Department of Neurophysiology, Nencki Institute, 3 Pasteur Street, 02-093 Warsaw, Poland
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Abstract |
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Introduction |
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The adult somatosensory cortex retains its ability to alter functional properties of neurons (for review see Kaas, 1991; Weinberger, 1995; Buonomano and Merzenich, 1998). Cortical body maps can be modified by elimination of sensory input or by behavioral training involving stimulation of cutaneous mechanoreceptors. We have found that denervation of selected rows of vibrissal follicles resulted in alteration of the functional cortical representation of the spared vibrissae, as revealed by 2-deoxyglucose (2DG) mapping of the barrel cortex (Siucinska and Kossut, 1994). We have also demonstrated that sensory conditioning, where stroking a selected row of vibrissae was paired with an aversive stimulus, increased the functional cortical representation of the trained row in cortical layer IV of the barrel field (Siucinska and Kossut, 1996
).
Plasticity of cortical representations triggered by vibrissectomy seems to depend upon NMDA receptor activation. We have previously found that, in adult mice, the blocking of NMDA receptors by APV significantly reduced cortical plastic changes seen after partial denervation of vibrissal follicles (Jablonska et al., 1995). Recently, the role of NMDA receptors in plasticity of adult barrel cortex partially deprived of sensory input was confirmed by Rema et al. (1998). In this study we investigated whether plastic changes of cortical functional representation in the barrel field of adult mice, induced by a short-lasting classical conditioning procedure, depend on the activation of NMDA receptors. One way to block NMDA receptors is to use an implant of slow-release polymer Elvax impregnated with APV. This procedure, introduced by Constantine-Paton and colleagues (Cline et al., 1987
) in the study of the frog tectum, was successfully applied to investigations of developmental plasticity in the barrel cortex (Schlaggar et al., 1993
; Fox et al., 1996
). In our experiments, the blockade of NMDA receptors introduced by ElvaxAPV implants was only partial. This did not disrupt the normal activation of the cortex, which was a problem in several previous studies (Kano et al., 1991
; Rauschecker, 1991
; Kasamatsu et al., 1998
).
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Materials and Methods |
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Swiss mice, 48 weeks old (n = 26), from the Nencki Institute colony were used. They were housed under standard conditions with a 12 h/12 h light/dark cycle and free access to water and food. They were cared for and surgically handled in accordance with The European Communities Council Directive (86/609/EEC) and NIH guidelines.
Four experimental groups were examined: one to estimate activitydependent 2DG uptake in control animals (n = 4); the second to estimate the effectiveness of the blocking of NMDA receptors by ElvaxAPV (n = 4) in control mice; the third to estimate changes of 2DG uptake in control mice with ElvaxAPV implants (n = 4); the fourth to estimate the effect of classical conditioning. This last group was composed of control trained mice (n = 4), trained mice implanted with ElvaxPBS (n = 4) and trained mice (n = 7) implanted with ElvaxAPV.
Elvax Preparation
The preparation of Elvax was based on the method of Simon et al. (1992). Elvax beads (Du Pont) were washed in distilled water followed by 95% and 100% ethanol. Washed Elvax was dissolved in 10% methylene chloride and 2% Fast Green was added. DL-2-Amino-5-phosphonovaleric acid (APV) was added to one portion of Elvax solution to obtain a final concentration of 50 mM, and stirred until homogenous. The other portion of Elvax was soaked with PBS instead of APV. The prepared Elvax was frozen and kept at 70°C overnight. Slabs of Elvax were cut into 60 µm thick sections on a cryostat and stored until use.
Elvax Implantation
One day before the start of training with classical conditioning procedures, the mice were anesthetized with Nembutal (35 mg/kg, i.p.). Sheets (~2 mm2) of Elvax, with or without APV, were placed subdurally on the surface of the cortex in posteromedially to the barrel field (Fig. 1), contralateral to the stimulated row of vibrissae during conditioning (as described by Jablonska et al., 1995). After implantation the bone was replaced and the skin glued with cyanoacrylate. In some animals the Elvax implants damaged the cortical surface or were placed incorrectly. Such brains were not taken to further analysis.
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All training procedures were performed as described previously by Siucinska and Kossut (1996). Mice were accustomed to a neck restraint by being placed in the restraining apparatus for 10 min a day for 3 weeks before experiments began. The mice had row B of whiskers stimulated (conditioned stimulus, CS) unilaterally by stroking with an artist's paintbrush. Great care was taken not to touch neighboring rows of whiskers. The CS lasted 9 s and consisted of three strokes. One stroke lasted 3 s, at the last second of the last stroke a single tail shock (unconditioned stimulus, UCS; 0.5 s, 0.5 mA) was applied. Pairings (CS + UCS) were repeated four times per minute for 10 min/day. The stimulation procedure was repeated for 3 successive days. Twenty-four hours after completion of classical conditioning the 2DG mapping was performed.
2-Deoxyglucose Mapping
2DG mapping (Sokoloff et al., 1977) of cortical representation of row B of vibrissae was performed in control untreated mice, in control mice with ElvaxAPV implants and in three groups which underwent classical conditioning. Prior to 2DG injection, all vibrissae except row B were clipped close to the skin on both sides of the snout, and the mice were restrained on a block. Then a single dose (5 µCi/ mouse) of [14C]2-deoxy-D-glucose (Amersham, sp. act. 55 Ci/mmol) was injected intraperitoneally, and the rows B on both sides of the snout were stroked using fine paintbrushes, held in a mechanical stimulator, with a frequency of 3 Hz, for 45 min. Mice were killed by an overdose of Nembutal and perfused with 3.3% formalin. The brains were removed, frozen and cut on a cryostat at 20°C in a plane tangential to the barrel field into 20 µm sections, and processed for 2DG autoradiography. The autoradiograms were generated by apposing the sections, together with radioactivity standards, to Kodak mammography film for 4 weeks. The sections from which the autoradiograms were obtained were counterstained with cresyl violet for identification of cortical barrels.
Quantification of Autoradiograms
The autoradiograms were quantified using an image analyzer (Imaging Res. Inc., Ontario, Canada) as previously described (Siucinska and Kossut, 1996). The software allowed us to display the image of Nissl-stained section, from which the autoradiogram was obtained, on a computer screen. The barrel outlines were marked and superimposed on the autoradiogram so that the relations of the labeled regions to morphological barrels could be accurately determined. The width of the labeled region (representation of row B whiskers) and its labeling intensity were measured on sections from cortical layer IV on which the barrels of row B were visible. Usually, 68 sections from each hemisphere were analyzed. We determined the width of labeling of row B representation using a previously established criterion (Chmielowska et al., 1986
; Siucinska and Kossut, 1996
), which considered as labeled the regions with a level of 2DG uptake 15% higher than in the unstimulated region of the barrel field. At least six readings were taken from each section. Values obtained from autoradiographic measurements were averaged to give a mean value of the labeling dimensions for the entire row B. The ratio of the width of labeled representation of row B to the width of morphological barrels on the experimental and control side was calculated for each mouse. Measurements of the morphological barrels helped to correct for possible variations in the plane of sections.
Statistical Analysis
A paired Student's t-test was used to analyze the difference between the width of the labeled representation of row B vibrissae in stimulated and control hemispheres in all experimental groups. The significance of differences in row B labeling between the trained groups of mice was evaluated using ANOVA followed by Tukey's post-hoc analysis.
[3H]MK-801 Binding Assay and Autoradiography
Mice implanted unilaterally with ElvaxAPV were killed 5 days after surgery. Brains were quickly removed and frozen in isopentane at 70°C. Coronal 20 µm sections were cut on a cryostat, thaw-mounted onto gelatin-coated slides and a [3H](+5)-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate ([3H]MK-801) binding assay was performed to reveal NMDA receptor sites. Briefly, sections were preincubated in 50 mM TrisHCl buffer (pH 7.4) containing 2.5 mM CaCl2 for 10 min at 5°C. The sections were then incubated in a medium containing 3 nM [3H]MK-801 (25.7 Ci/mmol, NEN, Du Pont), 5 µM glycine, 5 µM glutamate and 50 µM spermidine in 50 mM TrisHCl buffer (pH 7.4) for 1 h at room temperature. Unspecific binding was defined in the presence of 100 µM MK-801. Incubations were terminated by rinsing three times with ice-cold TrisHCl buffer for 15 s, twice with ice-cold distilled water (5 s) and finally rapidly dipped into two changes of acetone containing 2.5% glutaraldehyde and dried under a stream of warm air. Unspecific binding did not exceed 1% of total binding. Slides were apposed to tritium-sensitive Hyperfilm (Amersham, UK) in X-ray cassettes together with calibrated tritiated microscales (Amersham) at 5°C for 30 days. The optical density of autoradiograms was quantified using an image analyzer (Imaging Res. Inc.).
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Results |
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Since all the data resulted from comparisons of labeling in the two cerebral hemispheres, it was essential to verify that identical stimulation produces identical labeling in both barrel fields of one animal. We found that controlled stimulation of row B of vibrissae on each side of the snout during 2DG uptake labeled a well-defined band of the SI cortex, centered on row B of vibrissal barrels (Fig. 2). The labeling was observed in all cortical layers and no differences in the width of labeled cortical representation of row B in the right and left hemispheres were found (Fig. 3
). Consequently, we could compare the results from the two hemispheres after an unilaterally applied experimental treatment, since it was shown previously that unilateral vibrissae stimulation does not affect ipsilateral 2DG uptake in mice (Chmielowska et al., 1986
).
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The autoradiograms revealed a binding pattern typical for [3H]MK-801, with the highest binding density in cortical layer IIIII (Glazewski et al., 1995). The influence of APV was clearly visible in one hemisphere, where a region of lower labeling was detected, although the laminar pattern of labeling was preserved (Fig. 4
). Quantitative comparison of autoradiograms of [3H]MK-801 binding in the barrel cortex of control and ElvaxAPV implanted sides showed a decrease of binding by ~40% (control sides 1.63 ± 0.36 pmol/mg protein; experimental sides 0.98 ± 0.16 pmol/mg protein) 5 days after implantation.
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Measurements of 2DG labeling intensity, 5 days after ElvaxAPV implantation, revealed that basal metabolic 2DG uptake was decreased in the cortex directly below the implant. However, in the barrel field region of the SI cortex, situated anterior to the implant, the basal and stimulus-evoked 2DG uptake remained unchanged when compared to the same site in the control hemisphere (Figs 5 and 6).
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The cortical representation of the `trained' row B of vibrissae labeled with 2DG was enlarged following classical conditioning. The width of labeling (dimension across the row of barrels, estimated from optical density profiles and fulfilling the criterion of having labeling density 15% higher than in the unstimulated region of the barrel field) changed from 407 ± 43 µm in control rows to 663 ± 42 µm in trained rows (n = 4, P < 0.05); the mean increase amounted to 62% (Figs 7A,B,A',B' and 8A). These results fully confirmed a previous report (Siucinska and Kossut, 1996
) where the observed mean increase of cortical representation of the `trained' row of whiskers was 45%. Although labeling was observed in all cortical layers, the measurements of labeling are reported here only for cortical layer IV since the changes of vibrissal functional representation after conditioned training were found only in this layer (Siucinska and Kossut, 1996
). The intensity of labeling was not affected by the training and was the same in both hemispheres of the trained animal, as described previously.
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When ElvaxAPV implants were inserted into the brain before conditioning, subsequent 2DG mapping revealed no significant changes in the extent of the cortical representation of the `trained' row of vibrissae when compared to control row (Figs 7E,F,E',F' and 8B). The width of representation of trained rows was 521 ± 56.0 µm and in control rows 434 ± 62 µm (n = 7). The observed enlargement (20%) was not statistically significant and was significantly different from the effects in the two other experimental groups (trained, trainedElvaxPBS). The intensity of labeling of row B representation did not differ in the control and implanted hemispheres. The comparison of the effect of conditioned training in three experimental groups (trained, trainedElvaxPBS and trainedElvaxAPV) of mice show that APV released from Elvax significantly reduced the plastic changes induced by classical conditioning (Fig. 9
).
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Discussion |
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One can argue that ElvaxAPV implants may have affected the cortical 2DG uptake, and therefore the observed reduction of the functional representation of the trained row of vibrissae was due to a disturbance in the cortical metabolism. However, our control experiments showed that neither basal nor stimulus evoked 2DG uptake was impaired in the region of the barrel cortex. The experiments in which 2DG uptake was estimated in mice with ElvaxAPV implants revealed no significant influence from the implant upon the barrel-field region, in any examined cortical layers (Fig. 5 and Jablonska et al., 1995). The metabolic activation of the barrel cortex seemed unimpaired by partial blocking of NMDA receptors. However, we cannot exclude subtle effects that would not be detectable by our technique. For example, a small and not statistically significant decline of metabolic activity observed in layer II/III could have been detrimental to development of the plastic changes observed in layer IV. A drastically different result was obtained when APV was delivered via osmotic minipumps to the cortex the 2DG uptake was greatly decreased in a large area of cortex (Jablonska et al., 1994
). The same problem was encountered in studies of the effect of blocking NMDA receptors upon plastic changes of ocular dominance columns induced by monocular deprivation in the visual cortex of kittens (Bear et al., 1990
; Rauschacker, 1991). A number of results suggested that NMDA receptor antagonists prevent developmental plasticity (for review see Kaczmarek et al., 1997). The infusion of 50 mM APV to the visual cortex of kittens particularly disrupted the effect of monocular deprivation and the characteristic shift toward the open eye did not occur (Kleinschmidt et al., 1987
; Bear et al., 1990
; Rauschecker, 1991
). However, several authors conclude that this effect may be due primarily to blockade of normal synaptic transmission in the immature cerebral cortex (Rauschecker, 1991
; Miller et al., 1989
; Schlaggar et al., 1993
; Kasamatsu et al., 1998
). This question was addressed by Bear et al. (1990), who estimated that with a sufficiently low concentration of APV (i.e. sufficiently far from the cannula tip of the minipump ejecting APV) the blockade of plasticity can be dissociated from the blockade of activity. Some supportive data are provided by other experiments. ElvaxAPV implants over the superior colliculus (SC) of juvenile ferrets disrupted the formation of an auditory space map but did not affect the strength of responses of SC units (Schnupp et al. 1995
). Indirect support comes from the work of Garraghty and Muja (1996), where the NMDA receptor blocker 3-[(±)-2-carboxypiperazin4-yl]propyl-1-phosphonate (CPP) was injected systemically; obviously the degree of receptor blockade was small, but it prevented plastic change of receptive fields of area 3b neurons, although their responsiveness was not impaired. Recently, it was found that suppression of NMDA receptor function using antisense oligodeoxynucleotides complementary to mRNA coding the NR1 subunit of NMDA receptor blocked ocular dominance plasticity while preserving normal visual responses (Roberts et al. 1998
). On the other hand, Kano et al. (1991) showed that selective blockade of NMDA receptors in area 3b of the SI cortex of adult cats by infusion of APV from the minipump not only disrupted reorganization of the body map after hindlimb deafferentation but also that APV treatment depressed responses of SI neurons to natural sensory stimulation.
It should be noted that the efficacy of APV suppression of the sensory response diminishes with an animal's age (Tsumoto et al., 1987), especially in layer IV which was investigated in our study. Transmission of sensory information to cortical layer IV neurons in the barrel cortex is mediated mainly by non-NMDA receptors, although an NMDA component is also present (Armstrong-James et al., 1993
). Intracortical excitatory transmission involves a much greater NMDA receptor activation (Armstrong-James et al., 1993
). Since we found that after Elvax APV implantation NMDA receptor sites were only partially blocked, it seems that concentration of the APV present in the barrel cortex was low enough to allow for sensory transmission, as seen in our control 2DG experiments, but sufficiently high to affect plasticity; it appears that the level of receptor blocking may be critical for this kind of investigation. Rema et al. (1998), who used a concentration of APV that eliminated NMDA responses in layers I/IV, interpreted their results, which showed impairment of plasticity, as due to activity suppression. However, they did not examine the effects of lower concentrations of APV upon plasticity in their experimental paradigm. We estimated, using receptor-binding autoradiography, that after ElvaxAPV implantation, [3H]MK-801 binding in the barrel field was reduced by ~40%. This value is probably an underestimate because the binding procedure, involving preincubation of the sections, may cause dissociation of APV from its binding sites. Our previous estimation using binding to cortical homogenates also showed that the blocking of NMDA receptors was partial (Jablonska et al., 1995
). A more reliable evaluation of effectiveness of ElvaxAPV implants could be done using electrophysiological recordings. Nonetheless, the concentration of released APV was sufficient to significantly reduce the plastic change of the cortical functional map.
Plastic changes observed in the cortex could be a reflection of modifications occurring at the level of the thalamus. The resolution of [14C]2DG technique is not good enough to examine changes in the dimension of representation of a row of vibrissae in the ventrobasal nucleus, so we do not know if the training procedure modifies receptive fields in the thalamus. In the present study, ElvaxAPV implants had no effect upon MK-801 binding in the thalamus. Therefore the influence of APV upon plasticity was exerted in the cortex.
Using the changes in the owl's map of auditory space caused by prism-rearing, Feldman et al. (1996) demonstrated that NMDA receptors preferentially mediate the expression of newly learned neuronal responses in the inferior colliculus. They propose that, during prism-rearing, a distinct synaptic population develops by formation or functional activation of synapses enriched in NMDA receptors. It is possible that in our experiments involving short conditioning training, the formation of new circuitry is connected with similar mechanisms.
We have found that this training resulted in a transient increase of [3H]MK-801 and [3H]-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA) binding in the row of layer IV barrels corresponding to the trained row of vibrissae (Jablonska et al., 1996a
). The increase was due to a rise in the number of binding sites (Jablonska et al., 1996b
). These data can argue both for the formation of new synapses and for the strengthening of existing ones, which may be a more likely possibility in an adult brain. Apart from the formation of new NMDA synapses, the activation mechanism of `silent' synapses (Malenka and Nicoll, 1997
) can be considered. Crair and Malenka (1995) demonstrated the existence of silent synapses in the barrel cortex of rats. The number of silent synapses, very high in immature animals, is sharply reduced in postnatal development (Isaac et al., 1997
). However, a small fraction of silent synapses, that may be present in the adult cortex, could be critical for the observed changes of cortical maps.
In rats, the chronic exposure to APV that disrupts the topographic refinement of retinal inputs to the SC also prevents the developmental rise of NR1 mRNA (Hofer et al., 1994). Therefore, it can be speculated that APV not only blocks NMDA receptors but also causes a reduction in the number of newly formed NMDA receptor complexes. In our experiments, it could block the observed formation of new NMDA receptor sites. Additionally, the role of NMDA receptor activation has been implicated in the production of local postsynaptic alterations in protein synthesis and thus controlling synaptic remodelling (Scheetz et al., 1997
). An additional support for the involvement of NMDA receptors in learning is derived from correlative studies. An increase of NMDA receptor sites was found after imprinting (McCabe and Horn, 1988
) and after passive avoidance training in chicks (Stewart et al., 1992
; Steele et al., 1995
). In the hippocampus, a significantly higher NMDA receptor density was found in rats that had performed well in passive avoidance tasks as compared to poor performers (Stecher et al., 1997
). During song development in birds, a neural region that has been specifically implicated in song learning exhibits an increase in density of NMDA receptors (Basham et al., 1997
). These observations and recent reports on the effect of APV and NMDA on plasticity induced by whisker pairing procedure and associative learning paradigm in the barrel cortex of adult rat (Maalouf et al., 1998
; Rema et al., 1998
) strengthened the hypothesis regarding the involvement of NMDA receptors in neuronal modifiability, at least during the period when learning is taking place.
The present results, together with our previous data, show that partial blocking of NMDA receptors by APV reduces plastic changes induced by denervation and short-lasting classical conditioning. This suggests that activation of NMDA receptors is a critical step in the plasticity of the adult barrel cortex. They also stress the necessity of activating, in a plastic process, a very large fraction of the cortical NMDA receptors.
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Notes |
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Address correspondence to J. Skangiel-Kramska, Department of Neurophysiology, Nencki Institute, 3 Pasteur Street, 02093 Warsaw, Poland. Email: jolak{at}nencki.gov.pl.
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References |
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