Department of Neurophysiology, Ruhr-Universität Bochum, D-44780 Bochum, Germany
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Abstract |
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Introduction |
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The adult visual cortex has, however, a remarkable potential for plasticity, as has been shown by the extensive reorganization following retinal lesions in cat (Kaas et al., 1990) and monkey (Heinen and Skavenski, 1991
; Gilbert and Wiesel, 1992
). The post-lesion unresponsive region in the visual cortex regains excitability with time and cells inside the scotoma respond to visual stimulation at the border of the retinal lesions. This functional reorganization is ascribed to the synapses of the long-ranging, excitatory horizontal axonal system that are subthreshold after lesioning but increase efficacy during reorganization (Das and Gilbert, 1995
).
Quite differently, in our experiments we have introduced small cortical lesions in the adult cat visual cortex (area 17) by injection of the excitotoxin ibotenic acid. With this type of lesion cortical target cells and local intracortical processing are lost while the subcortical input fibers are maintained. Receptive field topography and size were mapped and functional cell properties ascertained with microelectrode recordings before lesioning and after survival times of 2 days and ~2 months. While no substantial changes of RF dimensions were observed subacutely after lesioning, individual cells with strongly enlarged receptive fields were found at the border of the chronic lesions.
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Materials and Methods |
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Adult cats (n = 8, 2.55 kg) were anesthetized with ketamine hydrochloride (20 mg/kg) and xylazine hydrochloride (2 mg/kg) for initial surgery (tracheotomy and insertion of a catheter into the femoral artery for acute recording experiments or tracheal intubation and flexible access to the brachial vein for placing a chronic lesion). Anesthesia was further maintained by respiration with a 70/30 mixture of N2O/O2 with halothane (0.20.6%) throughout the 14 day experiments. Nutrition and paralysis was provided by continuous vascular infusion of a Ringer solution containing alcuronium chloride (Alloferin®, 0.06 mg/kg//h) and glucose (1.25%). Pressure points and wound margins were locally anesthetized by infiltration of a long-lasting anesthetic (xylocaine), and the animals were fixed in a stereotaxic apparatus. A trepanation of 2 x 10 mm was centered at P2/L3 above the visual cortex. The physiological state of the animals and adequacy of anesthesia were ensured by continuous monitoring of arterial blood pressure, pulse rate, flow and mixture of O2/N2O and halothane used for respiration, end tidal carbon dioxide and body temperature. All experiments were carried out in accordance with the guidelines published in the European Communities Council Directive (86/609/EEC, 1986).
Ibotenic Acid Lesions
Ibotenic acid (1%, 300500 nl) was pressure injected through a glass micropipette with 18 µm tip diameter to introduce small focal cortical lesions. Two types of lesion experiments were performed. In the subacute experiments (n = 5) recordings were made before lesioning and 23 days post lesion from identical cortical positions (n = 15) with a linear array of seven electrodes. These animals were kept under continuous anesthesia in darkness except for the testing of visual receptive fields. In the chronic experiments, control recordings were made prior to lesioning (n = 14). After injection of ibotenic acid the trepanation was closed with the original bone piece and the wound was closed by suturing all anatomical layers. Wound margins were again infiltrated with the long-lasting local anesthetic. When infusion of relaxant was discontinued spontaneous respiration was re-established, respiration with O2/N2O/ halothane was stopped and the animals were extubated. The cats were then kept undeprived in large rooms in the animal house in a visually rich environment; they did not suffer from any visible disabilities. The chronic effects of the lesions on RFs (n = 18) were investigated between 55 and 76 days post lesion, when the animals were taken back into the experiment using the same procedures described above.
Recording and Receptive Field Mapping
The following methods were used for all recording experiments. The eyes were covered by zero power contact lenses and refraction was corrected with lenses for 28 cm viewing distance. Atropine sulfate (1%) and phenylephrine hydrochloride (5%) were applied for mydriasis and to retract the nictitating membranes.
Extracellular single and multiunit recordings were made from layers II/III of the striate cortex at a depth of 500800 µm with glass micropipettes (inner tip diameter 35 µm, impedance 12 M) filled with 3 M NaCl in the chronic experiments, and in the subacute experiments with a linear array of individually movable platinum-in-glass electrodes (Eckhorn-Array, Thomas Recording, Marburg, Germany) with 1 mm interelectrode distance that were left in the same places before and after lesioning. Responses were processed by a spike discriminator (Alpha-omega, Israel) and fed into a personal computer for storage and further processing.
Retinal landmarks (optic disc with main vessels, area centralis) were backprojected to a tangent screen with an opthalmoscope. Back-projections were regularly repeated to monitor eventual small drifts in eye position throughout the experiments.
Mapping of topography and size of the monocular receptive fields (Fig. 2) was carefully performed by hand with a stationary or flickering small light bar (0.30.5° x 35°). To functionally characterize the receptive fields, visual stimuli were monocularly presented on an oscilloscope 28 cm in front of the eyes. The light bars of optimal width (0.30.8°) and length (1.510°) were generated with a Picasso CRT image generator (Innisfree, Cambridge, UK) and moved under computer control in two directions at eight orientations (22.5° intervals) in pseudorandom order; peristimulus time histograms (PSTHs) were computed from 5 or 10 trials for each orientation and polar diagrams were constructed from the peak response rates obtained for each of the 16 directions of motion.
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At the end of the experiments the animals were killed with an overdose of anesthetic and perfused with 4% paraformaldehyde in phosphate buffer (pH 7.4). The cortical region containing the lesions and electrode tracks was blocked, kept overnight in 0.025 M PBS at 4°C, embedded in paraffin and cut in serial sections (5 µm). Consecutive sections were stained with Masson's trichrome stain for electrode track reconstruction or treated for immunohistochemistry with antibodies against microtubuli-associated proteins (MAPs) as neuronal marker, and glial fibrillary acidic protein (GFAP) to reveal glia cells. For immunohistochemistry (slide-method) the paraffin-embedded sections were dewaxed in xylene and transferred through a descending ethanol series into PBS. After treatment with n-Gt (normal goat, Dako) and n-Hrs (normal horse, Sigma) antiserum for 1 h, the sections were reacted with the primary antibodies (1:200) overnight (MAP-2, clone HM-2, Sigma; GFAP, clone GA5, Boehringer-Mannheim), and linked to biotinylated goatanti-rabbit and horseanti-mouse (Vectostain-Camon) antibody (1:200, 1.5 h). Detection was performed with a standard ABC kit (Vectostain-Camon) 1:100 in PBS for 1.5 h. The DAB reaction was used to visualize immunohistochemical labeling (0.5 mg DAB + 10 µl 0.5% H2O2). Sections were cleared in xylene and coverslipped with Depex (Serva).
The size of the lesions was measured from the serial sections and the electrode tracks were reconstructed to show their position relative to the border of the lesions.
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Results |
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The injection of ibotenic acid resulted in focal lesions characterized by a loss of all neurons as shown 76 days post lesion with MAP immunohistochemistry and with neurofilaments as neuronal markers (MAP2, NF200, Fig. 1A,B). The antibodies against MAP2 and NF200 indicate the loss of neuronal processes within the lesioned area, and at the same time show the unchanged density of neuronal elements at the immediate border of the lesion. The GFAP staining shows a glial scar that has developed in response to the excitotoxic lesion in the region free of neurons (Fig. 1C
). The neuronal loss was already evident within the first 2 days post lesion not only by the complete functional loss around the injection site but also by the disintegration of neurons histologically visible in Nissl-stained sections. The average diameter of the lesions (determined from the Nissl stains) in the five acute and three chronic animals was 2.9 mm (range 2.14.3 mm). The average depth of the lesions was 1.6 mm (range 1.252.0 mm); they typically extended to the layer 4/5 border.
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Before lesioning, RFs were mapped with penetrations spaced by ~1 mm both in subacute and chronic experiments, and the topography and size of RFs were carefully determined. The RF position of cells in the visual cortex (area 17) migrated from the upper to the lower visual field when penetrations were displaced in the AP plane from posterior to anterior (Fig. 2).
Figure 3 shows typical RF maps before and after an acute ibotenic acid lesion. We recorded with a linear array of seven electrodes spaced by 1 mm that was left in place throughout the 23 day experiment. RF position and size were mapped for each electrode and the ibotenic acid lesion was applied close to one of the recording electrodes (no. 6). At this and the neighboring electrodes neuronal activity ceased after a period of strongly increased firing. After the cats had been kept in darkness for 2 days the RFs were remapped at the still active electrode positions and no substantial changes in RF size or location were observed; this was true for the example shown in Figure 3
as well as for the other subacute experiments (Fig. 8
). In two cases where the lesion was placed in the middle of our electrode array (not shown) gaps of retinal representations (1° and 3°) were found in the RF map.
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Figure 4 summarizes a chronic experiment with 55 day survival time between lesioning and final experiment. The localization of penetrations was documented by photography of the cortical surface on the day of ibotenic acid injection (Fig. 4A
). This enabled us to retest the same cortical positions after 55 days survival time (Fig. 4B
). In Figure 4A,B
the recording sites are indicated, together with the lesion site on the cortical surface. Figure 4C
shows the RF locations and sizes as mapped before lesioning. The cells were vigorously responding and the location and outmost borders of the excitatory RF could be exactly mapped. The largest RF found in each penetration is outlined and labeled with the number of the respective electrode penetration. The ibotenic acid injection was applied at the location of recording site 1 (Fig. 4A,C
). In the experiment, after 55 days survival time this location is again labelled as recording site 1 (Fig. 4B,D
). In this location no activity was encountered up to a recording depth of 1500 µm where the first visually driven background activity was recorded. This was considered as the lower border of the lesion and the penetration was discontinued. During all the other penetrations anterior or posterior to the lesion site single cells with crisp responses, direction specificity and sharp tuning for orientation were recorded in the supragranular cortical layers. The location and spatial extent of the RFs of these cells could be determined with the same accuracy as the RFs during the initial lesioning experiment in the same animal. At the recording sites 2 and 2a, up to 1 mm anterior of the border of the lesion, individual cells displayed impressingly increased RF sizes (Fig. 4D
), although in the same penetrations we also encountered single cells with rather normal RF size (the smallest and largest fields obtained in the individual penetrations are shown). RFs returned to normal pre-lesion sizes at the most anterior recording site (no. 3). Due to the normal decrease in RF size towards the area centralis, there should be a continuous decrease in average RF size from the most anterior to the most posterior penetration.
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The cells with increased receptive field size were situated close to the border of the chronic lesions as evident from the relative position of the recording sites to the ibotenic acid injection site. This close vicinity is shown histologically for penetration 7 of Figure 5 by the reconstructed electrode track passing down at the very border of the lesion as visualized in a Nissl-stained section (Fig. 7
). From the known recording depth and the limits of the lesion seen in the Nissl stain we can conclude that the cell with the enlarged RF (Fig. 5D
) was located directly at the border of the cortical lesion.
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Discussion |
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Many studies have made use of striate cortex lesions in the adult for various reasons; however, this is the first study to investigate receptive field size at the border of chronic lesions in the striate cortex. Earlier studies have employed surgical striate cortex lesions in adult cats and monkeys to investigate area 17/18 interactions (Donaldson and Nash, 1973), cortical blindness (Keating, 1977
), visual capacity (blind sight) remaining after the lesion (Weiskrantz and Cowey, 1970
; Weiskrantz, 1978
), intracortical axonal degeneration (Creutzfeldt et al., 1977
), retinal degeneration (Dineen and Hendrickson, 1981
), hypertrophy of dorsal lateral geniculate nucleus (dLGN) and alterations of retinal input after striate cortex lesions (Hendrickson and Dineen, 1982
; Dineen et al., 1982
), projection patterns of surviving neurons in the dLGN (Cowey and Stoerig, 1989
), and deactivation of area MT (Kaas and Krubitzer, 1992
), as well as small excitotoxic striate cortex lesions to study the effects on eye movements (Newsome et al., 1985
). In an earlier study we have used small acute heat lesions in the striate cortex to disclose the effects of lateral signal processing on cat single visual cortex cells (Eysel et al., 1987
). In the present study we have applied excitotoxic striate cortical lesions to study possible changes in receptive field size that could lead to a functional reduction of the size of a cortical scotoma. While receptive fields of cells at the border of the lesion remained unchanged during the first 2 days, a significant enlargement of receptive fields was observed when the same cortical region surrounding the lesion was investigated after 2 months.
Feedforward and Feedback Pathways for Reorganization
When cell death takes place in the striate cortex, the visual field region represented by the lesioned part of cortex is lost, but the unsevered geniculocortical afferents still offer the complete retinal topography as feedforward input and also as feedback input via area 18 to the surviving cortical cells at the border of the lesion (Fig. 9A). It is therefore possible that surviving cortical cells at the border of the lesion in area 17 can learn to respond to inputs from retinal regions that have been deprived of their original cortical targets. This could make the lost information from the intact retina available again in the primary visual cortex for further cortical processing.
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The finding of enlarged receptive fields at the border of cortical lesions raises the question why these cells do develop exceptionally large excitatory RFs, whereas under control conditions RF areas in that cortical region were significantly smaller.
Increased Excitability at the Border of the Lesion
Increased excitation seems to be one key step to initiate reorganization at the border of cortical lesions. In the first week post lesion we have observed increased spontaneous and visual excitability in the immediate surrounding of cortical lesions (Eysel and Schmidt-Kastner, 1991), and in the somatosensory cortex of the rat we have seen increased N-methyl-D-aspartate-mediated EPSPs at the border of such lesions in vitro (Mittmann et al., 1994
). This increased excitability at the border of lesions could facilitate changes of synaptic efficiency that can lead to the enlargement of receptive fields by activation of previously subthreshold (silent) synapses. However, passive facilitation alone does not seem sufficient to lead to the increase of RF sizes since the observed expansion of receptive fields did not occur spontaneously within the first 2 days when the animals were kept under continuous anesthesia and darkness. This indicates that use and/or time are necessary to bring about the RF size increases. In vivo we have observed long-term potentiation (LTP)-like increases of RF size after repetitive visual stimulation in the normal cortex of the anesthetized adult cat (Eysel et al., 1998a
). Increased excitability and reduced inhibition in the surround of lesions could facilitate such mechanisms to become effective during coactivation of the target cell from its RF proper and from adjacent RFs via geniculocortical input or area 18 feedback collaterals, leading to increased efficacy of the synapses and consequently to the observed expansion of RFs. Indeed, signs of increased LTP have recently been described with in vitro field potential recordings at the border of somatosensory cortex lesions after a survival time of 14 days (Hagemann et al., 1998
).
Cortical inhibition has been proposed in general to control plasticity in the adult mammalian visual cortex (Jones, 1993). Accordingly, reduction of lateral inhibition at the border of a lesion could additionally support plasticity. This hypothesis is also related to the suggestion of Artola and Singer (1987) that inhibitory synapses at layer III neurons could reduce synaptic plasticity by shunting excitatory postsynaptic currents. In fact, Hirsch and Gilbert (1993) often observed failure to induce LTP-like changes in the cat visual cortex in vitro when the responses included strong inhibition. In another in vitro study, Kirkwood and Bear (1994) ascribed a critical role to inhibitory intracortical circuits for gating of visual cortical plasticity at the network level. Inhibition might even lead to depression of the respective inputs due to the described voltage dependence of long-term plasticity (Artola et al., 1990
) in the rat visual cortex in vitro. In fact, strongly decreased GABAergic IPSPs have been described close to the border of cortical lesions (Mittmann et al., 1994
), and GABA receptors are downregulated in the surrounding of cortical lesions (Schiene et al., 1996
).
Temporal and Spatial Aspects of Reorganization
A transient increase in visual receptive field size was reported for cells at the border of excitotoxic lesions in area MT of the monkey between 6 and 13 days post lesion (Wurtz et al., 1990). In our study the changes in RF size were more persistent; however, we do not know when the increase of RF size began with normal use of vision during the 2 months survival time. As shown in Figure 4D
the enlarged fields were found not only directly adjacent to but also ~1 mm distant from the border of a lesion. By demonstrating the degeneration of axons after localized striate cortical lesions, Creutzfeldt et al. (1977) have elegantly shown the range of the direct anatomical effects of a small lesion in area 17 extending horizontally up to 1800 µm in layer III. In addition, the direct lateral extent of inhibitory connections in the upper cortical layers was found in the range of 12.5 mm with the large majority confined to 1 mm (Albus et al., 1991
; Kisvárday et al., 1997
). This lateral range of supposed disinhibitory effects due to loss of inhibition from the lesioned area is in keeping with the distance of 1 mm from the border of a visual cortical lesion at which the peak of increased excitability was observed in vivo 17 days after lesioning (Eysel and Schmidt-Kastner, 1991
).
Parallel Effects Following Retinal and Somatosensory Cortex Lesions
The predominant effect of retinal lesions at striate cortex cells is a significant shift of receptive field topography that leads to a filling-in of the scotoma from the border of the retinal lesion due to lateral signal processing in the visual cortex (Kaas et al., 1990; Heinen and Skavenski, 1991
; Gilbert and Wiesel, 1992
). Interestingly an increase of receptive field size can also be found in the surrounding of cortical scotomata induced by retinal lesions (Gilbert and Wiesel, 1992; review by Chino, 1997). In fact there are striking similarities between the cortical effects of retinal lesions and the effects observed in the surrounding of cortical lesions. Retinal lesions induce increased excitability (increased spontaneous and visual excitability) at the border of the scotoma (Arckens et al., 1998
; Eysel et al., 1998a
) and changes in the GABAergic system (reduced GAD immunocytochemistry, Rosier et al., 1995) in the time window where changes in RF size and topography are also observed (Gilbert and Wiesel, 1992
). Terminal sprouting of horizontal axons was observed in the cat visual cortex 6 and more months following retinal lesions (Darian-Smith and Gilbert, 1994
). Sprouting of cortical axons has also been observed following radiation lesions of the upper layers in young and adult rabbit striate cortex, where the 3.04.5 mm diameter regions completely devoid of nerve cells were invaded by supposedly newly grown nerve fibers within 7 weeks post lesion (Rose et al., 1960
). In the present experiments we did not observe nerve fibers inside the lesion with neurofilament immunohistochemistry (Fig. 1B
); however, there might be sprouting phenomena involved in the reorganization at the border of the lesion. Regarding the differences between the two types of lesion, it appears important to mention that after the excitotoxic lesion destruction of cells was visible in Nissl stains within the first 2 days, while it took 12 weeks until the first histological changes were seen after radiation lesions; moreover, glial cells produced a scar after the excitotoxic lesions, while glia was rare in regions lesioned by radiation.
The somatosensory cortex responds to remote and local lesions in a way very similar to the visual cortex: changes of cortical topography were observed in response to deafferentation (for review, see Kaas, 1991), and Jenkins and Merzenich (1987) reported a complete filling-in of the lost representation of the palm representation by strongly enlarged RFs of cells surrounding a lesion in the primary somatosensory cortex after 129 days in the owl monkey. Such signs of adult plasticity appear to be a general feature of sensory cortices (for review, see Kaas, 1991; Eysel, 1992).
Reducing the Size of the Scotoma
Patients with visual field loss due to vascular or traumatic postgeniculate damage with homonymous defects that were quantitatively determined with static and dynamic visual field perimetry were trained in the border regions of their residual visual fields by repeated stimulation to improve light-difference thresholds (Zihl and von Cramon, 1979) or by locating targets within the blind field region (Zihl and von Cramon, 1985
). Both types of training led to a reduction of the scotoma size and consequently an enlargement of the visual field in the majority of patients. The recovery was specifically dependent on practice; this was also the case in a study where patients with homonymous visual field deficits were exposed to a computer-based restitution training that specifically activated the border region of the visual field defect (Kasten and Sabel, 1995
; Kasten et al., 1998
). It was hypothesized that this recovery might take place at the level of the striate cortex.
The enlarged RFs of cells at the border of the cortical lesion represent a mechanism for functional recovery of primarily lost parts of the visual field and thus lead to a reduction of the size of a scotoma as shown in Figure 9B. This is a non-redundant, functionally useful reorganization since inputs that have lost their target cells are reconnected to surviving cortical cells. The absolute increase of RF size (Figs 4, 5
) observed here would allow for a shift of the border of a scotoma by ~34°, which is in the range of the 4.9 ± 1.7° recently observed in patients treated with computer-based visual field training (Kasten et al., 1998
). This suggests that the long-term plasticity of cells at the border of visual cortical lesions may represent a model in the mature visual system of the cat for the long-term reduction of visual field defects observed in human patients.
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Notes |
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Address correspondence to Ulf T. Eysel, Abteilung für Neurophysiologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany. Email: eysel{at}neurop.ruhr-uni-bochum.de.
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