A neurochemical signature of visual recovery after extrastriate cortical damage in the adult cat

Abstract

In adult cats, damage to the extrastriate visual cortex on the banks of the lateral suprasylvian (LS) sulcus causes severe deficits in motion perception that can recover as a result of intensive direction discrimination training. The fact that recovery is restricted to trained visual field locations suggests that the neural circuitry of early visual cortical areas, with their tighter retinotopy, may play an important role in attaining perceptual improvements after damage to higher level visual cortex. The present study tests this hypothesis by comparing the manner in which excitatory and inhibitory components of the supragranular circuitry in an early visual cortical area (area 18) are affected by LS lesions and postlesion training. First, the proportion of LS-projecting pyramidal cells as well as calbindin- and parvalbumin-positive interneurons expressing each of the four AMPA receptor subunits was estimated in layers II and III of area 18 in intact animals. The degree to which LS lesions and visual retraining altered these expression patterns was then assessed. Both LS-projecting pyramidal cells and inhibitory interneurons exhibited long-term, differential reductions in the expression of glutamate receptor (GluR)1, -2, -2/3, and -4 following LS lesions. Intensive visual training post lesion restored normal AMPAR subunit expression in all three cell-types examined. Furthermore, for LS-projecting and calbindin-positive neurons, this restoration occurred only in portions of the ipsi-lesional area 18 representing trained visual field locations. This supports our hypothesis that stimulation of early visual cortical areas-in this case, area 18-by training is an important factor in restoring visual perception after permanent damage to LS cortex.

(c) 2008 Wiley-Liss, Inc.

Figures

Fig. 1

Visual cortical areas in the cat. Lateral view of the cat brain, illustrating the relative location of principal visual cortical areas. The adjacent schematic diagram is a simplified rendition of connectivity between these different visual cortical areas. It demonstrates the strong, direct interconnection between lower level visual areas (17, 18, and 19) and LS cortex. Dark gray shading indicates visual areas damaged in the present study. AEV, anterior ectosylvian visual area; LS, lateral suprasylvian.

Fig. 2

Behavioral training paradigm. A–C: Maps of visual field space illustrating the location, size, and shape of visual stimuli used during initial, prelesion training of direction discrimination in Cats 1, 2, and 3. Axes are labeled in degrees of visual angle. Note the relative symmetry of trained locations across the vertical meridian. D: Direction discrimination task used to train and test cats before and after LS lesions. First, a fixation spot appeared on the computer monitor, and the animals had to fixate it for 800–1,000 ms in order for a random dot stimulus to appear. The stimulus drifted either leftward or rightward for 500 ms, during which the cats were required to maintain fixation on the central target. After 500 ms, the stimulus and fixation target disappeared and were replaced by two “response” spots. The cats were required to saccade to the rightmost spot on the monitor if the global direction of motion of the stimulus had been to the right, and to the leftmost spot if the global direction of motion had been to the left.

Fig. 3

Location of visual retraining after LS lesions in Cats 1, 2, and 3. A: Visual field map illustrating visual field locations chosen for retraining (black circles labeled a, b, and c) in the impaired hemifields of Cats 1, 2, and 3. Performance was also mapped at corresponding, control locations in the intact hemifields of Cats 1, 2, and 3 (white circles labeled a*, b*, and c*). B: Histogram plotting mean direction range thresholds at control and retrained locations (shown in A), averaged among Cats 1, 2, and 3. The white bar indicates thresholds at control locations (a*, b*, and c* in A) in the intact hemifields, where cats can tolerate a large range of dot directions and still correctly perceive the global direction of motion of the random dot stimulus. Black and gray bars show performance at contralesional locations a, b, and c (shown in A) before (black) or after (gray) direction discrimination training by using random dot stimuli in which the range of dot directions was varied. Note the significantly abnormal performance before the onset of training and the recovery to normal direction range thresholds after training. Error bars = standard deviations. **, P < 0.05, by two-tailed Student’s t-test.

Fig. 4

Retinotopy of training-induced visual recovery in Cats 1, 2, and 3. A–C: Maps of the visual field in Cats 1, 2, and 3 illustrating, via the indicated gray scale, the magnitude of training-induced improvements in direction range thresholds (relative to immediate postlesion performance) at locations “a”, “b,” and “c” within the contralesional, impaired hemifields, as well as at several adjacent locations. Circles (drawn to scale) represent the size and position of random dot stimuli used to measure direction range thresholds at each of the locations tested. White circles denote the largest improvements attained, which averaged above 230° of direction range and resulted in recovery to normal levels of performance relative to equivalent locations in the intact hemifield. Light gray circles indicate moderate improvements to less than normal levels of performance. Dark gray circles denote little to no improvement. D–F: Schematic diagrams indicating the approximate locations of regions within area 18 that corresponded retinotopically to retrained locations “a,” “b,” and “c” in Cats 1 (D), 2 (E), and 3 (F), respectively. The lateral views of the cat brain are displayed in an “open sulcus” configuration, and illustrate the location of cortical area 18 (red shading) relative to areas 17 (white), 19 (gray), and LS cortex (damaged in all three cats). Coronal sections (traced by using the NeuroLucida software) from locations I (~7 mm posterior to the interaural line) and II (~1 mm anterior to the interaural line for Cat 2 and ~8 mm anterior to the interaural line for Cat 3) illustrate the different retinotropic regions of area 18 selected for analysis. According to the electrophysiological maps of Tusa and colleagues (1979, , the area 18 representation of location “a” in the mid-lower field is more anterior and dorsal than the brain location of far upper field region “b,” but it is more posterior than the brain location where the far lower field location “c” is represented.

Fig. 5

Lesion reconstructions. Brain sections stained for cytochrome oxidase (gray shading in cortex and lateral geniculate nucleus) were reconstructed by using the NeuroLucida software. Visual cortical areas of interest are labeled in the left hemisphere of Cat 1, with white lines separating the different areas. LGN, lateral geniculate nucleus; AMLS, anteromedial lateral suprasylvian visual area; ALLS, anterolateral lateral suprasylvian visual area; PMLS, posteromedial lateral suprasylvian visual area; PLLS, posterolateral lateral suprasylvian visual area; DLS, dorsal lateral suprasylvian visual area; VLS, ventral lateral suprasylvian visual area; AEV, anterior ectosylvian visual area. Approximate anteroposterior location of the sections in each row is indicated in mm relative to the interaural line. Negative values are located posterior, and positive values are anterior to the interaural line. Note the areas of missing gray matter around the lateral suprasylvian sulcus in the right hemisphere of Cats 1, 2, 4 and 5 and the left hemisphere of Cats 3, 4, 5, and 6. Areas PMLS and PLLS were completely destroyed in all cats, with no islands of spared tissue. In addition, there was extensive, often complete damage to areas VLS, DLS, 21a, AMLS, and ALLS. A small part of area 19 was also damaged in Cats 3–6, but areas 17 and 18 and AEV were completely intact in all cats.

Fig. 6

Neuronal labeling in supragranular layers of area 18. A: Distribution of LS-projecting cells in a normal cat (Cat 7) illustrated in a NeuroLucida tracing of a coronal brain section. The section shows two DiI injection sites, one into each bank of the LS sulcus (gray arrows), and the distribution of retrogradely labeled cells (gray dots) in areas 17, 18, and 19. B: Photomontage of the rectangular region outlined in A, illustrating the supragranular distribution of labeled cells, each marked with a white dot. C: High-power photomicrograph of DiI-labeled, LS-projecting cells in area 18, highlighting the pyramidal morphology of these cells. D: NeuroLucida tracing of a coronal brain section from Cat 4, who had received injections of DiI into LS cortex 2 weeks prior to damaging LS cortex. E: Photomontage of the rectangular region outlined in D, illustrating the supragranular distribution of labeled cells, each marked with a white dot. F: High-power photomicrograph of DiI-labeled, LS-projecting cells in area 18 of Cat 4. Note the significant number of DiI-labeled cells, which survive for several months after the lesion. G: Area 18 of a normal cat showing the distribution of neurons expressing calbindin (green) in supragranular layers (II and III). Cortical layers I, II, and III are separated by dashed white lines. The white arrow indicates a calbindin-negative pyramidal cell, which is magnified in the inset. H: Same field as in G, viewed under rhodamine fluorescence, to illustrate DiI-labeled cells. Note the arrowed pyramidal cell, whose location is marked in G–I. I: Merged images from G and H, demonstrating a complete lack of colocalization between calbindin and DiI. J: Area 18 of a normal cat showing the distribution of neurons expressing parvalbumin (green) in supragranular layers. The white arrow indicates a parvalbumin-negative pyramidal cell, which is magnified in the inset. K: Same field as in J, viewed under rhodamine fluorescence, to show DiI-labeled cells. Note the arrowed pyramidal cell, originally shown in J. I: Merged images from J and K, demonstrating a complete lack of colocalization between parvalbumin and DiI. Labeling conventions as in G–I. A magenta-green version of this figure can be found online for color-blind readers. Scale bar = 100 µm in C (applies to B,C), F (applies to E,F), and insets to G,J (applies to insets in G–L.

Fig. 7

AMPAR and NMDAR subunit expression in supragranular layers of area 18. A: High-power photomicrograph illustrating two DiI-positive cells in supragranular layers of area 18 (arrowed). B: Same field of view as in A, showing staining for the GluR2 subunit of the AMPAR. C: Merged image of A and B, showing that the two arrowed DiI-positive cells express the GluR2 subunit of the AMPAR. D: High-power photomicrograph illustrating a calbindin-positive cell in supragranular layers of area 18 (arrowed). E: Same field of view as in D, showing staining for GluR2/3. F: Merged image of D and E, showing that the arrowed calbindin-positive cell expresses GluR2/3. G: High-power photomicrograph illustrating two parvalbumin-positive cells in supragranular layers of area 18 (arrowed). H: Same field of view as in G, showing staining for the GluR2 subunit of the AMPAR. I: Merged image of G and H, showing that the two arrowed cells express the GluR2 subunit of the AMPAR. J: High-power photomicrograph illustrating two parvalbumin-positive cells in supragranular layers of area 18 (arrowed). K: Same field of view as in J, showing staining for the NR1 subunit of the NMDAR. L: Merged image of J and K, showing that the two arrowed cells express NR1. A magenta-green version of this figure can be found online for colorblind readers. Scale bar = 20 µm in C (applies to A–C), F (applies to D–F), I (applies to G–I), and L (applies to J–L).