Krystel R. Huxlin

Perceptual relearning of complex visual motion after V1 damage in humans

Damage to the adult, primary visual cortex (V1) causes severe visual impairment that was previously thought to be permanent, yet several visual pathways survive V1 damage, mediating residual, often unconscious functions known as “blindsight.” Because some of these pathways normally mediate complex visual motion perception, we asked whether specific training in the blind field could improve not just simple but also complex visual motion discriminations in humans with long-standing V1 damage. Global direction discrimination training was administered to the blind field of five adults with unilateral cortical blindness. Training returned direction integration thresholds to normal at the trained locations. Although retinotopically localized to trained locations, training effects transferred to multiple stimulus and task conditions, improving the detection of luminance increments, contrast sensitivity for drifting gratings, and the extraction of motion signal from noise. Thus, perceptual relearning of complex visual motion processing is possible without an intact V1 but only when specific training is administered in the blind field. These findings indicate a much greater capacity for adult visual plasticity after V1 damage than previously thought. Most likely, basic mechanisms of visual learning must operate quite effectively in extrastriate visual cortex, providing new hope and direction for the development of principled rehabilitation strategies to treat visual deficits resulting from permanent visual cortical damage.

Retinal ganglion cells in the albino rat: Revised morphological classification

Rat retinal ganglion cells were traditionally classified on the basis of soma size and the morphology of their dendritic fields. However, in the past, techniques used to label ganglion cells (horseradish peroxidase, Golgi, or the neurofibrillar stain) did not always stain the axon and/or the entire dendritic field. In the present study, we have labelled retinal ganglion cells in the adult albino rat with the carbocyanine dye 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindo‐carbocyanine perchlorate (DiI) or have intracellularly injected them with Neurobiotin. Such procedures enabled us to completely fill these neurons, and our findings prompted us to modify the existing retinal ganglion cell classification in the rat. First, cells were categorised into three groups on the basis of soma and dendritic field size: Group RGA cells have large somata and dendritic field diameters, Group RGB cells have small somata and dendritic field diameters, whereas Group RGC cells have small to medium‐sized somata and medium‐to‐large dendritic field diameters. On the basis of dendritic field morphology and presence across the retina, each Group was then subdivided into subgroups. The significance of our results in terms of retinal ganglion cell function is discussed. J. Comp. Neurol. 385:309–323, 1997.

The origin and development of retinal astrocytes in the mouse

SummaryAstrocytes, a class of glia which appear in the mammalian retina late in development, have been postulated either to originatein situ from Müller cells or extra-retinally from the optic stalk epithelium, only subsequently invading the eye. The site of origin and the developmental characteristics of retinal astrocytes were examined in the mouse, a species not previously studied for this purpose. Sections of normal eyes and stalks at different ages were examined. Cells positive for glial fibrillary acidic protein (GFAP) were first observed at post-conceptional day 17 at the optic disc end of the stalk. From this site, the GFAP-positive cells migrated into and across the retina at a rate of ∼290 μm per day, reaching its edge by post-conceptional day 28. While migrating across the retina, the astrocytes progressively increased in size and morphological complexity, observations confirmed by measurement of their fractal dimension. Over the same period, a wave of differentiation swept along the stalk in the cranial direction. Further evidence that retinal astrocytes are born outside the retina emerged when foetal hemiretinae with or without optic stalks were explanted to the chorioallantoic membrane of the chick. When examined one to twelve days later, no expiant cultured without the optic stalk contained GFAP-positive astrocytes, while expiants with the stalk left attached contained relatively normal numbers of astrocytes. We observed, using fluorescence confocal microscopy, that retinal astrocytes in the mouse as in the rat, associate predominantly with blood vessels, not axonal bundles. It was of interest to determine whether this class of glia is essential to the normal cytoarchitectural development of the neural retina. Morphological analysis of the expiants revealed no observable differences in cytoarchitecture or in the timing of developmental events between retinae maturing with or without astrocytes. It was therefore concluded that astrocytes may not be essential to the normal structural development of the murine retina.

Electrophilic Peroxisome Proliferator–Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts

Pulmonary fibrosis is a progressive scarring disease with no effective treatment. Transforming growth factor (TGF)-beta is up-regulated in fibrotic diseases, where it stimulates differentiation of fibroblasts to myofibroblasts and production of excess extracellular matrix. Peroxisome proliferator-activated receptor (PPAR) gamma is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that a novel PPARgamma ligand, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), is a potent inhibitor of TGF-beta-stimulated differentiation of human lung fibroblasts to myofibroblasts, and suppresses up-regulation of alpha-smooth muscle actin, fibronectin, collagen, and the novel myofibroblast marker, calponin. The inhibitory concentration causing a 50% decrease in aSMA for CDDO was 20-fold lower than the endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15 d-PGJ(2)), and 400-fold lower than the synthetic ligand, rosiglitazone. Pharmacologic and genetic approaches were used to demonstrate that CDDO mediates its activity via a PPARgamma-independent pathway. CDDO and 15 d-PGJ(2) contain an alpha/beta unsaturated ketone, which acts as an electrophilic center that can form covalent bonds with cellular proteins. Prostaglandin A(1) and diphenyl diselenide, both strong electrophiles, also inhibit myofibroblast differentiation, but a structural analog of 15 d-PGJ(2) lacking the electrophilic center is much less potent. CDDO does not alter TGF-beta-induced Smad or AP-1 signaling, but does inhibit acetylation of CREB binding protein/p300, a critical coactivator in the transcriptional regulation of TGF-beta-responsive genes. Overall, these data indicate that certain PPARgamma ligands, and other small molecules with electrophilic centers, are potent inhibitors of critical TGF-beta-mediated profibrogenic activities through pathways independent of PPARgamma. As the inhibitory concentration causing a 50% decrease in aSMA for CDDO is 400-fold lower than that in rosiglitazone, the translational potential of CDDO for treatment of fibrotic diseases is high.

Perceptual plasticity in damaged adult visual systems

Plasticity appears to be a ubiquitous property of nervous systems, regardless of developmental stage or complexity. In the visual system of higher mammals, perceptual plasticity has been intensively studied, both during development and in adulthood. However, the last few years have seen some significant controversies arise about the existence and properties of visual plasticity after permanent damage to the adult visual system. The study of perceptual plasticity in damaged, adult visual systems is of interest for several reasons. First, it is an important means of unmasking the relative contribution of individual visual areas to visual learning, adaptation and priming, among other plastic phenomena. Second, it can provide knowledge that is essential for the development of effective therapies to rehabilitate the increasing number of people who suffer the functional consequences of damage at different levels of their visual hierarchy. This review summarizes the available evidence on the subject and proposes that visual plasticity may be just as ubiquitous after damage as it is in the intact visual system. However, damage may alter visual plasticity in ways that are still being defined.

New Approaches to Visual Rehabilitation for Cortical Blindness: Outcomes and Putative Mechanisms

Cortical blindness is a chronic loss of vision following damage to the primary visual cortex (V1) or its postchiasmal afferents. Such damage is followed by a brief period of spontaneous plasticity that rarely lasts beyond 6 months. Following this initial phase, the visual deficit is thought to be stable, intractable, and permanent. Cortically blind subjects demonstrate spontaneous oculomotor adaptations to their deficits that can be further improved by saccadic localization training. However, saccadic training does not improve visual sensitivity in the blind field. In contrast, recent studies by a number of independent groups suggest that localized, repetitive perceptual training can improve visual sensitivity in the blind field, although mechanisms underlying the observed recovery remain unclear. This review discusses the current literature on rehabilitative strategies used for cortical blindness with emphasis on the use of perceptual training methods. The putative mechanisms that underlie the resulting, training-induced visual improvements are then outlined, along with the special challenges posed to their elucidation by the great variability in the extent and sometimes nature of the V1 damage sustained in different individuals.

NADPH diaphorase expression in the rat retina after axotomy--a supportive role for nitric oxide.

The large majority of mammalian retinal ganglion cells degenerate following section of their axons in the optic nerve. It has been suggested that some axotomized retinal ganglion cells die because of toxic agents produced within their immediate environment. Our hypothesis was that nitric oxide might be one of the toxic factors implicated in the death of adult retinal ganglion cells post‐axotomy. In the first instance, we determined whether there were any changes in the retinal expression of NADPH diaphorase both 3 and 14 days following intraorbital section of the optic nerve in adult rats. Secondly, if nitric oxide was indeed implicated in the death of ganglion cells, then trophic factors which rescue these neurons might do so by decreasing the expression of nitric oxide synthase. Recently, we found that a collicular proteoglycan purified from the major target of retinal ganglion cells, the superior colliculus, rescued a greater proportion of adult ganglion cells from axotomy‐induced death than most other known trophic factors. We thus injected this proteoglycan intraocularly after section of the optic nerve and examined its effect on the expression of NADPH diaphorase in the retina. Thirdly, an inhibitor of nitric oxide synthetase was repeatedly injected into the eye following the section of the optic nerve in order to determine if such a treatment might improve the survival of retinal ganglion cells. The present results indicate that section of the optic nerve does not alter the overall levels of NADPH diaphorase within the adult rat retina. Intraocular injections of the collicular proteoglycan actually increased the number of neurons expressing NADPH diaphorase, particularly in the ganglion cell layer. Finally, inhibition of nitric oxide synthetase following axotomy resulted in increased loss of retinal ganglion cells over a 2 week period when compared with controls. Our findings indicate that, rather than being toxic, small amounts of nitric oxide may be important for the survival of a proportion of injured retinal ganglion cells.

Beyond Blindsight: Properties of Visual Relearning in Cortically Blind Fields

Damage to the primary visual cortex (V1) or its immediate afferents results in a dense scotoma, termed cortical blindness (CB). CB subjects have residual visual abilities, or blindsight, which allow them to detect and sometimes discriminate stimuli with high temporal and low spatial frequency content. Recent work showed that with training, discriminations in the blind field can become more reliable, and even reach consciousness. However, the narrow spatiotemporal bandwidth of blindsight limits its functional usefulness in everyday vision. Here, we asked whether visual training can induce recovery outside the spatiotemporal bandwidth of blindsight. Specifically, could human CB subjects learn to discriminate static, nonflickering stimuli? Can such learning transfer to untrained stimuli and tasks, and does double training with moving and static stimuli provide additional advantages relative to static training alone? We found CB subjects capable of relearning static orientation discriminations following single as well as double training. However, double training with complex, moving stimuli in a separate location was necessary to recover complex motion thresholds at locations trained with static stimuli. Subjects trained on static stimuli alone could only discriminate simple motion. Finally, both groups had approximately equivalent, incomplete recovery of fine orientation and direction discrimination thresholds, as well as contrast sensitivity. These results support two conclusions: (1) from a practical perspective, complex moving stimuli and double training may be superior training tools for inducing visual recovery in CB, and (2) the cortically blind visual system can relearn to perform a wider range of visual discriminations than predicted by blindsight alone.

Visually-guided behavior of homonymous hemianopes in a naturalistic task

The gaze behavior of homonymous hemianopes differs from that of visually intact observers when performing simple laboratory tasks. To test whether such compensatory behavior is also evident during naturalistic tasks, we analyzed the gaze patterns of three long-standing hemianopes and four visually intact controls while they assembled wooden models. No significant differences in task performance, saccade dynamics or spatial distribution of gaze were observed. Hemianopes made more look-ahead fixations than controls and their gaze sequences were less predictable. Thus hemianopes displayed none of the compensatory gaze strategies seen in laboratory tasks. Instead, their gaze patterns suggest greater updating of, and greater reliance on a spatial representation.

Effect of Collicular Proteoglycan on the Survival of Adult Rat Retinal Ganglion Cells Following Axotomy

Consistent with numerous previous studies, we have found that in adult rats 29% of cells retrogradely prelabelled by injections into retino‐recipient nuclei are lost 1 week after intraorbital section of the optic nerve. This figure increases to 76% 2 weeks after axotomy. Intraocular injections of 150 ng of 480 kda chondroitin sulphate proteoglycan purified from the superior colliculi of neonatal rats were performed every third day after axotomy. This procedure resulted in the loss of only 3 and 28% of the axotomized retinal ganglion cells 7 and 14 days respectively after optic nerve section. Intraocular injections of chondroitin sulphate type C, one of the sugar types present on the collicular proteoglycan, also resulted in a significant saving of axotomized ganglion cells (with the loss of only 48% 14 days after optic nerve lesion). These findings suggest that the collicular proteoglycan, and to a lesser extent its sugar moieties, substantially slows down the degeneration of adult retinal ganglion cells following axotomy.