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Mutations in the cellular retinaldehyde-binding protein (CRALBP, encoded by RLBP1) can lead to severe cone photoreceptor-mediated vision loss in patients. It is not known how CRALBP supports cone function or how altered CRALBP leads to cone dysfunction. Here, we determined that deletion of Rlbpl in mice impairs the retinal visual cycle. Mice lacking CRALBP exhibited M-opsin mislocalization, M-cone loss, and impaired cone-driven visual behavior and light responses. Additionally, M-cone dark adaptation was largely suppressed in CRALBP-deficient animals. While rearing CRALBP-deficient mice in the dark prevented the deterioration of cone function, it did not rescue cone dark adaptation. Adeno-associated virus- mediated restoration of CRALBP expression specifically in Muller cells, but not retinal pigment epithelial (RPE) cells, rescued the retinal visual cycle and M-cone sensitivity in knockout mice. Our results identify Muller cell CRALBP as a key component of the retinal visual cycle and demonstrate that this pathway is important for maintaining normal cone-driven vision and accelerating cone dark adaptation., Introduction Photoactivation of a visual pigment molecule in vertebrate rod and cone photoreceptors rapidly triggers a light response and concomitantly renders the activated pigment unable to detect a subsequent photon [...]

Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, [alpha]-, [beta]-, and [gamma]-synuclein. [alpha]-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized [alpha][beta][gamma]-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by ~30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease. neurodegeneration | loss-of-function | Lewy bodies | ultrastructure | retina doi/ 10.1073/pnas.1005005107

Humans can resolve the fine details of visual stimuli although the image projected on the retina is constantly drifting relative to the photoreceptor array. Here we demonstrate that the brain must take this drift into account when performing high acuity visual tasks. Further, we propose a decoding strategy for interpreting the spikes emitted by the retina, which takes into account the ambiguity caused by retinal noise and the unknown trajectory of the projected image on the retina. A main difficulty, addressed in our proposal, is the exponentially large number of possible stimuli, which renders the ideal Bayesian solution to the problem computationally intractable. In contrast, the strategy that we propose suggests a realistic implementation in the visual cortex. The implementation involves two populations of cells, one that tracks the position of the image and another that represents a stabilized estimate of the image itself. Spikes from the retina are dynamically routed to the two populations and are interpreted in a probabilistic manner. We consider the architecture of neural circuitry that could implement this strategy and its performance under measured statistics of human fixational eye motion. A salient prediction is that in high acuity tasks, fixed features within the visual scene are beneficial because they provide information about the drifting position of the image. Therefore, complete elimination of peripheral features in the visual scene should degrade performance on high acuity tasks involving very small stimuli. computation | fixational eye motion | neural network | retina | codex doi/ 10.1073/pnas.1006076107

Epiretinal prostheses are being developed to bypass a degenerated photoreceptor layer and excite surviving ganglion and inner retinal cells. We used custom microfabricated multielectrode arrays with 200-[micro]m-diameter stimulating electrodes and 10-[micro]m-diameter recording electrodes to stimulate and record neural responses in isolated tiger salamander retina. Pharmacological agents were used to isolate direct excitation of ganglion cells from excitation of other inner retinal cells. Strength-duration data suggest that, if amplitude will be used for the coding of brightness or gray level in retinal prostheses, shorter pulses (200 [micro]s) will allow for a smaller region in the area of the electrode to be excited over a larger dynamic range compared with longer pulses (1 ms). Both electrophysiological results and electrostatic finite-element modeling show that electrode-electrode interactions can lead to increased thresholds for sites half way between simultaneously stimulated electrodes (29.4 [+ or -] 6.6 nC) compared with monopolar stimulation (13.3 [+ or -] 1.7 nC, p < 0.02). Presynaptic stimulation of the same ganglion cell with both 200- and 10-[micro]m-diameter electrodes yielded threshold charge densities of 12 [+ or -] 6 and 7.66 [+ or -] 1.30 nC/[cm.sup.2], respectively, while the required charge was 12.5 [+ or -] 6.2 and 19 [+ or -] 3.3 nC. Index Terms--Microelectrodes arrays, retinal electrophysiology, retinal prosthesis.

The widespread availability of electronic imaging devices throughout the medical community is leading to a growing body of research on image processing and analysis to diagnose retinal disease such as diabetic retinopathy (DR). Productive computer-based screening of large, at-risk populations at low cost requires robust, automated image analysis. In this paper we present results for the automatic detection of the optic nerve and localization of the macula using digital red-free fundus photography. Our method relies on the accurate segmentation of the vasculature of the retina followed by the determination of spatial features describing the density, average thickness, and average orientation of the vasculature in relation to the position of the optic nerve. Localization of the macula follows using knowledge of the optic nerve location to detect the horizontal raphe of the retina using a geometric model of the vasculature. We report 90.4% detection performance for the optic nerve and 92.5% localization performance for the macula for red-free fundus images representing a population of 345 images corresponding to 269 patients with 18 different pathologies associated with DR and other common retinal diseases such as age-related macular degeneration. Index Terms--Bayesian classifier, diabetic retinopathy, feature analysis, macula localization, optic nerve detection, red-free fundus imagery, vascular segmentation.

In the framework of computer-aided diagnosis of eye diseases, retinal vessel segmentation based on line operators is proposed. A line detector, previously used in mammography, is applied to the green channel of the retinal image. It is based on the evaluation of the average grey level along lines of fixed length passing through the target pixel at different orientations. Two segmentation methods are considered. The first uses the basic line detector whose response is thresholded to obtain unsupervised pixel classification. As a further development, we employ two orthogonal line detectors along with the grey level of the target pixel to construct a feature vector for supervised classification using a support vector machine. The effectiveness of both methods is demonstrated through receiver operating characteristic analysis on two publicly available databases of color fundus images. Index Terms--Classification, line detector, retinal imaging, support vector machines (SVM), vessel segmentation.

Segmentation of bright blobs in an image is an important problem in computer vision and particularly in biomedical imaging. In retinal angiography, segmentation of drusen, a yellowish deposit located on the retina, is a serious challenge in proper diagnosis and prevention of further complications. Drusen extraction using classic segmentation methods does not lead to good results. We present a new segmentation method based on new transformations we introduced in mathematical morphology. It is based on the search for a new class of regional maxima components of the image. These maxima correspond to the regions inside the drusen. We present experimental results for drusen extraction using images containing examples having different types and shapes of drusen. We also apply our segmentation technique to two important cases of dynamic sequences of drusen images. The first case is for tracking the average gray level of a particular drusen in a sequence of angiographic images during a fluorescein exam. The second case is for registration and matching of two angiographic images from widely spaced exams in order to characterize the evolution of drusen. Index Terms--Drusen, edge detection, eye fundus angiography, geodesic reconstruction, image segmentation, mathematical morphology, registration.

Retinoblastoma is a rapidly growing, usually inherited tumor originating in retinal germ cells. The tumor may invade the brain and spread to distant sites. It is the most common primary malignant eye tumor in children. The usual pattern of inheritance is autosomal dominant; parents with the gene have a 50 percent chance of passing the mutant gene on to their children. About 10 percent of those carrying the mutant gene do not develop the tumor. Retinoblastoma may spontaneously regress, resulting in normal vision, so that the disease may remain undetected. Retinoblastoma may occur sporadically without obvious inheritance; parents of these cases should be examined for regressed retinoblastoma scars. A case is presented of a family where the phenotype segregated with unusual characteristics. The phenotype was expressed in varying degrees ranging from asymptomatic carriers of the gene or regressed tumors, to unifocal and bilateral multifocal tumors. Initial genetic counseling was difficult because of the incomplete penetrance (frequency of manifestation of a genetic feature) and complete ophthalmological examination of the seemingly normal family members was not performed. Using DNA probes, regressed tumors were shown in founder members of the family; this confirmed inherited disease. The pedigree of this family reinforces the need for detailed genetic analysis using DNA probes as well as ophthalmological examination of close relatives. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abstract Aims--To investigate the predictive value of the cone b-wave implicit time in the photopic compared with the scotopic 30 Hz flicker ERG for rubeosis in central retinal vein occlusion. [...]