Neurotrophin-4/5 alters responses and blocks the effect of monocular deprivation in cat visual cortex during the critical period

Abstract

The mechanisms underlying changes in neural responses and connections in the visual cortex may be studied by occluding one eye during a critical period in early postnatal life. Under these conditions, neurons in the visual cortex rapidly lose their responses to the deprived eye and ultimately lose many of their inputs from that eye. Cats at the peak of the critical period received infusions of exogenous neurotrophin NT-4/5 into primary visual cortex beginning before a short period of monocular deprivation. Within areas affected by NT-4/5, cortical cells remained responsive to the deprived eye, and maps of ocular dominance were no longer evident using intrinsic-signal optical imaging. Cortical cells also became broadly tuned for stimulus orientation and less responsive to visual stimulation through either eye. These effects required at least 48 hr exposure to the neurotrophin and were specific for trkB, because they were not seen with the trkA or trkC ligands NGF or NT-3. Even after neurons had already lost their responses to the deprived eye, subsequent NT-4/5 infusion could restore them. The NT-4/5 effects were not seen after the critical period. Together, these results suggest that trkB activation during the critical period may promote promiscuous connections independent of correlated activity.

Fig. 1.

NT-4/5 prevents ocular dominance plasticity. Ocular dominance histograms compiled from cells recorded in primary visual cortex of five animals that received the treatment protocol shown in a, in which drug infusion lasted for 4 d, the last 2 d concomitant with monocular deprivation. Extracellular recordings were made from isolated cortical cells in electrode penetrations no more than 1.5 mm from infusion site of vehicle (b) or NT-4/5 (c). Units were classified on the basis of their responses to monocular stimulation, in which 1 indicates that the cell responded exclusively to input from the nondeprived eye, 7 indicates that the cell responded exclusively to deprived-eye input, and 4 indicates that either eye drove the cell equally well. For the vehicle group, BI of 0.85, MI of 0.77; for the NT-4/5 group, BI of 0.51, MI of 0.25. d, Ocular dominance histogram compiled from cells recorded in untreated primary visual cortex of six cats with normal visual experience, age 36–51d (data from Stryker and Harris, 1986) BI of 0.57, MI of 0.41.

Fig. 2.

Optical imaging and dose dependence of the NT-4/5 effect. a, b, Typical grayscale optical images for vehicle and NT-4/5 infusion, showing that NT-4/5 infusion causes response to the deprived (D) eye to more nearly equal response to the nondeprived (ND) eye than in control. Shown are response patterns to four stimulus orientations (0, 45, 90, and 135°) through either ND orD eye for control-treated (a) and NT-4/5-treated (b) hemispheres. Tip ofarrowhead at left of image indicates position of infusion cannula. Grayscale bar at rightshows percent change in reflectance from baseline, in whichdarker areas indicate areas of greater response to a particular stimulus. Average visual responsiveness in area near a cannula that was affected by NT-4/5 is 12.8 · 10⁻⁴; visual response in the control area of the same image is 17.0 · 10⁻⁴. Vertically orientedopen arrows in b indicate approximate extent of NT-4/5 effect as judged from the optical images. In this and subsequent figures, all images shown have been normalized to the response to a gray screen stimulus, and all images shown for a given treatment (control or experimental) have been clipped and filtered identically. Branch-like solid black or white patterns (one such indicated by curved arrow atright) in this and subsequent images are usually attributable to artifact associated with blood vessels. Scale bararrow: 1 mm, points to anterior. White stars in D eye 90° frame indicate nonorientation-selective patches of residual deprived-eye response.c, Picture of the cortical surface from which imagesa and b were obtained, showing location of electrode penetrations relative to infusion site.d–f, Ocular dominance histograms constructed from all cells encountered in electrode penetrations at sites markedd (2 penetrations), e, andf, respectively. Bias and monocularity indices near the cannula, BI of 0.60, MI = 0.23 (d); near the border delineated by the arrows, BI of 0.78, MI of 0.61 (e); and far from the cannula, BI of 0.95, MI of 0.95 (f).

Fig. 3.

Ocular dominance computed from the optical maps in NT-4/5-treated cortex show results similar to those obtained with single-unit recording. A, Ocular dominance ratio map showing an area of faint ocular dominance pattern near the cannula and more strongly modulated pattern farther from the infusion site. Nondeprived-eye response is dominant in darker areas.b, c, Color and vector field polar maps computed from the response maps, showing areas used for computation of optical CBIs near (blue dashed line) and far from (orange dashed line) the infusion site.

Fig. 4.

Polar, HLS, and ocular dominance ratio maps for control (a–c) and experimental (d–f) hemispheres after 4 d NT-4/5 infusion, with 2 d MD (same hemispheres shown in Fig. 2). In the color polar maps, hue encodes the stimulus orientation that best drives a response at a given cortical location. Regions that are sharply tuned to stimulus orientation are bright, and areas of poor orientation selectivity are darker. The HLS maps also encode stimulus orientation by color, but saturation is incorporated to indicate degree of tuning, and lightness is used instead to encode responsiveness. Conventional color polar and HLS maps (a, d) are shown for comparison with the vector field polar maps (c,f) that will be used in subsequent figures. In these maps at the right, the length of each orientedline indicates the degree of selectivity in the area surrounding that pixel. In the ocular dominance ratio maps (b, e), darker areasindicate dominance of nondeprived-eye response. Figure 3 shows a similar effect. Scale bar arrow: 1 mm, points to anterior.

Fig. 5.

Orientation selectivity of individual cortical neurons is affected by NT-4/5 infusion. a, Cortical surface of imaged area, showing position of cannula and sites of penetrations 1 and 2, overlaid by vector polar map showing extent of effect (open arrows). Average visual responsiveness in area near cannula that was affected by NT-4/5 is 2.0 · 10⁻⁴; visual response in the control area of the same image is 3.1 · 10⁻⁴.b, Polar plots of firing rate at 12 orientations for a cell encountered along penetration 1, through both deprived (D) and nondeprived (ND) eyes. Polar plots are constructed from vectors whose orientation indicates the stimulus orientation and whose magnitude shows the response to that stimulus orientation.c, Polar plots of orientation tuning for a cell recorded along penetration 2, through deprived and nondeprived eyes.d, Polar plots of orientation tuning for four cells recorded in control cortex; all responded to stimulation only through the nondeprived eye. e, Polar plots of orientation tuning of individual cortical neurons in another animal, close to the NT-4/5 cannula, for eight stimulus orientations. Inner dashed circles indicate baseline spontaneous activity. Scale bararrow: 1 mm, points to anterior

Fig. 6.

Summary figure of dose dependence of NT-4/5 effect on ocular dominance shift and on orientation selectivity in four animals, showing that the effect of NT-4/5 on ocular dominance shift, monocularity, and orientation selectivity decreases with distance from the infusion site. a, Average orientation selectivity for each penetration plotted against distance from the infusion site.b, The BI was calculated for each electrode penetration and then plotted as a function of distance of that penetration from the infusion cannula. c, The MI was calculated for each electrode penetration and plotted as a function of distance from cannula. d, Average responsiveness for each penetration as a function of distance from the infusion cannula.Filled circles indicating control values are from penetrations in control hemispheres.

Fig. 7.

Intracortical infusion of NGF did not prevent the ocular dominance shift in two animals, one of which received NGF infusion for 4 d and one for 7 d, both with 2 d MD over the final 2 d of infusion. a, b, Ocular dominance histograms constructed from cells recorded near the cannula in the two control hemispheres (a) and the two experimental hemispheres (b). NGF-treated, BI of 0.85, MI of 0.82; control, BI of 0.88, MI of 0.78.c, Immunostaining for recombinant human NGF near the cannula site, showing high levels of NGF within the area sampled by optical imaging and extracellular recording.

Fig. 8.

Intracortical infusion of NT-3 did not prevent the ocular dominance shift in two animals with 4 d NT-3 infusion and 2 d MD. a, Polar maps of cortex in which NT-3 was infused, showing well organized signal up to the cannula when stimulated through the nondeprived eye. Black dotsindicate positions of electrode penetrations for this hemisphere.b, c, Ocular dominance histograms for control (b; BI of 0.80, MI of 0.73) and experimental (c; NT-3, BI of 0.91, MI of 0.83) hemispheres.d, Immunostaining revealed that recombinant human NT-3 had reached the area from which the images and single-cell recordings were obtained (lesion in left hemisphere corresponds to tip of infusion cannula). Scale bar and scale bar arrow, 1 mm.

Fig. 9.

NT-4/5 nullifies a previous ocular dominance shift. a, Schematic of protocol for the two hemispheres shown in this figure. b–d, NT-4/5-treated hemisphere of animal whose MD began at P31. b, Polar map showing extent of infusion effect. Locations of cannula and electrode penetrations are indicated, respectively, by filled arrowheads and dots. c, Ocular dominance histograms constructed from all penetrations shown toleft of arrow in b: BI of 0.49, MI of 0.61. d, Ocular dominance histograms constructed from all penetrations shown to right ofarrow in b: BI of 0.98, MI of 0.97.e, Polar map showing extent of effect in animal whose MD began at P28. f, g, Ocular dominance histograms constructed from all cells within the penetrations, respectively, to left and right ofarrow in e. f, BI of 0.53, MI of 0.45. g, BI of 0.84, MI of 0.78. Scale bararrows, 1 mm.

Fig. 10.

Acute administration of NT-4/5 does not cause noticeable effects in <2 d. The animal shown in aexperienced MD (2 d), but no neurotrophin infusion, before physiological recording. Onset of neurotrophin infusion coincided with the beginning of recording. a, Polar maps for the NT-4/5-treated hemisphere of this animal. Black dotsindicate locations of two penetrations from which ocular dominance histogram (b) was made. BI of 0.83, MI of 0.78.c, Immunostaining reveals the presence of high levels of recombinant human NT-4/5 within the area from which imaging and electrode recordings had taken place. Cannula lesion is visible in tissue section at this level. d, Polar maps for animal that experienced MD for 2 d concurrent with NT-4/5 infusion. Scale bar and scale bar arrows, 1 mm.

Fig. 11.

NT-4/5 infusion has no effect on cortex of an animal 6 months of age. a, Polar maps from the hemisphere of a 6-month-old animal, monocularly deprived at P28, that received 4 d NT-4/5 infusion immediately before recording.Black dot indicates position of penetration from which ocular dominance histogram (b) was made. BI of 1.0, MI of 1.0. c, Tissue section at level of cannula, immunostained for recombinant human NT-4/5, showing extent of NT-4/5 spread from cannula. Scale bar and scale bar arrow, 1 mm.