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Focus on Fellows 2012 Abstracts


Reticular Drusen: Natural History and Effect on Retinal Function

Benjamin Nicholson1, Divya Nigam1, Mei Zhou2, Brett Jeffrey3, Wai Wong4, Elvira Agron5, Emily Chew1

1Clinical Trials Branch, Division of Epidemiology & Clinical Application, National Eye Institute, National Institutes of Health; 2Pritzker School of Medicine, University of Chicago; 3Ophthalmic Genetics & Visual Function Branch; 4Unit on Neuron-Glia Interactions in Retinal Disease; & 5Biostatistics Branch, Division of Epidemiology & Clinical Application, National Eye Institute, National Institutes of Health

Purpose: To better understand the natural history of reticular drusen and their effect on retinal function.
Methods: Fundus images of patients with AMD were evaluated retrospectively for reticular drusen. A retrospective, longitudinal analysis of reticular drusen number, area, and density was then conducted. Patients with known reticular drusen who presented to the NEI in late 2011 underwent microperimetry. The mean retinal sensitivities within areas of reticular drusen were compared with mean retinal sensitivities in unaffected areas. Patients in the NEI study of dark adaptation in AMD were retrospectively screened for reticular drusen, and their standard dark adaptometry results were assessed. A subset underwent modified dark adaptation testing at a point twelve degrees from the fovea since most subjects timed out at five degrees.
Results: 28 eyes of 19 patients qualified for longitudinal analysis. All 28 eyes developed more reticular drusen over time, and this occurred at a mean rate of 119±49.1 drusen/year. The affected area also grew in all patients at a rate of 4.3±2.7 mm2/year. The density of reticular drusen increased at a rate of 2.8±3.2 reticular drusen/mm2 yearly. 36 eyes of 23 patients underwent microperimetry. The mean retinal sensitivity in areas of reticular drusen was 9.79 dB (95% CI 9.25-10.32) and the mean sensitivity in unaffected areas was 13.00 dB (12.47-13.54, p < 0.001). Eight eyes with reticular drusen underwent standard dark adaptometry, and all had severely prolonged rod intercept times (>20 minutes). Six eyes underwent modified dark adaptation testing, and the mean rod intercept time was 22.2±6.60 minutes. A greater area of reticular drusen was associated with a longer modified rod intercept time (p < 0.001).
Conclusions: This small study suggests that reticular drusen increase in number, area, and density over time. They appear to be associated with reduced retinal sensitivity. Reticular drusen also may be associated with impaired dark adaptation.

Understanding the Genetic Architecture of Macular Degeneration using Exome Sequencing

Rinki Ratna Priya1, Xiaowei Zhan2, Robert Fariss3, Christina Chakarova4, Milton English1, Yuri Sergeev5, Kari Branham6, Mercedes Campos4, Margaux Morrison7, Naushin Waseem4, James Friedman8, Matthew Brooks1, Harsha Rajasimha1, Samuel G. Jacobson9, Raman Sood10, Paul Liu10, Michael Klein11, Emily Chew12, Dwight Stambolian113, Margaret M. DeAngelis7, Shomi Bhattacharya4, John R. Heckenlively6, Goncalo Abecasis2, Anand Swaroop1

1Retinal Development & Genetics Section, Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health; 2Center for Statistical Genetics, Department of Biostatistics, University of Michigan; 3Biological Imaging Core, National Eye Institute, National Institutes of Health; 4Department of Molecular Genetics, Institute of Ophthalmology, United Kingdom; 5Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health; 6Department of Ophthalmology, University of Michigan; 7Department of Ophthalmology & Visual Sciences, University of Utah; 8Department of Ophthalmology, University of Colorado, Anschutz Medical Campus; 9Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania; 10Genetics & Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health; 11Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University; 12Clinical Trials Branch, Division of Epidemiology & Clinical Application, National Eye Institute, National Institutes of Health; 13Departments of Ophthalmology & Genetics, University of Pennsylvania

Inherited macular dystrophies are a collection of clinically and genetically heterogeneous group of disorders characterized by progressive loss of visual acuity due to macular dysfunction. Age-related macular degeneration (AMD) represents the most common late-onset heritable macular disease, affecting nearly 0.2% of the population between 55 to 64 years of age and 13% of those above 85 years of age in developed countries. Stargardt macular dystrophy, Best macular dystrophy, Sorsby’s fundus dystrophy and Doyne honeycomb retinal dystrophy are some of the early onset macular forms. Both early and late disease share clinical features and thus identification of causative genes in various early-onset forms has often provided important genetic insights into pathogenesis of AMD.

Remarkable progress has been made in delineating the genetics of AMD, with over 50% of the heritability explained by the 19 genetic loci so far. However understanding their role in disease has been challenging as most common associated variants have only subtle functional consequences. It has been recently postulated that disease risk could be cumulative effect of multiple rare and low-frequency causal alleles. Exome sequencing provides a systematic and high-throughput method for identification of coding variant. Thus in an attempt to identify the variants that might confer risk I have done exome sequencing in several families with early and late onset macular degeneration. In one such instance, I have identified a novel extracellular matrix gene, FBN2 in a two-generation family with early onset dominant macular dystrophy. Immunofluorescence studies in human and monkey eyes localized FBN2 in Bruch’s membrane, choroid, and sclera. Extra¬cellular deposits within or adjacent to Bruch’s membrane are often clinically associated with AMD and that prompted us to explore the role of common variants in FBN2 with AMD. Our analysis revealed the association of a non-synonymous (Val965Ile) SNP, rs154001, with AMD (p value=1.03×10-4; odds ratio= 0.85). Our results advocate the role of a novel ECM gene, FBN2, in macular pathogenesis, and establishes an important link between rare and common forms of maculopathy.

Role of Interleukin-27 and IRF Transcription Factors in the Regulation of Complement Factor H (CFH) Expression in the Retina and Intraocular Inflammation

Sung-Hye "Grace" Kim, Ahjoku Amadi-Obi, Cheng-Rong Yu, Ivy Dambuza, Bernadette Marrero, Charles Egwuagu

Molecular Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health

Complement factor H (CFH) is a central regulator of the complement system and has been implicated in the etiology of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Defects in CFH expression in the retina is a risk factor for AMD and this has led to significant interest in understanding how CFH expression is regulated in the retina. In this study, we have shown that the anti-inflammatory cytokine, IL-27, regulates CFH expression in mouse retinal cells and human retinal pigmented epithelial cells (RPE) through STAT1-mediated up-regulation of Interferon Regulatory Factor-1 (IRF-1) and IRF-8. We further show that cells in the ganglion and inner-nuclear layers of the retina constitutively express IRF-1 and IRF-8 and enhanced CFH expression in the retina during ocular inflammation correlated with significant increase in the expression of IRF-1, IRF-8, and IL-27 (IL-27p28 and Ebi3). Our data thus reveal a novel role of IL-27 and IRFs in regulating CFH and possibly the activation of complement and other pro-inflammatory proteins. To further understand the role of IRFs in the retina, particularly during intraocular inflammation, we have generated mice with a conditional deletion of IRF-8 in the retina as well as in CD4 T cells. Partial analysis of these mutant mice reveals a double-edge effect of IRF-8 during experimental autoimmune uveitis, a model of human uveitis. While deletion of IRF-8 in T cells exacerbated EAU, deletion of IF8 in retinal cells appears to confer protection of the retina from intraocular inflammation.

Believing is Seeing: Constructing the Visual World with Cortical Neurons

Ali Moeeny, Bruce Cumming

Vision Section, Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health

To study the role of individual neurons in transforming the sensory input into actions, we chose to present neurons in area MT with an unchanging stimulus while manipulating subject’s perception in each trial and study the relation of neuronal activity with decisions. We trained monkeys for a rotation direction discrimination task. On each trial, two cylinders (made by dots randomly placed on the surface of a transparent cylinder rotating about its axis) were presented for two seconds. One cylinder were positioned inside the receptive field (RF) of the neurons under study and the other one (biasing cylinder) was positioned outside the RF, oriented so that it was rotating about the same axis. Dots on the biasing cylinder carried binocular disparity. In each trial disparity was assigned so that the cylinder was rotating with its front surface moving to either the left or right (randomly chosen), while all the dots on the cylinder inside the receptive field had zero disparity, as a result the cylinder was physically ambiguous. In each trial, the biasing cylinder affects the way the stimulus is being perceived. We found that neurons in visual area MT respond differently when subject’s perception of the stimulus is biased to different choices. We quantified this effect by calculating the area under the ROC curve, and showed that these differences are not only significant but also comparable in size to what previous studies attributed to the differences in the input signal caused by fluctuations in the input noise. This implies that there is a top-down component contributing to fluctuations in responses of sensory neurons in area MT, and this top-down component can explain a significant part of what previously believed to be random noise in the afferent input these cells receive. This suggests that the animal’s perception causes the changes in firing rate associated with choice, rather than firing rate causing the choice.

Sterculic Acid Inhibits 7-ketocholesterol-mediated Corneal Angiogenesis

Joshua Chou, Juan Amaral, Ignacio Rodriguez

Mechanisms of Retinal Disease Section, Laboratory of Retinal Cell & Molecular Biology, National Eye Institute, National Institutes of Health

Purpose: The purpose of this study is to determine if sterculic acid (SA) and sterculia oil (SO) will inhibit 7-ketocholesterol (7KCh)-mediated inflammation and angiogenesis in vivo.
Methods: An angiogenesis model was developed in rats by placing implants containing 7KCh, SA, and/or SO in the anterior chamber of the eye. The implants were prepared using a mixture of poly (2-hydroxyethymethacrylate) and polyethylene glycol 20K (50:50 w/w) then adding the appropriate amount of 7KCh, SA, and/or SO. Corneal vessel growth was imaged at 7, 10, 14, and 21 days after implantation by fluorescein angiography using a dissecting microscope equipped with a fluorescent lamp. Neovessels were quantified by area measurement using the Nikon NIS elements software.
Results: Four different 7KCh concentrations were used in the implants, 5%, 7%, 10%, and 15% (w/w). All concentrations of 7KCh consistently induced corneal angiogenesis. Peak neovessel growth was observed for all concentrations at 7 days after implantation. Neovessel area regressed after 21 days. Various combinations of 7KCh and SA were tested (0.1, 1, 2.5, 5% SA + 5% 7KCh; 0.1, 0.5% SA+7% 7KCh; 10% SA + 10% 7KCh). SA significantly inhibited 7KCh-mediated angiogenesis at a concentration as low as 0.1% SA and 7% 7KCh (w/w). The reduction in neovessel growth in SA-containing implants ranged from 30% to 60%. SO also significantly inhibited 7KCh-mediated angiogenesis at a concentration as low as 1% SO + 7% 7KCh (w/w).
Conclusions: 7KCh promotes angiogenesis and inflammation in vivo, while SA and SO effectively antagonizes these effects. Our results further support our hypothesis that 7KCh accumulation in Bruch’s membrane and the choroid may be an "age-related" risk factor in the pathogenesis of AMD. SA and/or SO may be potential therapeutic agents for the treatment of AMD.

Low-hydration, Compact Structure in Solution is a Conserved Property of Diverse γ-Crystallins from Fish to Mammals

Yingwei Chen1, Huaying Zhao2, Peter Schuck2, Graeme Wistow1

1Molecular Structure & Functional Genomics Section, National Eye Institute & 2Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health

Γ-crystallins are highly specialized, long-lived proteins in the vertebrate eye lens. They have strongly conserved structural features but also show striking differences among species. The amino acid compositions of these proteins are unusual, probably evolutionarily selected for their contribution to refractive index. In mammals, γ-crystallins have high contents of sulfur-containing methionine and cysteine but this reaches extremes in fish γM-crystallins (up to 14% Met). In addition, fish γM-crystallins do not conserve the paired tryptophan residues found in each domain in mammalian γ-crystallins. To gain insight into the core conserved functionality of γ-crystallins, γM2b (21 Met, 10 Cys, 1 Trp) and γM7 (16 Met, 8 Cys, 2 Trp) from zebrafish (Danio rerio) lens were compared with mouse γS (4 Met, 7 Cys, 4 Trp) and human γD (4 Met, 6 Cys, 4 Trp). The far UV CD spectra of both γM2b and γM7 showed the expected β-sheet secondary structure. Like the mammalian proteins, γM7 was highly soluble but γM2b was much less so. The thermal and denaturant stability of both fish proteins was lower than either mammalian protein. All four proteins could be protected from aggregation by human αβ-crystallin, but to differing degrees, suggesting differences in chaperone affinity. Solution behavior was investigated by analytical ultracentrifugation (AUC). Surprisingly, despite other differences, both fish and mammalian γ-crystallins had very similar hydrodynamic properties consistent with unusually compact, low hydration structures. The solution behavior of γ-crystallins seems key to their primary function in lens: it is highly conserved and appears largely independent of amino acid composition.

Role of CEP290 in Ciliogenesis in Photoreceptors and Other Cells

Erin Yamamoto1, Rivka Rachel1, Helen May-Simera2, Tiansen Li2, Lijin Dong3, Anand Swaroop1

1Retinal Development & Genetics Section & 2Retinal Cell Biology & Degeneration Section, Neurobiology-Neurodegeneration & Repair Laboratory & 3Genetic Engineering Facility, National Eye Institute, National Institutes of Health

Mutations in CEP290, which encodes a centrosomal/cilia protein, result in a range of human ciliopathies including Leber congenital amaurosis. The aim of this project is to understand CEP290 function by analyzing phenotypes of the CEP290-knockout (CEP290-/-) mouse. We have observed phenotypes in the retina, brain, and kidney. In the retina, CEP290 localizes to connecting cilia of the photoreceptor cells. The absence of CEP290 leads to early retinal degeneration in the CEP290-/- mice, characterized by loss of photoreceptors and a substantial decrease in ONL thickness between P14 and P28. Although basal bodies and associated microtubule assemblies are present, photoreceptor connecting cilia and outer segments fail to develop; CEP290 expression is also found in the ciliary transition zone of ependymal cells of the brain ventricles. A vast majority (80-100%) of CEP290-/- mice develop lethal hydrocephalus between two and four weeks of age. Compared to tufts of cilia lining the WT ventricular epithelium, ependymal cells in the CEP290-/- mice have reduced numbers of unorganized cilia. CEP290 also localizes to cilia in the renal tubules. Lack of CEP290 causes a mild/delayed development of kidney cysts. Our results indicate that CEP290 plays a critical role in ciliogenesis and/or cilia function, particularly in photoreceptors, and have begun to shed light on underlying mechanisms in ciliopathies. Our studies of CEP290 action and function aim to develop therapeutic approaches to rescue retinal degeneration and other ciliopathy phenotypes as a result of cilia dysfunction.

Nlz1 is Required for Cilia Formation and Regulated by Wnt/β-catenin Signaling

Sunit Dutta, Shahila Sriskanda, Ramakrishna Alur, Brian Brooks

Unit on Pediatric, Developmental, & Genetic Ophthalmology, Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health

Cilia are microtubule-based cellular structures that have been implicated in diverse biological functions, including motility, cell signaling and sensory perception. In human, impaired biogenesis or function of cilia results in a spectrum of phenotypes, collectively termed ciliopathies.
Recent studies in our lab identified a unique role of Nlz1/Znf703 in optic fissure closure. However, its role in development of other organ systems is not well understood. In this report, we describe a novel role of Nlz1 protein in motile cilia formation by utilizing zebrafish and mammalian cell culture systems. We show that morpholino-mediated knock down of Nlz1 in zebrafish embryos show a spectrum of defects that are reminiscent of human ciliopathies. Nlz1 is essential for motile cilia formation in Kuffer’s vesicle (KV, the analogous structure to the mammalian node), kidney, and floorplate. Moreover, we observed Nlz1 expression in zebrafish KV as well as in the ciliary basal body of mouse inner medullary collecting duct cells, suggest a possible role of Nlz1 in cilia formation and its function. Genetic analysis in vertebrates identified a forkehead transcription factor, FoxJ1 as the "master regulator" of motile cilia formation. We identified a FoxJ1 consensus element in the Nlz1 promoter and demonstrate by foxJ1 knockdown in zebrafish and chromatin immune precipitations (CHIP) assay that FoxJ1 acts upstream of Nlz1. Finally, we provide evidence that suggest Nlz1 expression in zebrafish is regulated by Wnt signaling and overexpression of the protein in cultured cells antagonize canonical Wnt signaling. Together our results suggest a role of Nlz1 in cilia formation by repressing canonical Wnt signaling pathway. Furthermore, we have identified three mutations in Nlz1 gene, P307L, P253L, and T178A, from human patients with coloboma, Joubert syndrome, and heterotaxy syndrome. Our current research is focused on understanding the function of the mutant proteins to get insight on molecular mechanism of Nlz1.

Cone Photoreceptor Afferents and Dendritic Development of S-cone Bipolar Cells in the Mouse Retina

Li Jia, Wei Li

Unit on Retinal Neurophysiology, National Eye Institute, National Institutes of Health

How neuronal processes develop and establish connections with proper synaptic partners is one of the fundamental questions of neuroscience. The vertebrate retina offers an outstanding model system. One of the critical visual functions, color vision, requires precise wiring of retinal neurons. In the mouse retina, there are two types of cone photoreceptors, the short wavelength sensitive cones (S-cones), which only express S-opsin, and the long wavelength sensitive cones (M-cones), many of which co-express S-opsin. In order to generate color opponency, signals from these two types of cones have to be segregated before they are contrasted at the ganglion cell level. S-cones only account for 3-5% of the total cone population. Thus, the downstream S-cone bipolar cells (SCBCs) face the daunting task of seeking out very sparse S-cones from a sea of M-cones. The outcome is that SCBCs develop a very unique dendritic arbor with long, meager dendrites contacting a handful of S-cones. This distinctive connection between S-cones and SCBCs makes it an excellent system to study how presynaptic neurons affect the dendritic development and synaptic targeting of postsynaptic neurons.
We ask whether alteration in number and type of cone afferents will affect the dendritic development and synapse formation of SCBCs. SCBCs were labeled in a transgenic mouse line expressing Clomeleon (Clm), driven by thy1 promoter. Two mouse models were used to change the density and type of cones. In Thrb2-/- mice which lack thyroid hormone receptor β2 (TRβ2), M-opsin expression is abolished and all M-cones are turned into S-cones. In S-opsin-/- mice, S-opsin gene is knocked out. We obtained Clm;Thrb2+/+, Clm;Thrb2-/-, Clm;S-opsin-/- and Clm;Thrb2-/- ;S-opsin-/- (DKO) mice and compared dendritic morphology of SCBCs in these mice. mCAR expression is retained in these mice, and is therefore used to label the cone pedicles. We found that the numbers of SCBCs in Thrb2-/- and S-opsin-/- and DKO mice are comparable to that in wildtype. Morphologically, SCBCs in Thrb2-/- and S-opsin-/- mice are indistinguishable from those in wildtype in terms of length of dendrites, number of dendritic branches, and number of cone contacts. Our results indicate that dendritic development of SCBCs appears to be intrinsic and independent of the afferent input from "true" S cones, and that "true" S-cone identity may be specified by factors other than the expression of S-opsin.

Multiple Roles of Olfactomedin Domain-containing Proteins (Olfm1-3) in Vision, Olfaction, Motor Functions, and Anxiety

Afia Sultana, Naoki Nakaya, Stanislav Tomarev

Section on Retinal Ganglion Cell Biology, Laboratory of Retinal Cell & Molecular Biology, National Eye Institute, National Institutes of Health

Olfactomedin (Olfm) 1, Olfm2 and Olfm3 are highly conserved secretory glycoproteins that are preferentially expressed in neuronal tissues including the retina and optic nerve. The main goal of this study was to elucidate the roles of Olfm1-3 in eye and brain during development and in adult mice. Olfm1-3 interacts with each other, and mutations in any one of these proteins may inhibit secretion of others. Based on these results, we hypothesized that Olfm1-3 perform similar functions and might compensate for each other. To test this hypothesis, we generated a triple KO line deficient for Olfm1-3 genes (Olfm1 mutant/Olfm2 KO/Olfm3 KO). Olfm1 mutant mice showed 10% postnatal lethality due to defective feeding behavior. Surviving Olfm1 mutants showed reduced body weight, a decrease in the number of retinal ganglion cells and a 25% reduction in a total cross-sectional area of the optic nerve. Visual evoked potential test revealed a significantly delayed latency and reduced amplitude in Olfm1 mutant and Olfm2 KO mice, respectively. Most of the triple KO mice die postnatally due to abnormal feeding behavior. Surviving Olfm1 mutant double and triple KO mice showed severe defects in olfaction and changes in anxiety. Defects in motor functions were also detected in surviving triple KO mice. Transcriptome analysis of mutated Olfm1 and Olfm1-3 KO mouse brains by RNA sequencing suggested significant alterations in synapse functions and cation channels. Shotgun proteomic analysis of proteins co-precipitated with wild-type and/or mutated Olfm1 from the mouse brain led to the identification of several synaptic membrane proteins including GluR2, a component of AMPA receptors. Our results suggest that Olfm1-3 proteins play shared important roles in the development and function of visual, olfactory, and motor systems as well as in anxiety behavior through a modulation of the calcium signaling resulting from their interactions with postsynaptic membrane receptors in the brain and retina.

Epigenetic Regulation of Photoreceptor Gene Expression

Hyun-Jin Yang, Anand Swaroop

Retinal Development and Genetics Section, Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health

Gene regulatory networks govern diverse cellular processes of normal photoreceptor development and maintenance. Studies have shown the importance of epigenetic factors in gene regulation during lineage restriction and fate specification of embryonic stem cells. These findings led us to hypothesize that epigenetic program may be an essential regulator of gene regulatory networks, which permits proper photoreceptor development. However, the difficulty of obtaining sufficient amounts of isolated photoreceptor cells for chromatin immunoprecipitation (ChIP) assay has greatly limited researches on how epigenetic factors are established and regulate gene expression during photoreceptor development. We have recently established a new protocol for using a small number of flow-sorted rod photoreceptor cells for ChIP-seq, which allowed us to examine genome wide profile of important histone posttranslational modifications in rod photoreceptor specific manner. Preliminary ChIP-qPCR data suggest that rhodopsin promoter in P2 mouse rod photoreceptors is highly enriched with H3K27me3, a repressive histone modification, whereas H3K27me3 is replaced with H3K4me3, an active histone modification, in P28 mouse rods. This temporal difference in histone modification on the rhodopsin promoter is consistent with the late onset of rhodopsin expression in developing rods. We are currently generating genome wide profiles of histone modifications and RNA polymerase II occupancy in P2, P10, and P28 mouse rods. The role of Nrl in establishment of rod specific histone modification will be also addressed in the near future.

Diagnostic Procedures in Primary Intraocular Lymphoma (PIOL)

Monica Dalal1, Megan Casady2, Emily Moriarty3, Lisa Faia4, Robert Nussenblatt1, Chi-Chao Chan5, H. Nida Sen1

1Clinical Immunology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health; 2University of Maryland School of Medicine, Baltimore, MD; 3Georgetown University Hospital/Washington Hospital Center, Washington, DC; 4Riverside Eye Center, Detroit, MI; 5Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health

Purpose: To evaluate the type, sequence, and number of diagnostic interventions needed to confirm the presence of PIOL.
Method: Retrospective chart review of all patients referred to and diagnosed with primary intraocular lymphoma at the National Eye Institute, National Institutes of Health, between 1994 and 2012.
Results: 27 cases were identified. The diagnosis was made by pars plana vitrectomy in 13 cases (48.1%), vitreous aspiration in 2 (7.4%), anterior chamber aspiration in 1 (3.7%), chorioretinal biopsy in 2 (7.4%), brain biopsy in 5 (18.5%), and CSF cytology via lumbar puncture in 4 (14.8%). Ten (37%) had the definitive results on the first procedure, and 17 (63%) had at least one false negative procedure. Vitrectomy was the most common procedure performed. Patients required a mean of 2.1 procedures to establish the diagnosis of PIOL. Average time from the onset of symptoms to confirmed histopathologic diagnosis was 13.9 months.
Conclusion: PIOL is often difficult to recognize and requires a high degree of clinical suspicion by the physician. It often takes more than one invasive procedure to make the diagnosis in PIOL, and vitreous biopsy has a high diagnostic yield even when done as a secondary procedure.

Robust Memory of Stable Object Values in the Oculomotor Basal Ganglia

Masaharu Yasuda1, Shinya Yamamoto2, Okihide Hikosaka1

1Neuronal Networks Section, Laboratory of Sensorimotor Research, NEI; 2National Institute of Advanced Industrial Science & Technology, Tsukuba, Japan

We are surrounded by so many visual objects, yet we can find valuable ones quickly and effortlessly. Such an efficient choice should require the memory of many objects’ value. Also, the memory should be stably retained because you may encounter valuable objects only occasionally. Where in the brain is the high capacity memory of visual objects stably stored? We hypothesized that a major output structure of basal ganglia, the substantia nigra pars reticulata (SNr), is a key structure for the everyday choice mechanism. Anatomical studies suggest that the SNr may receive visual object information from the inferotemporal cortical areas through the tail of the caudate nucleus. Furthermore, the SNr controls the initiation of saccadic eye movements through its inhibitory connections to the superior colliculus (SC).
We first let two monkeys experience many computer-generated fractal objects. Importantly, half of objects were associated with a large reward (high valued object) and the other half were associated with a small reward (low valued object). The object-reward association was fixed throughout the learning session. New object-reward associations were introduced for more than half a year so that the two monkeys have experienced many reward-biased objects (n=776 and 712, respectively). We then identified SNr neurons that project to the ipsilateral SC (identified by antidromic activation) and examined their responses to the experienced fractal objects.
After across-day learning of object-reward association, SNr neurons gradually showed a response bias to many visual objects: an inhibition and excitation, respectively, to high and low valued objects. This neuronal bias remained intact even after >100 days without further learning. In parallel with the neuronal bias, the monkeys tended to look at high valued objects. These results suggest that SNr neurons biases gaze toward objects that were consistently associated with high values in one’s history.

Department of Health and Human Services NIH, the National Institutes of Health