Retinal Connectomics: A Review.

The retina is an ideal model for understanding the fundamental rules for how neural networks are constructed. The compact neural networks of the retina perform all of the initial processing of visual information before transmission to higher visual centers in the brain. The field of retinal connectomics uses high-resolution electron microscopy datasets to map the intricate organization of these networks and further our understanding of how these computations are performed by revealing the fundamental topologies and allowable networks behind retinal computations.

Unbalanced redox status network as an early pathological event in congenital cataracts.

The lens proteome undergoes dramatic composition changes during development and maturation. A defective developmental process leads to congenital cataracts that account for about 30% of cases of childhood blindness. Gene mutations are associated with approximately 50% of early-onset forms of lens opacity, with the remainder being of unknown etiology.

Retinal Pathoconnectomics: A Window into Neurodegeneration.

Over the past decade, the field of retinal connectomics has made huge strides in describing the precise topologies underlying retinal visual processing. The same techniques that allowed these advancements are also applicable to understanding the progression of rewiring in retinal remodeling: retinal pathoconnectomics. Pathoconnectomics is unique in its unbiased approach to understanding the impacts of deafferentation on the remaining network components and identifying aberrant connectivities leading to visual processing defects.

Current perspective on retinal remodeling: Implications for therapeutics.

The retinal degenerative diseases retinitis pigmentosa and age-related macular degeneration are a leading cause of irreversible vision loss. Both present with progressive photoreceptor degeneration that is further complicated by processes of retinal remodeling. In this perspective, we discuss the current state of the field of retinal remodeling and its implications for vision-restoring therapeutics currently in development.

Model-based comparison of current flow in rod bipolar cells of healthy and early-stage degenerated retina.

Retinal degenerative diseases, such as retinitis pigmentosa, are generally thought to initiate with the loss of photoreceptors, though recent work suggests that plasticity and remodeling occurs prior to photoreceptor cell loss. This degeneration subsequently leads to death of other retinal neurons, creating functional alterations and extensive remodeling of retinal networks. Retinal prosthetic devices stimulate the surviving retinal cells by applying external current using implanted electrodes.

A pathoconnectome of early neurodegeneration: Network changes in retinal degeneration.

Connectomics has demonstrated that synaptic networks and their topologies are precise and directly correlate with physiology and behavior. The next extension of connectomics is pathoconnectomics: to map neural network synaptology and circuit topologies corrupted by neurological disease in order to identify robust targets for therapeutics. In this report, we characterize a pathoconnectome of early retinal degeneration.

Network Architecture of Gap Junctional Coupling among Parallel Processing Channels in the Mammalian Retina.

Gap junctions are ubiquitous throughout the nervous system, mediating critical signal transmission and integration, as well as emergent network properties. In mammalian retina, gap junctions within the Aii amacrine cell-ON cone bipolar cell (CBC) network are essential for night vision, modulation of day vision, and contribute to visual impairment in retinal degenerations, yet neither the extended network topology nor its conservation is well established. Here, we map the network contribution of gap junctions using a high-resolution connectomics dataset of an adult female rabbit retina.

Müller Cell Metabolic Signatures: Evolutionary Conservation and Disruption in Disease.

Müller cells are glia that play important regulatory roles in retinal metabolism. These roles have been evolutionarily conserved across at least 300 million years. Müller cells have a tightly locked metabolic signature in the healthy retina, which rapidly degrades in response to insult and disease.

Optic cup morphogenesis requires neural crest-mediated basement membrane assembly.

Organogenesis requires precise interactions between a developing tissue and its environment. In vertebrates, the developing eye is surrounded by a complex extracellular matrix as well as multiple mesenchymal cell populations. Disruptions to either the matrix or periocular mesenchyme can cause defects in early eye development, yet in many cases the underlying mechanism is unknown.

Pathoconnectome Analysis of Müller Cells in Early Retinal Remodeling.

Glia play important roles in neural function, including but not limited to amino acid recycling, ion homeostasis, glucose metabolism, and waste removal. During retinal degeneration and subsequent retinal remodeling, Müller cells (MCs) are the first cells to show metabolic and morphological alterations in response to stress. Metabolic alterations in MCs chaotically progress in retina undergoing photoreceptor degeneration; however, what relationship these alterations have with neuronal stress, synapse maintenance, or glia-glia interactions is currently unknown.

Contrast sensitivity isocontours of the central visual field.

Standard automated perimetry (SAP), the most common form of perimetry used in clinical practice, is associated with high test variability, impacting clinical decision making and efficiency. Contrast sensitivity isocontours (CSIs) may reduce test variability in SAP by identifying regions of the visual field with statistically similar patterns of change that can be analysed collectively and allow a point (disease)-to-CSI (normal) comparison in disease assessment as opposed to a point (disease)-to-point (normal) comparison. CSIs in the central visual field however have limited applicability as they have only been described using visual field test patterns with low, 6° spatial sampling.

Persistent remodeling and neurodegeneration in late-stage retinal degeneration.

Retinal remodeling is a progressive series of negative plasticity revisions that arise from retinal degeneration, and are seen in retinitis pigmentosa, age-related macular degeneration and other forms of retinal disease. These processes occur regardless of the precipitating event leading to degeneration. Retinal remodeling then culminates in a late-stage neurodegeneration that is indistinguishable from progressive central nervous system (CNS) proteinopathies.

Development of a Spatial Model of Age-Related Change in the Macular Ganglion Cell Layer to Predict Function From Structural Changes.

Purpose: To develop location-specific models of normal, age-related changes in the macular ganglion cell layer (GCL) from optical coherence tomography (OCT). Using these OCT-derived models, we predicted visual field (VF) sensitivities and compared these results to actual VF sensitivities.

Design: Retrospective cohort study.

Heterocellular Coupling Between Amacrine Cells and Ganglion Cells.

All of retinal neurons, including bipolar cells (BCs), amacrine cells (ACs) and ganglion cells (GCs), display gap junctional coupling. However, coupling varies extensively by . Heterocellular AC coupling is common in many mammalian GC classes.

Pattern Recognition Analysis Reveals Unique Contrast Sensitivity Isocontours Using Static Perimetry Thresholds Across the Visual Field.

Purpose: To determine the locus of test locations that exhibit statistically similar age-related decline in sensitivity to light increments and age-corrected contrast sensitivity isocontours (CSIs) across the central visual field (VF). We compared these CSIs with test point clusters used by the Glaucoma Hemifield Test (GHT).

Methods: Sixty healthy observers underwent testing on the Humphrey Field Analyzer 30-2 test grid using Goldmann (G) stimulus sizes I-V.

Pattern Recognition Analysis of Age-Related Retinal Ganglion Cell Signatures in the Human Eye.

Purpose: To characterize macular ganglion cell layer (GCL) changes with age and provide a framework to assess changes in ocular disease. This study used data clustering to analyze macular GCL patterns from optical coherence tomography (OCT) in a large cohort of subjects without ocular disease.

Methods: Single eyes of 201 patients evaluated at the Centre for Eye Health (Sydney, Australia) were retrospectively enrolled (age range, 20-85); 8 × 8 grid locations obtained from Spectralis OCT macular scans were analyzed with unsupervised classification into statistically separable classes sharing common GCL thickness and change with age.

Retinal Remodeling and Metabolic Alterations in Human AMD.

Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression.

Müller cell metabolic chaos during retinal degeneration.

Müller cells play a critical role in retinal metabolism and are among the first cells to demonstrate metabolic changes in retinal stress or disease. The timing, extent, regulation, and impacts of these changes are not yet known. We evaluated metabolic phenotypes of Müller cells in the degenerating retina.

Serial section registration of axonal confocal microscopy datasets for long-range neural circuit reconstruction.

In the context of long-range digital neural circuit reconstruction, this paper investigates an approach for registering axons across histological serial sections. Tracing distinctly labeled axons over large distances allows neuroscientists to study very explicit relationships between the brain's complex interconnects and, for example, diseases or aberrant development. Large scale histological analysis requires, however, that the tissue be cut into sections.

Age-dependent expression of MeCP2 in a heterozygous mosaic mouse model.

Functional deficiency of the X-linked methyl-CPG binding protein 2 (MeCP2) leads to the neurodevelopmental disorder Rett syndrome (RTT). Due to random X-chromosome inactivation (XCI), most RTT patients are females who are heterozygous for the MECP2 mutation and therefore mosaic in MeCP2 deficiency. Some MECP2 heterozygote females are found to have unbalanced XCI, which may affect the severity of neurological symptoms seen in these patients; however, whether MeCP2 deficiency affects XCI in the postnatal and adult brain is unclear.

MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1.

The maturation of young neurons is regulated by complex mechanisms and dysregulation of this process is frequently found in neurodevepmental disorders. MicroRNAs have been implicated in several steps of neuronal maturation including dendritic and axonal growth, spine development, and synaptogenesis. We demonstrate that one brain-enriched microRNA, miR-137, has a significant role in regulating neuronal maturation.

Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells.

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels.