1 Department of Morphology, University of Geneva Medical School, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland, 2 Department of Neuropharmacology, University of Geneva Medical School, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland, 3 Department of Psychopharmacology, University of Geneva Medical School, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland, 4 IBCM, University of Lausanne, Switzerland
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: behavior, evoked potentials, metabolic activity, mouse model, neural cell adhesion molecule, somatosensory cortex
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In an attempt to develop a clinically relevant analysis of cortical recovery in animals, we recently introduced an epicranial approach for multi-electrode recording of vibrissal sensory evoked potentials (SEP) in the mouse (Troncoso et al., 2000). The vibrissaebarrel-field circuit is of particular interest in mice. Mystacial whiskers are sensitive tactile organs that selectively activate a predictable area, the barrel in the somatosensory cortex (Woolsey and Van der Loos, 1970
). The topographic disposition of barrel-like structures in this cortical region obeys the same arrangement as the vibrissae on the mystacial pad. Due to this modular somatotopic characteristic, this sensory system has become one of the major models for assessing the cortical reorganization. Using an epicranial multi-array recording system, we showed that SEP could be repeatedly assessed over different cortical areas in the same animal (Troncoso et al., 2000
). By applying this approach to mice, we report here that the time course of deficit and recovery produced by a focal cortical injury can be monitored over time and that this recovery process is correlated with corresponding changes in cortical metabolic activity and behavior. Application of this model to NCAM knockout mice reveals major deficits in the recovery process. This mouse model of functional recovery opens therefore new possibilities to investigate the cellular, molecular and genetic determinants of cortical reorganization triggered by a focal lesion.
![]() |
Materials and Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A total number of 38 male C57BL/6 mice aged 1420 weeks and weighing 2730 g were individually housed with water and food ad libitum at 12 h light/12 h dark cycle and removed from the housing environment only on experimental days. NCAM-deficient mice have been described previously (Cremer et al., 1994). All analyses were performed on a C57BL/6J background (five backcrosses) in mice between 3 and 6 months of age. All experimental procedures were in accordance with Swiss laws, previously approved by the Office Vétérinaire Cantonal of Geneva.
Lesions
Cortical injuries were performed under general anesthesia (pentobarbital 60 mg/kg, with an additional dose of 20 mg/kg if it was necessary) and sterile conditions. The skull was exposed and a small hole of 0.5 mm was made with a stereotaxic micromotor drill over the left hemisphere 1.5 mm posterior to the bregma and 2.3 mm lateral to the midline. These coordinates targeted the barrel. Through the hole on the skull, a solid needle with 0.5 mm diameter was introduced in the cortex (1 mm deep from the surface) with a rotation rate of 20 000 r.p.m.; finally the skin was closed with surgical suture (Safil® 5/0). There was no evident morbidity associated with this injury. In the control (sham operated) group, injury was made outside the barrel cortex 2 mm posterior to the bregma and 2.0 mm lateral to the midline.
Histological Control of Cortical Injury
The localization and extension of the lesion were histologically confirmed on cytochrome oxidase or Nissl-stained sections. Mice were killed 2 or 6 weeks after the injury with an overdose of pentobarbital and their brains were removed and fixed by chilled (4°C) 4% paraformaldehyde. Brains were kept in the same fixative for 24 h and then dipped in a 30% sucrose for another 24 h. For cytochrome oxidase reaction, cerebral hemispheres were frozen and serially sectioned at 40 µm tangential to the pial surface. Sections were treated for reaction according to a protocol described by Wong-Riley (1979). Alternatively, 20 µm thick coronal sections were cut with a cryostat and stained with cresyl violet. Injury of all mice was histologically verified
SEP Recordings
These experiments were conducted on two control groups of eight animals each (sham operated, and barrel cortex injury) and two groups of four NCAM mutant animals each (sham operated and injured). SEP were recorded in both groups three times (before and 2 and 6 weeks after cortical injury). Epicranial SEP recordings were performed as described previously (Troncoso et al., 2000). Briefly, the mouse head was placed in a stereotaxic frame under pentobarbital anesthesia (60 mg/kg i.p.) and loss of eye blink and withdrawal reflexes were observed for the assessment of anesthesia depth. Body temperature was maintained at
37°C. An array of five stainless steel electrodes (0.45 mm in external diameter and 2 cm length), were positioned over the skull, in a row with the following coordinates related to bregma: AP +1/L 1.5, AP 0/L 2.0, AP 1/L 2.5, AP 2/L 3.0 and AP 3/L 3.5 (distances in millimetres). Series of 10 electromechanical stimuli driven by a computer-controlled signal were applied unilaterally at 10 min intervals to all whiskers at a distance of 10 mm from the face, with a vertical excursion of 300 µm in the dorso-ventral direction and an inter-stimulus-interval of 3 s. Signals were amplified (x10 000) and filtered (high pass 4 Hz, low pass 300 Hz), then hooked up and digitally converted (16 bits, 2 kHz with triggered scan) and stored for post-hoc analysis. At the end of the recordings, the skull was carefully cleaned and the skin closed with surgical suture.
Data were then processed by statistical elimination of responses that fulfilled the rejection criteria (to be beyond 2 standard deviation from the original mean). The mean of three series obtained after signal processing was calculated for each experimental condition. The values obtained by the three series of stimulation were very constant. The peak positive and negative values between 10 and 30 ms post-stimulus were measured. Results are expressed as mean ± SEM of voltage amplitude (µV) and latency (ms).
Assessment of Metabolic Activity by 2 Deoxy-D-glucose (DG) Uptake
Three control groups of four animals each (before and 2 and 6 weeks survival after lesion) and three groups of NCAM knockout animals of four animals each (before and 2 and 6 weeks survival after lesion) were used for deoxy-D-glucose (DG) experiments. These animals were recorded before and 2 or 6 weeks after lesion. At the end of the last trial of SEP recording and before the recovery from anesthesia, all whiskers excepting , E1 and E2 were bilaterally trimmed. Then animals were food-deprived overnight. On the next day, animals received a single injection of DG (167 nCi/kg i.p. of [1-14C]deoxy-D-glucose MC355S; Moravek Biochem, Brea, CA), as described previously (Welker et al., 1992
) and bilateral
, E1 and E2 barrels were spontaneously activated during 45 min, by stimulation of the corresponding untrimmed whiskers. At the end of the experiment, animals received a lethal dose of pentobarbital (i.p.) and were perfused transcardially (cold formalin 3.3%, 0.1 M phosphate buffer, for 10 min). Then brains were removed and immediately frozen on dry ice. Serial 20 µm thick sections were cut in a cryostat in a plane tangential to the pial surface overlying the barrel cortex. Design of experimental groups for SEP and DG uptake analysis is shown in Table 1.
|
To localize the site of lesion, the outlines of barrels in layer IV were drawn from Nissl-stained sections using a camera lucida. The corresponding autoradiograms were digitized with a digital video camera (Sony TRV-900) mounted on a macroscope. The images obtained were aligned with the images of the drawings. Then, three consecutive Nissl-stained sections where the D or E row barrels were clearly identifiable, were considered as representative for layer IV, with two for layer II/III and two for layer V/VI (10 sections above and 10 sections under those from layer IV, respectively). The corresponding optical density of stimulated and inactive areas was measured with image analysis software (NIH Image). Digitized autoradiograms were calibrated using the co-exposed C14-microscales (RPA504; Amersham, UK). At 200 µm from the center of the lesion, an area situated over the stimulated barrels in the intact tissue was measured (400 x 400 µm, black square in Fig. 4A). Another similar area over inactive barrels, 600 µm away from the injury (gray square in Fig. 4A), was considered as a reference for background activity. The same procedure was applied to the contralateral non-injured cortex, where equivalent areas from stimulated (over E1 barrel) and inactive barrels (over C1) were measured. The ratio between stimulated/inactive areas was compared between injured and normal barrel cortex. The results are expressed as a percentage of activity related to uninjured barrel cortex.
|
Post-hoc analysis with unpaired t-test was used to compare the relative DG uptake between groups 2-w and 6-w of experiment III. One-way analysis of variance (ANOVA) followed by paired t-test corrected for multiple comparisons (Dunnett) was performed where the time course after cortical injury was assessed (GCt performance and SEP monitoring).
Behavioral Assessment by the Gap-crossing Test (GCt)
The gap-crossing test was carried out as adapted to mice by Barnéoud et al. (1991) with the following modifications: mice were placed on a small platform (6 x 6 cm) and trained to cross spontaneously to a transparent tube (54 mm in inner diameter, 12 cm length, built in transparent acrylic), without food reward; during the training period (2 weeks before the test), the distance from the platform to the tube was incremented by steps of 0.5 cm, from 3 to 6 cm. Whiskers were always trimmed to the skin surface on one side and mice were not blinded; vibrissa sensory function on the other side was sufficient to limit the performance. Trials were recorded with a video camera (Sony CCD-TRV69E) and the maximum distance crossed by each animal was measured. Video recordings allowed for precisely measuring the time spent to cross the gap and to observe the different strategies adopted.
Two groups of 10 mice each were tested. In the first group, five mice with all left whiskers trimmed, the innervation of right mystacial pad was blocked with local anesthesia (bupivacaine 0.5%, 100 µl, s.c.), while the five control mice received 100 µl,.NaCl (9%) s.c. In the second group of 10 mice, animals were trained for a period of 2 weeks and the maximum distance that mice could cross was assessed before and after injury. Trials with video recordings were carried out before and 1, 2 and 4 weeks after a cortical lesion similar to that described above. All animals were injured and in all mice all whiskers but three (, D1 and E1), corresponding to those represented at the injured site, were trimmed. In the test group (n = 5), the spared whiskers were contralateral to the lesion, while in the control group (n = 5) the spared whiskers were ipsilateral to the injured cortex.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In order to produce a small localized lesion in the barrel cortex a focal lesion was performed with coordinates that targeted the barrel in the left hemisphere. The injured area extended through the entire cortical thickness down to the subcortical white (Fig. 1A). Most of the lesions produced a superficial injury to the subcortical white matter. On tangential cytochrome oxidase stained sections, the lesion was centered on the
barrel and often extended into neighboring barrels (D1, E1, E2; Fig. 1B). The injured area shrank over the first 2 weeks after the lesion and by 6 weeks post-lesion, it corresponded to a discreet glial scar of
200 µm (Fig. 1C). Although there was some variability in the extent and position of the lesion, no major difference in the measured physiological and behavioral data could be traced to apparent differences in lesion placement and size. The lesion did not result in any apparent changes in food intake and body weight and caused no mortality.
|
To investigate whether and to what extent focal lesions affected the global activity of the barrel cortex, we applied multielectrode epicranial recordings. Sensory evoked potentials were elicited by stimulating all contralateral whiskers and recorded using an array of five electrodes placed in line at 1 mm distance from each other (Fig. 2B). The typical responses recorded over the barrel cortex before and 2 and 6 weeks after injury are shown in Figure 2A. Before lesion, the characteristic biphasic response was composed of a rapid positive peak (P1; mean delay of 1314 ms) followed by a negative wave (N1; mean delay of 2527 ms). At 8 ms there is another smaller positive peak that was more clearly distinguishable from P1 after the lesion. These short latency responses concur with those recorded earlier in the rat somatosensory cortex (Di and Barth, 1991
; Seo, 1992
). An almost complete absence of P1 as well as a shorter N1 latency was typically observed 2 weeks after injury. However, a clear recovery was observed 6 weeks post lesion. A detailed quantitative analysis of the responses was performed using a group of 12 injured mice. To quantify data, we used as an index, the peak-to-peak amplitude (P1/N1), calculated as the difference between P1 and N1 values. SEP recorded in absence of injury showed that contralateral stimulation evoked similar responses in the left (LH) and right (RH) hemispheres. Mean P1/N1 values were 84.5 ± 7.9 and 89.9 ± 8.0 µV for LH and RH, respectively, while P1 and N1 latencies were 13.6 ± 0.4 and 26.7 ± 0.9 ms at LH and 13.1 ± 0.5 and 25.9 ± 1.2 ms at RH (Fig. 2C). Since there was no evident asymmetry in amplitude and latency, the right uninjured hemisphere was considered as control and all values measured in the left, injured cortex normalized to right values. Two weeks after cortical injury P1/N1 amplitude decreased significantly from 104.7 ± 15.6 to 29.7 ± 4.9% (n = 8, P < 0.001). Also, N1 latency decreased from 98.5 ± 1.8 to 79.1 ± 5.4% (P < 0.01). However, P1 latency did not change significantly (99.7 ± 1.3 versus 96.7 ± 6.5%). Records performed 6 weeks after the injury showed a partial reversion of these changes: P1/N1 amplitude recovered to 88.4 ± 12.4% and N1 latency to 94.4 ± 5.8% (n = 8, 1 < 0.01, for comparison between recordings performed 2 and 6 weeks after injury; t-test corrected for multiple comparisons). In another group of eight mice, a similar lesion was made outside the barrel cortex. In this group, P1/N1 amplitude and N1 latency values in the recordings performed before and 2 and 6 weeks after the cortical injury, showed no significant changes (Fig. 2C).
|
[14C]2-DG Uptake
We investigated whether the recovery process demonstrated by SEP recording could be confirmed using quantitative [14C]2-deoxyglucose (DG) autoradiography. To do this, we measured DG uptake in response to whisker activation in injured mice 2 and 6 weeks after lesion. In these experiments, all whiskers except three (, E1 and E2) were clipped on both sides, so as to make sure that activity was evoked only in the area of the lesion. Following DG injection, animals were allowed to explore a cage during 45 min to obtain spontaneous activation of intact whiskers (see Material and Methods). In tangential sections from control mice, the metabolic uptake occurred in areas that corresponded to the three stimulated barrels (Fig. 3). For the quantitative analyses, the metabolic activity of stimulated barrels was normalized to that of an inactive reference region (C1; Fig. 4A). In the right, uninjured hemisphere, this value, expressed as a percentage of a reference barrel, was very constant before and 2 weeks (33.8 ± 3.4%, n = 3) and 6 weeks (30.4 ± 3.5%, n = 3) after injury (Fig. 4B). Therefore we considered these values as control for comparisons with changes in relative DG uptake in the injured barrel cortex. The effect of injury on metabolic uptake was assessed in the intact barrels adjacent to the lesion. The quantitative analysis indicated that DG uptake was significantly (P < 0.05) lower in the injured than in intact barrel cortex in all layers studied 2 weeks after lesion. This deficit in metabolic uptake partially recovered 6 weeks after lesion; the difference between the 2 and 6 weeks groups being significant (P < 0.05).
|
An important question with regard to the recovery of electrical and metabolic activity in the barrel cortex concerned the possibility that this process could have functional consequences. To address this issue, we used a gap-crossing test to assess the functional importance of whisker-mediated information. In these experiments, whiskers were clipped on the left side and right vibrissae-dependent performance was analyzed by measuring the size of the gap that the mouse was capable of crossing using its whiskers. Infiltration of mystacial pad with local anesthetics (on one side and saline on the other; see Fig. 5) was used to test the reliability of gap-crossing task. Figure 5 shows that local anesthesia in the right mystacial pad produced a significant (P < 0.01) decrease in the performance of animals compared to the control saline injected group. The control group with local anesthesia on the trimmed side did not show any decrease of the performance in the task. Injury in the left barrel cortex, however, resulted in a significant deficit in right vibrissae-dependent gap-crossing task 1 week after the injury (6.8 ± 0.14 versus 6.0 ± 0.25 cm, P < 0.01). Nevertheless, animals were always able to make the movements required to cross the gap. Mice made use of their nose tips or paws to gauge the distance to cross the gap in the dark. The performance then recovered and no significant deficit was detected when mice were tested 4 weeks after the injury. Clipping whiskers on the right side abolished the functional recovery (not shown), indicating that this phenomenon depended on the intact vibrissaebarrel cortex pathway. The control group, with spared whiskers ipsilateral to the lesion (unaffected cortical representation), did not show any deficit 1 week after the injury. In all these experiments, the sensory deficit, whether produced at the peripheral or cortical level, corresponded to a distance (0.70.8 cm) that is detected by whiskers.
|
Since previous research had identified a key role for NCAM in different processes that could participate to functional recovery (see review in Kiss et al., 2001), we decided to take advantage of NCAM knockout mice lacking all isoforms of NCAM to evaluate the recovery process using this model. As previously reported (Cremer et al., 1994
), NCAM knockout mice exhibit a reduced size of the olfactory bulb, but no other identified abnormalities in the size and organization of the central nervous system. On Nissl-stained sections, the rest of the brain displayed a normal cytoarchitectonics. The cerebral cortex had a typical six-layer organization and on tangential cytochrome oxidase-stained sections we observed a normal barrel pattern (not shown). Finally, the whisker pad in wild type and mutant animals showed no difference. The histological appearance of the lesion and the subsequent repair had the same characteristics in wild type and mutant animals. In a group of four animals, SEP responses were recorded before and 2 and 6 weeks after the lesion. As illustrated in Figure 6, SEP responses showed a similar deficit in control and mutant animals 2 weeks after the lesion. However, after 6 weeks, almost no recovery was perceptible in transgenic mice: the positive and negative peaks remained essentially unchanged. Overall, the peak-to-peak amplitude obtained by subtraction of the voltages measured at the times of the positive and negative peaks showed only
10% recovery, which is in marked contrast with what was observed in wild type animals (Fig. 6C). Similarly, measurement of DG uptake confirmed a reduced recovery of metabolic activity 6 weeks after the lesion. Figure 7 illustrates the level of uptake observed in an NCAM knockout mouse before and 2 and 6 weeks after a lesion made in the region of the
barrel. While some activity is taken over by the adjacent barrels, the recovery at 6 weeks is significantly less than in control animals (compare with Fig. 4). A quantitative analysis (Fig. 7B) indicates that the level of metabolic activity recovered in the adjacent barrels is significantly lower in NCAM knockout mice than in control animals both 2 and 6 weeks after the lesion. These results thus clearly indicate that functional recovery is deficient in the NCAM mutant animal. Whether this defect also resulted in behavioral deficits could unfortunately not be tested, because, surprisingly, NCAM knockout mice used a different strategy than wild type animals in the gap-crossing test: they jumped over the gap rather than extending one leg. The reasons for this difference are unknown, but this prevented comparison between control and transgenic mice.
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In these studies, activity in the barrel cortex was analyzed by recording potentials evoked by whisker deflection using an epicranial multielectrode recording system (Troncoso et al., 2000). These surface potentials are thought to reflect the activation of apical dendrites of thousands of pyramidal cells sharing architectural and temporal coherence and generating post-synaptic activity. Intra-cortical laminar recordings of evoked field potentials in the rat barrel cortex have established that the primary responses of the surface SEP complex are produced by synchronized activation of both supra- and infra-granular pyramidal cells (Di et al., 1990
). In the current study, SEP recordings were performed after deflection of all contra-lateral whiskers in order to evaluate the impact of a small focal lesion on the global activity of the barrel cortex. These recordings, made 2 weeks after injury, disclosed a measurable deficit that involved mainly the (first) main positive peak of the SEP complex, occurring
1314 ms after the vibrissae were mechanically stimulated. This positive peak of the SEP complex most likely reflects intra-cortical integrative processes (Di and Barth, 1991
). The present results indicate that a focal lesion of a few barrels markedly affected this integration, making it an interesting tool to monitor recovery. It is of interest that this peak is preceded by an earlier and lower amplitude positive response (occurring at a latency of
8 ms). This earliest positive signal is most likely due to direct thalamocortical activation and, as illustrated in Figure 3, was not significantly modified after the lesion upon stimulation of all contra-lateral whiskers. Importantly also, spatiotemporal analyses indicated that the deficit and recovery observed 4 weeks later were restricted to the barrel cortex. No changes of activity were observed in the somatomotor cortex. Together, these results indicate therefore that a focal injury to the barrel cortex is associated with a loss of the cortical activity evoked by stimulation of all contra-lateral whiskers and a recovery process that take place within a few weeks.
In agreement with the results of previous studies (Glassman, 1971), the present data are consistent with and support the interpretation that functional recovery may take place due to a reorganization of cortical activity in the regions around the lesion. The lesion-induced SEP deficit was paralleled by a hypo-metabolism (28% decrease) detected by stimulus-induced DG uptake in the region surrounding the lesion. Similarly also, the recovery specifically occurred in the barrels adjacent to the lesion within the next 4 weeks. These observations are also consistent with previous reports showing dynamic changes in the functional representation of whiskers after focal lesions. Schiene et al. (1999
) demonstrated in a rat model that photo-chemically induced ischemic lesions resulted in an enlargement of cortical vibrissa representation in the surrounding cortical area. They attributed the expansion of the activated area to a decreased GABA-ergic inhibition that facilitates a remapping of the cortical representation in neighboring brain areas. Similar changes in representation area of whiskers after kainate lesions were detected using repeated optical imaging (Nguyen et al., 2000
). These results indicate that dynamic changes in juxtalesional areas could play an important role in remapping of cortical representation. In this regard, lesion studies are in agreement with earlier publications showing expansion or retraction of whisker cortical maps after activation (Polley et al., 1999
) or inactivation by peripheral deafferentation (Silva et al., 1996
; Bronchti et al., 1999
; Kossut and Juliano, 1999
). In contrast to small focal lesions, however, larger injuries appear to produce persistently depressed metabolic activity in adjacent regions (Dunn-Meynell and Levin, 1995
; Passineau et al., 2000
).
Interesting information added by this study is that the small deficit and recovery in cortical activity had functional consequences at the behavioral level. Using the gap-crossing test we could find a correlated deficit and recovery of performance. This test is sensitive and clearly depended upon a functionally intact vibrissaesomatosensory cortex pathway, as both anesthesia of the vibrissae and lesion of barrels resulted in behavioral deficit. Recovery of behavioral performance took place within 4 weeks, a time course very consistent with those found by previous studies using the gap-crossing test and diverse lesion models (Hutson and Masterton, 1986; Barnéoud et al., 1991
; Pazos et al., 1995
). Also, the time course of behavioral recovery closely corresponded to that of functional cortical activity (present study). A simple explanation for this observation could be a reorganization of whisker representations in the barrels adjacent to the lesion, although others factors, such as learning of new strategies to cross the gap, cannot be excluded. Similar conclusions were reached by other authors (Hutson and Masterton, 1986
) who suggested that destruction of the barrel may impair a higher-order integration necessary for a complex task such as sensory-guided movement and that the motor system involved in gap crossing might require sensory input from the somatosensory cortex. Studies in animal models and human data suggest that small lesions in the motorcortex or in the somatosensory cortex recover from the ipsilateral cortex adjacent to the lesion, whereas large lesions recover from the contralateral cortex. (Jenkins and Merzenich, 1987
; Witte et al., 2000
). Human data also indicate that a new lesion in the surround of the lesioned cortex abolishes previous recovery (Jenkins and Merzenich, 1987
; Witte et al., 2000
). It would be of particular interest to test in our model if lesions of the adjacent cortex 6 weeks after the first lesion would affect functional recovery.
The present model also opens the way to analyze the cellular and molecular mechanisms underlying the recovery. Several possibilities have been considered. One involves the resolution of acute pathological mechanisms such as edema, vascular perturbation and excitotoxicity. These events, however, are thought to be at least partially resolved by 2 weeks after the lesion. Another mechanism contributing to recovery could be a gradual reversal of diaschisis, a temporal suppression of surrounding and remote cortical tissues after focal lesions (Witte, 1998). The effect of diaschisis has been substantiated by recent metabolic studies showing a persistent hypoactivity in perilesional areas (Schiene et al., 1999
; Passineau et al., 2000
). Finally, growth mechanisms and functional reorganization of cortical networks could also account for the take over of function (vicariation of function) of the damaged area by adjacent or remote areas (Witte, 1998
). This process is likely to be complex and involve several cellular and molecular events, including a modulation of the expression of receptors (Schiene et al., 1996
), axonal sprouting and new synapse formation (Stroemer et al., 1993
). The use of transgenic models could reveal of interest to distinguish between all these possibilities.
The experiments with the NCAM knockout mice demonstrate the interest of this recovery model to identify, through the use of transgenic animals, the role of candidate molecules in functional recovery. While the functional organization of the whisker-barrel system in WT and NCAM mutant animals displayed no apparent differences, the functional recovery 6 weeks after the lesion was significantly reduced. This conclusion was reached through the use of epicranial SEP recordings and analyses of metabolic activity. The precise mechanism of the deficient recovery in the mutant mice remains unknown. It is of particular interest that NCAM/PSA-NCAM has been localized in synapses and that long-term synaptic potentiation (LTP) is impaired in CA1 synapses of the hippocampus in NCAM knockout animals (Muller et al., 1996). It is thus possible that an altered synaptic plasticity in cortical circuits underlies the observed deficit in functional recovery. Alternatively, the absence of NCAM during development could results in a modified organization of cortical circuits that could lead to reduced plasticity and capacity to reorganize after a lesion. Clearly, further studies involving intra-cortical recordings and analyses of the synaptic organization of the barrel cortex will be required to verify these hypotheses.
![]() |
Conclusions |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Notes |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Address correspondence to J.Z. Kiss, Department of Morphology, University of Geneva Medical School, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland. Email: jozsef.kiss{at}medecine.unige.ch
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Becker CG, Artola A, Gerardy-Schahn R, Becker T, Welzl H, Schachner M (1996) The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation. J Neurosci Res 45:143152.[CrossRef][ISI][Medline]
Bronchti G, Corthesy ME, Welker E (1999) Partial denervation of the whiskerpad in adult mice: altered patterns of metabolic activity in barrel cortex. Eur J Neurosci 11:28472855.[CrossRef][ISI][Medline]
Buonomano DV, Merzenich MM (1998) Cortical plasticity: from synapses to maps. Annu Rev Neurosci 21:149186.[CrossRef][ISI][Medline]
Cremer H, Lange R, Christoph A, Plomann M, Vopper G, Roes J, Brown R, Baldwin S, Kraemer P, Scheff S (1994) Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367:455459.[CrossRef][ISI][Medline]
Cremer H, Chazal G, Carleton A, Goridis C, Vincent JD, Lledo PM (1998) Long-term but not short-term plasticity at mossy fiber synapses is impaired in neural cell adhesion molecule-deficient mice. Proc Natl Acad Sci USA 95:1324213247.
Di S, Barth DS (1991) Topographic analysis of field potentials in rat vibrissa/barrel cortex. Brain Res 546:106112.[CrossRef][ISI][Medline]
Di S, Baumgartner C, Barth DS (1990) Laminar analysis of extracellular field potentials in rat vibrissa/barrel cortex. J Neurophysiol 63:832840.
Dunn-Meynell AA, Levin BE (1995) Lateralized effect of unilateral somatosensory cortex contusion on behavior and cortical reorganization. Brain Res 675:143156.[CrossRef][ISI][Medline]
Geschwind N (1985) Mechanisms of change after brain lesions. Ann N Y Acad Sci 457:111.[ISI]
Glassman RB (1971) Recovery following sensorimotor cortical damage: evoked potentials, brain stimulation and motor control. Exp Neurol 33:1629.[ISI][Medline]
Hutson KA, Masterton RB (1986) The sensory contribution of a single vibrissas cortical barrel. J Neurophysiol 56:11961223.
Jenkins WM, Merzenich MM (1987) Reorganization of neocortical representations after brain injury: a neurophysiological model of the bases of recovery from stroke. Prog Brain Res 71:249266.[Medline]
Kiss JZ, Troncoso E, Djebbara Z, Vutskits L, Muller D (2001) The role of neural cell adhesion molecules in plasticity and repair. Brain Res Rev 36:175184.[ISI][Medline]
Kossut M, Juliano SL (1999) Anatomical correlates of representational map reorganization induced by partial vibrissectomy in the barrel cortex of adult mice. Neuroscience 92:807817.[CrossRef][ISI][Medline]
Muller D, Wang C, Skibo G, Toni N, Cremer H, Calaora V, Rougon G, Kiss JZ (1996) PSA-NCAM is required for activity-induced synaptic plasticity. Neuron 17:413422.[ISI][Medline]
Nguyen TT, Yamamoto T, Stevens RT, Hodge CJ Jr (2000) Reorganization of adult rat barrel cortex intrinsic signals following kainic acid induced central lesion. Neurosci Lett 288:58.[CrossRef][ISI][Medline]
Passineau MJ, Zhao W, Busto R, Dietrich WD, Alonso O, Loor JY, Bramlett HM, Ginsberg MD (2000) Chronic metabolic sequelae of traumatic brain injury: prolonged suppression of somatosensory activation. Am J Physiol Heart Circ Physiol 279:H924H931.
Pazos AJ, Orezzoli SL, McCabe PM, Dietrich WD, Green EJ (1995) Recovery of vibrissae-dependent behavioral responses following barrelfield damage is not dependent upon the remaining somatosensory cortical tissue. Brain Res 689:224232.[CrossRef][ISI][Medline]
Polley DB, Chen-Bee CH, Frostig RD (1999) Varying the degree of single-whisker stimulation differentially affects phases of intrinsic signals in rat barrel cortex. J Neurophysiol 81:692701.
Schiene K, Bruehl C, Zilles K, Qu M, Hagemann G, Kraemer M, Witte OW (1996) Neuronal hyperexcitability and reduction of GABAA-receptor expression in the surround of cerebral photothrombosis. J Cereb Blood Flow Metab 16:906914.[ISI][Medline]
Schiene K, Staiger JF, Bruehl C, Witte OW (1999) Enlargement of cortical vibrissa representation in the surround of an ischemic cortical lesion. J Neurol Sci 162:613.[CrossRef][ISI][Medline]
Seo ML (1992) Effect of environmental complexity on the latency of cortical vibrissa potentials. Dev Psychobiol 25:6776.[ISI][Medline]
Silva AC, Rasey SK, Wu X, Wall JT (1996) Initial cortical reactions to injury of the median and radial nerves to the hands of adult primates. J Comp Neurol 366:700716.[CrossRef][ISI][Medline]
Stroemer RP, Kent TA, Hulsebosch CE (1993) Acute increase in expression of growth associated protein GAP-43 following cortical ischemia in rat. Neurosci Lett 162:5154.[CrossRef][ISI][Medline]
Troncoso E, Muller D, Czellar S, Kiss JZ (2000) Epicranial sensory evoked potential recordings for repeated assessment of cortical functions in mice. J Neurosci Meth 97:5158.[CrossRef][ISI][Medline]
Welker E, Rao SB, Dorfl J, Melzer P, van der Loos H (1992) Plasticity in the barrel cortex of the adult mouse: effects of chronic stimulation upon deoxyglucose uptake in the behaving animal. J Neurosci 12:153170.[Abstract]
Witte OW (1998) Lesion-induced plasticity as a potential mechanism for recovery and rehabilitative training. Curr Opin Neurol 11:655662.[CrossRef][ISI][Medline]
Witte OW, Bidmon HJ, Schine K, Redecker C, Hagemann G (2000) Functional differentiation of multiple perilesional zones after focal cerebral ischemia. J Cereb Blood Flow Metab 20:11491165.[ISI][Medline]
Wong-Riley M (1979) Changes in the visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry. Brain Res 171:1128.[CrossRef][ISI][Medline]
Woolsey TA, Van der Loos H (1970) The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res 17:205242.[CrossRef][ISI][Medline]