Seeing the World

Outer Retina ◽

Modern Life ◽

Form Vision ◽

Visual Objects ◽

Age Related ◽

Neural Processes ◽

High Acuity

Modern life is highly dependent on high-acuity vision, and this chapter emphasizes the mechanisms and pathways that support high-acuity or form vision. Because the most common visual impairment is refractive error, the refractive power of the cornea and lens is described at some length. The processes of emmetropization, accommodation, and far viewing are considered. The participation of the outer retina in phototransduction and the visual cycle are detailed, and relevant diseases, including retinitis pigmentosa and age-related macular degeneration, are introduced. The neural processes that transform different wavelengths of light into color perception and common forms of color blindness are explained. Visual processing within cortex, including processing through the dorsal and visual streams, are presented. The process through which babies learn to interpret the firing in their brains as representing visual objects and the importance of the initial years of life to this process are described.

Perceptual and conceptual processing of visual objects across the adult lifespan

Scientific Reports ◽

10.1038/s41598-019-50254-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Rose Bruffaerts ◽

◽

Lorraine K. Tyler ◽

Meredith Shafto ◽

Kamen A. Tsvetanov ◽

...

Keyword(s):

Visual Processing ◽

Semantic Information ◽

Fluid Intelligence ◽

Naming Task ◽

Object Processing ◽

Adult Lifespan ◽

Conceptual Processing ◽

Mature Adults ◽

Visual Objects ◽

Abstract Making sense of the external world is vital for multiple domains of cognition, and so it is crucial that object recognition is maintained across the lifespan. We investigated age differences in perceptual and conceptual processing of visual objects in a population-derived sample of 85 healthy adults (24–87 years old) by relating measures of object processing to cognition across the lifespan. Magnetoencephalography (MEG) was recorded during a picture naming task to provide a direct measure of neural activity, that is not confounded by age-related vascular changes. Multiple linear regression was used to estimate neural responsivity for each individual, namely the capacity to represent visual or semantic information relating to the pictures. We find that the capacity to represent semantic information is linked to higher naming accuracy, a measure of task-specific performance. In mature adults, the capacity to represent semantic information also correlated with higher levels of fluid intelligence, reflecting domain-general performance. In contrast, the latency of visual processing did not relate to measures of cognition. These results indicate that neural responsivity measures relate to naming accuracy and fluid intelligence. We propose that maintaining neural responsivity in older age confers benefits in task-related and domain-general cognitive processes, supporting the brain maintenance view of healthy cognitive ageing.

Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-related Macular Degeneration?

International Journal of Molecular Sciences ◽

10.3390/ijms20030762 ◽

2019 ◽

Vol 20 (3) ◽

pp. 762 ◽

Cited By ~ 23

Author(s):

Thierry Léveillard ◽

Nancy Philp ◽

Florian Sennlaub

Keyword(s):

Macular Degeneration ◽

Aerobic Glycolysis ◽

Tricarboxylic Acid Cycle ◽

Retinal Pigment ◽

Basolateral Membrane ◽

Subretinal Space ◽

Outer Retina ◽

Choroidal Circulation ◽

The retinal pigment epithelium (RPE) forms the outer blood–retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE. In age-related macular degeneration this delicate ménage à trois is disturbed by the chronic infiltration of inflammatory macrophages. These immune cells also rely on aerobic glycolysis and compete for glucose and produce lactate. We here review the glucose metabolism in the homeostasis of the outer retina and in macrophages and hypothesize what happens when the metabolism of photoreceptors and the RPE is disturbed by chronic inflammation.

Nonexudative Macular Neovascularization Supporting Outer Retina in Age-Related Macular Degeneration

Ophthalmology ◽

10.1016/j.ophtha.2020.01.040 ◽

2020 ◽

Vol 127 (7) ◽

pp. 931-947 ◽

Cited By ~ 15

Author(s):

Ling Chen ◽

Jeffrey D. Messinger ◽

Kenneth R. Sloan ◽

Thomas A. Swain ◽

Yoshimi Sugiura ◽

...

Keyword(s):

Macular Degeneration ◽

Outer Retina ◽

Infiltration of Proinflammatory M1 Macrophages into the Outer Retina Precedes Damage in a Mouse Model of Age-Related Macular Degeneration

International Journal of Inflammation ◽

10.1155/2013/503725 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 62

Author(s):

Fernando Cruz-Guilloty ◽

Ali M. Saeed ◽

Jose J. Echegaray ◽

Stephanie Duffort ◽

Asha Ballmick ◽

...

Keyword(s):

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Lipid Peroxidation Product ◽

Outer Retina ◽

Photoreceptor Outer Segments ◽

Age Related ◽

M1 Phenotype ◽

Peroxidation Product

Age-related macular degeneration (AMD) is a major cause of blindness in the developed world. Oxidative stress and inflammation are implicated in AMD, but precise mechanisms remain poorly defined. Carboxyethylpyrrole (CEP) is an AMD-associated lipid peroxidation product. We previously demonstrated that mice immunized with CEP-modified albumin developed AMD-like degenerative changes in the outer retina. Here, we examined the kinetics of lesion development in immunized mice and the presence of macrophages within the interphotoreceptor matrix (IPM), between the retinal pigment epithelium and photoreceptor outer segments. We observed a significant and time-dependent increase in the number of macrophages in immunized mice relative to young age-matched controls prior to overt pathology. These changes were more pronounced in BALB/c mice than in C57BL/6 mice. Importantly, IPM-infiltrating macrophages were polarized toward the M1 phenotype but only in immunized mice. Moreover, when Ccr2-deficient mice were immunized, macrophages were not present in the IPM and no retinal lesions were observed, suggesting a deleterious role for these cells in our model. This work provides mechanistic evidence linking immune responses against oxidative damage with the presence of proinflammatory macrophages at sites of future AMD and experimentally demonstrates that manipulating immunity may be a target for modulating the development of AMD.

Simulated central vision loss impairs implicit location probability learning

10.31234/osf.io/a4q9k ◽

2020 ◽

Author(s):

Douglas A Addleman ◽

Gordon E Legge ◽

Yuhong Jiang

Keyword(s):

Vision Loss ◽

Target Location ◽

Probability Learning ◽

Oculomotor Control ◽

Central Scotoma ◽

Central Vision ◽

Central Vision Loss ◽

Age Related ◽

High Acuity

Central vision loss (CVL) occurs in advanced forms of age-related macular degeneration (AMD). It impairs high-acuity vision and results in difficulties with oculomotor control. Goal-driven guidance of attention is less effective in people with CVL, but do central scotomas also affect implicit, experience-driven attention? We investigated how simulated central scotomas affect young adults’ ability to prioritize locations that frequently contain a visual search target (location probability learning). Experiment 1 successfully induced probability learning in a no scotoma phase, regardless of whether participants became aware of the target’s location probability. Subsequently, central scotomas were introduced using a gaze-contingent eye tracking paradigm. The previously learned spatial bias persisted for a short time in this phase, an effect that was statistically comparable for no-scotoma and scotoma testing. Experiment 2 investigated whether participants could acquire location probability learning when trained with a simulated central scotoma. Unlike Experiment 1, training with a central scotoma yielded location probability learning only in participants who were aware of the target’s location probability. This effect transferred to search with no scotoma in aware but not unaware participants. Together, the results show that simulated central vision loss interferes with the acquisition of implicitly learned location probability learning, supporting a role of central vision in implicit spatial attentional biases.

Need for manual segmentation in optical coherence tomography angiography of neovascular age-related macular degeneration

PLoS ONE ◽

10.1371/journal.pone.0244828 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244828

Author(s):

Supriya Dabir ◽

Vaidehi Bhatt ◽

Deepak Bhatt ◽

Mohan Rajan ◽

Preetam Samant ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Optical Coherence Tomography Angiography ◽

Subretinal Fluid ◽

Automated Segmentation ◽

Optical Coherence ◽

Manual Segmentation ◽

Outer Retina ◽

Age Related ◽

En Face

Purpose To compare the characteristics of eyes that had manual vs. automated segmentation of choroidal neovascular membrane (CNVM) using optical coherence tomography angiography (OCTA). Methods All patients with CNVM underwent OCTA using the Zeiss Angioplex Cirrus 5000. Slabs of the avascular outer retina, outer retina to choriocapillaris (ORCC) region and choriocapillaris were generated. Manual segmentation was done when there were significant segmentation artifacts. Presence of activity of CNVM was adjudged by the presence of subretinal fluid (SRF) on structural OCT and was compared to activity detected on en face OCTA slabs based on well-defined criteria. Results Eighty-one eyes of 81 patients were recruited of which manual segmentation was required in 46 (57%). Eyes with automated segmentation had significantly more CNVM in the ORCC (75%) whereas those with manual segmentation had deeper CNVM (sub-RPE = 22%, intra-PED = 22%) (p<0.001). Twenty eyes (25%) were found to have active CNVM on both the structural OCT and OCTA while an additional 19 eyes were presumed to have active CNVM on OCTA alone. There was only modest concordance between disease activity detected using structural OCT and OCTA (Kappa = 0.47, 95% CI = 0.30 to 0.64). Conclusions Manual segmentation of OCTA is required in more than 50% eyes with CNVM and this progressively increases with increasing depth of CNVM location from the ORCC to below the RPE. There is moderate concordance between OCTA and structural OCT in determining CNVM activity.

Loss of PGC-1α in RPE induces mesenchymal transition and promotes retinal degeneration

Life Science Alliance ◽

10.26508/lsa.201800212 ◽

2019 ◽

Vol 2 (3) ◽

pp. e201800212 ◽

Cited By ~ 7

Author(s):

Mariana Aparecida Brunini Rosales ◽

Daisy Y Shu ◽

Jared Iacovelli ◽

Magali Saint-Geniez

Keyword(s):

Visual Processing ◽

Epithelial To Mesenchymal Transition ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Conditional Knockout ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Mesenchymal Transition ◽

The retinal pigment epithelium (RPE) supports visual processing and photoreceptor homeostasis via energetically demanding cellular functions. Here, we describe the consequences of repressing peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α), a master regulator of mitochondrial function and biogenesis, on RPE epithelial integrity. The sustained silencing of PGC-1α in differentiating human RPE cells affected mitochondria/autophagy function, redox state, and impaired energy sensor activity ultimately inducing epithelial to mesenchymal transition (EMT). Adult conditional knockout of PGC-1 coactivators in mice resulted in rapid RPE dysfunction and transdifferentiation associated with severe photoreceptor degeneration. RPE anomalies were characteristic of autophagic defect and mesenchymal transition comparable with the ones observed in age-related macular degeneration. These findings demonstrate that PGC-1α is required to maintain the functional and phenotypic status of RPE by supporting the cells’ oxidative metabolism and autophagy-mediated repression of EMT.

A convenient protocol for establishing a human cell culture model of the outer retina.

F1000Research ◽

10.12688/f1000research.15409.1 ◽

2018 ◽

Vol 7 ◽

pp. 1107 ◽

Cited By ~ 6

Author(s):

Savannah A. Lynn ◽

Eloise Keeling ◽

Jennifer M. Dewing ◽

David A. Johnston ◽

Anton Page ◽

...

Keyword(s):

Pigment Epithelium ◽

Retinal Pigment ◽

Experimental Manipulation ◽

Attractive Alternative ◽

Outer Retina ◽

Rpe Cells ◽

Age Related ◽

Culture Model

The retinal pigment epithelium (RPE) plays a key role in the pathogenesis of several blinding retinopathies. Alterations to RPE structure and function are reported in Age-related Macular Degeneration, Stargardt and Best disease as well as pattern dystrophies. However, the precise role of RPE cells in disease aetiology remains incompletely understood. Many studies into RPE pathobiology have utilised animal models, which only recapitulate limited disease features. Some studies are also difficult to carry out in animals as the ocular space remains largely inaccessible to powerful microscopes. In contrast, in-vitro models provide an attractive alternative to investigating pathogenic RPE changes associated with age and disease. In this article we describe the step-by-step approach required to establish an experimentally versatile in-vitro culture model of the outer retina incorporating the RPE monolayer and supportive Bruch’s membrane (BrM). We show that confluent monolayers of the spontaneously arisen human ARPE-19 cell-line cultured under optimal conditions reproduce key features of native RPE. These models can be used to study dynamic, intracellular and extracellular pathogenic changes using the latest developments in microscopy and imaging technology. We also discuss how RPE cells from human foetal and stem-cell derived sources can be incorporated alongside sophisticated BrM substitutes to replicate the aged/diseased outer retina in a dish. The work presented here will enable users to rapidly establish a realistic in-vitro model of the outer retina that is amenable to a high degree of experimental manipulation which will also serve as an attractive alternative to using animals. This in-vitro model therefore has the benefit of achieving the 3Rs objective of reducing and replacing the use of animals in research. As well as recapitulating salient structural and physiological features of native RPE, other advantages of this model include its simplicity, rapid set-up time and unlimited scope for detailed single-cell resolution and matrix studies.

Core outcomes for geographic atrophy trials

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-314949 ◽

2019 ◽

pp. bjophthalmol-2019-314949

Author(s):

Aniela Krystyna Krezel ◽

Ruth Hogg ◽

Lynne Lohfeld ◽

Usha Chakravarthy ◽

Augusto Azuara-Blanco

Keyword(s):

Visual Acuity ◽

Focus Groups ◽

Reading Speed ◽

Geographic Atrophy ◽

Outer Retina ◽

Age Related ◽

Patient Reported ◽

Core Outcomes ◽

Delphi Exercise

Background/AimsOngoing and recent clinical trials for geographic atrophy (GA) have used different outcomes. The goal of this study was to identify a core outcome set (COS) important for patients, clinicians and researchers, and to propose the use of COS in the design of future GA trials.MethodsFive-component project including: Delphi method with patients and experts, focus groups and interviews with patients, relatives and workers supporting patients. Three hundred and one patients (301) with age-related macular degeneration participated in round 1 of a Delphi exercise. Most subjects had GA; 183 patients (61%) were females and the median (range) age was 77 (50–99) years. In round 2, of the 301 of the first round, 100 participants were randomly selected of whom 76 agreed to take part. In a parallel Delphi exercise, panellists comprised a mix of non-clinical scientists and clinicians (43 in the initial and 21 in the final round). In addition, interviews and focus groups consisting of patients (n=20), family members (n=4) and support workers (n=5) were undertaken.ResultsCore outcomes identified as important for age-related macular degeneration trials were the health of the outer retina, multimodal estimation of lesion size, reading speed, best corrected distance and near acuity, low luminance visual acuity, patient reported visual performance and safety.ConclusionThis study identified a set of core outcomes that should be used in GA trials. The COS include patient-reported outcome measures, near visual acuity, reading speed and assessment of the outer retina.

Enriched environment and visual stimuli protect the retinal pigment epithelium and photoreceptors in a mouse model of non-exudative age-related macular degeneration

Cell Death and Disease ◽

10.1038/s41419-021-04412-1 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Hernán H. Dieguez ◽

Juan S. Calanni ◽

Horacio E. Romeo ◽

Agustina Alaimo ◽

María F. González Fleitas ◽

...

Keyword(s):

Oxidative Stress ◽

Retinal Pigment Epithelium ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Outer Retina ◽

Melanin Content ◽

Thickness Increase ◽

Visual Functions ◽

AbstractNon-exudative age-related macular degeneration (NE-AMD), the main cause of blindness in people above 50 years old, lacks effective treatments at the moment. We have developed a new NE-AMD model through unilateral superior cervical ganglionectomy (SCGx), which elicits the disease main features in C57Bl/6J mice. The involvement of oxidative stress in the damage induced by NE-AMD to the retinal pigment epithelium (RPE) and outer retina has been strongly supported by evidence. We analysed the effect of enriched environment (EE) and visual stimulation (VS) in the RPE/outer retina damage within experimental NE-AMD. Exposure to EE starting 48 h post-SCGx, which had no effect on the choriocapillaris ubiquitous thickness increase, protected visual functions, prevented the thickness increase of the Bruch’s membrane, and the loss of the melanin of the RPE, number of melanosomes, and retinoid isomerohydrolase (RPE65) immunoreactivity, as well as the ultrastructural damage of the RPE and photoreceptors, exclusively circumscribed to the central temporal (but not nasal) region, induced by experimental NE-AMD. EE also prevented the increase in outer retina/RPE oxidative stress markers and decrease in mitochondrial mass at 6 weeks post-SCGx. Moreover, EE increased RPE and retinal brain-derived neurotrophic factor (BDNF) levels, particularly in Müller cells. When EE exposure was delayed (dEE), starting at 4 weeks post-SCGx, it restored visual functions, reversed the RPE melanin content and RPE65-immunoreactivity decrease. Exposing animals to VS protected visual functions and prevented the decrease in RPE melanin content and RPE65 immunoreactivity. These findings suggest that EE housing and VS could become an NE-AMD promising therapeutic strategy.