environment.

Graft Morphology and Connective Integration in Host Brain
The grafts were generally large (18.6±4.8 mm3 in rats housed in standard cages and 17.4±13.1 mm3 in rats in an enriched environment) and located at the bottom of the cortical infarct cavity, where they fused with the host brain parenchyma (Fig 2Down, left panel). Nissl stain of the grafts revealed typical pyramidal cells but no distinct lamination (Fig 2Down, right panel). In the AChE-stained sections, numerous AChE-positive fibers were seen to enter and fill the graft, but the density of fibers in the grafts was less than in the surrounding host neocortex. Fluorescence microscopy showed that the Fluoro-Gold deposits were confined to the grafts in 6 rats, resulting in numerous retrogradely labeled graft cells that clearly delineated the transplant from the host. Retrogradely labeled host neurons were also seen in the adjacent host cortex and in the host basal nucleus of Meynert, ventrobasal thalamic nucleus, and dorsal raphe nucleus (Fig 3Down). In the same animals, anterograde tracing with biotinylated dextran amine showed projections of fibers to the ipsilateral host neocortex, the dorsal striatum underlying the graft, and in a few cases the lateral part of the host thalamus. In the other brains, where the mixed Fluoro-Gold and biotinylated dextran amine injection included the host cortex, labeling of the normal corticipetal and corticifugal connections was observed.



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  		Figure 2. Left, Brain of a rat killed 20 weeks after a right distal middle cerebral artery occlusion followed by neocortical tissue block transplantation 7 days later. The transplant (Tp) is seen in the right frontoparietal region. Right, Nissl-stained coronal section. Bar=25 mm (left); bar=15 mm (right).



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  		Figure 3. Fluorescence micrographs of neurons retrogradely labeled with Fluoro-Gold. a, Many Fluoro-Gold–labeled cells are seen in the transplant (Tp) and several in the host (H). Broken line indicates host-transplant interface. b, Labeled cells in the host basal nucleus of Meynert. c, Labeled cells in the posterior thalamic nucleus. d, Labeled cells in the dorsal raphe nucleus. aq indicates cerebral aqueduct. Bar corresponds to 100 µm in panels a and c and 200 µm in b and d.

Infarct Volumes and Thalamic Atrophy
The loss of host cortical tissue in the right infarcted hemisphere did not differ between the groups (42.1±7.4, 42.5±13, and 42.6±8.2 mm3 for transplanted, transplanted plus enriched, and enriched control rats, respectively). In contrast, the volume of the posterior thalamus was significantly less reduced on both the infarcted and noninfarcted, contralateral side in the transplanted rats with enriched housing compared with the lesioned but not transplanted controls with the same enriched housing (Fig 4Down). The volume of the posterior thalamus of the transplanted rats kept in standard cages tended to be in between these groups, with no significant difference from either. The difference in thalamic atrophy in transplanted enriched and nontransplanted enriched rats is illustrated in Fig 5Down.



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  		Figure 4. Right and left thalamic areas at different anteroposterior levels 20 weeks after right middle cerebral artery occlusion with transplantation 1 week later. T indicates transplanted rats housed in standard laboratory cages; T+E, transplanted rats housed in an enriched environment; and E, control infarcted rats housed in an enriched environment. The thalamic volumes below the line on the right side are 30±3, 32±4, and 26±3 mm3 for T, T+E, and E, respectively. Corresponding values for the left intact side are 38±4, 40±5, and 36±2 mm3, respectively. *P<.05 for difference between T+E and E on both left and right sides (ANOVA with Scheffé's post hoc test).



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  		Figure 5. A brain from a transplanted rat housed in an enriched environment (T+E) has less thalamic atrophy than the brain from a control infarcted rat housed in the same enriched environment (E).

Behavior
Both grafted and nongrafted rats kept in the enriched environment performed significantly better than rats kept in standard cages in the prehensile traction test (Fig 6Down) and on the rotating pole (Fig 7Down). On the inclined plane this difference was significant only at 10 weeks postoperatively. In the rotometer test, transplanted rats in the enriched environment showed significantly less side asymmetry in circling after amphetamine injection in contrast to the two other groups, which rotated preferentially to the right side, ie, the side of the infarct (P<.05 for difference between transplanted enriched and control enriched rats). Furthermore, transplanted rats housed in an enriched environment had a significantly better postural and locomotor tail position than the other two groups (Figs 8Down and 9Down). The sensorimotor integration and the water maze performance did not differ between the groups.



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  		Figure 6. Prehensile traction score 11 weeks after a distal ligation of the middle cerebral artery. T indicates transplanted rats housed in standard laboratory cages; T+E, transplanted rats housed in an enriched environment; and E, control infarcted rats housed in an enriched environment. Maximal score (best performance) is 3 (for details, see text). Median and upper and lower 25% percentile values are shown. *Significantly different from the other two groups (Kruskal-Wallis nonparametric ANOVA with a multiple comparison post hoc test at the 95% significance level).



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  		Figure 7. The rotating pole test assessed the rat's ability to traverse a pole, rotating with 3 or 10 turns per minute, after distal ligation of the right middle cerebral artery. T indicates transplanted rats housed in standard laboratory cages; T+E, transplanted rats housed in an enriched environment; E, control infarcted rats housed in an enriched environment; and op, operation. Only median values are shown because the 25th percentile values are omitted for the sake of clarity. *P<.05 for difference from T; {dagger}P<.05 for difference from E (Kruskal-Wallis nonparametric ANOVA with a multiple comparison post hoc test at the 95% significance level).



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  		Figure 8. Rat tail and body position while the rat traverses a rotating pole. The highest score of 5 (top) was given for the best (normal) performance. Successively lower scores were given for worse performances, down to a score of 1 (bottom) (for details, see text).



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  		Figure 9. Tail and body position scores as defined in text and illustrated in Fig 8Up. Median and upper and lower 25th percentile values are shown. *Significantly different from T; {dagger}significantly different from T and E (Kruskal-Wallis nonparametric ANOVA with a multiple comparison post hoc test at the 95% significance level).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Our results are consistent with earlier data on environmental effects on functional outcome after an experimental brain infarction.12 17 21 26 An enriched environment can induce extensive chemical and anatomic alterations, including changes in cortical weight and protein content, dendritic branching, size of synaptic contact areas, transmitter content, and number and size of astrocytes in intact animals.27 28 29 A possible explanation of the improved performance is that the enriched environment stimulates brain plasticity after brain damage.

The postoperative enriched environment improved functional outcome in both transplanted and nontransplanted rats, but transplantation had the additional benefits of reversing the turning pattern in the rotometer test and improving tail and body posture. The muscles of the rat tail are involved in the control of both tail and body posture, and their motoneurons receive corticospinal inputs.30 31 32 Despite the consistent tail deviation, nontransplanted rats in the enriched environment performed as well as transplanted rats on the rotating pole, indicating that they had no problem compensating for the pathological posture.

The atrophy of the posterior thalamus, which contains major sensorimotor cortex relay nuclei, was significantly reduced in transplanted rats housed in the enriched environment compared with nongrafted infarcted rats in the same environment. The fact that thalamic sparing was significant only in infarcted rats that were both transplanted and housed in an enriched environment suggests a combined effect of the two. Fetal grafts can influence the host brain in several ways, including replacement of lesioned neuronal connections, provision of trophic support for host neurons that have lost their normal targets, and release of trophic factors that may facilitate plastic changes in the adjacent host brain.33 34

Efferent nerve connections from graft to host brain can be clearly demonstrated but are rather sparse after grafting to adult recipient brains, and graft projections have thus far not been shown to increase in animals housed in an enriched environment (Reference 99 and this study). After experimental brain infarcts, thalamic atrophy can be attenuated by intracisternal injections of basic fibroblast growth factor,35 indicating that actual innervation of a target is not necessary for neuronal rescue. Human fetal cortical xenografts transplanted to cortical cavities in immunosuppressed rats express nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 mRNA.36 There is also evidence for environmental regulation of brain trophic interactions,37 38 39 40 a regulation that appears to be quite complex. The currently available data are not easy to interpret, and different levels of environmental challenge to the animals may well have different effects on the developing graft and the lesioned and the intact adult brain. Accordingly, the actual mechanisms behind the combined beneficial effect observed in our study remain to be clarified.

The present results are to our knowledge the first indications that neocortical grafting can have a functional effect after brain infarction. Some partial41 or transient42 behavioral effects have been reported in smaller cortical aspiration lesions that are likely to have a less damaging effect on the surrounding tissue than brain infarction, in which excess release of excitotoxic transmitters and potentially harmful breakdown products from the necrotic tissue are likely to aggravate brain edema and substantially influence the surrounding brain tissue.43 The fact that we observed no effect of neural grafts if not combined with an enriched environment suggests that more attention should be paid to the environment in experiments, including grafting experiments aimed at restoring function after brain lesions.


*    Acknowledgments
 
This study was supported by grants from the Swedish Medical Research Council (project 14X-4968), the Bank of Sweden Tercentenary Foundation, the King Gustaf V and Queen Victoria Research Foundation, the Swedish Association for the Neurologically Disabled, the Swedish Stroke Foundation, the Lundbeck Foundation, the Danish Medical Research Council, and the Danish State Biotechnology Program.

Received February 25, 1997; accepted March 12, 1997.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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