Tag Archives: Bryan William Jones

Retinal Remodeling in Human Retinitis Pigmentosa

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We have a new publication out (Direct Link, Free Open Access), Retinal Remodeling in Human Retinitis Pigmentosa authored by Bryan W. Jones, Rebecca Pfeiffer, Drew Ferrell, Carl Watt, Michael Marmor and Robert Marc.

Abstract: Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.

Store-Operated Calcium Entry In Müller Glia Is Controlled By Synergistic Activation Of TRPC And Orai Channels

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We have a new publication out as collaborators with colleages, Store-Operated Calcium Entry In Müller Glia Is Controlled By Synergistic Activation Of TRPC And Orai Channels authored by Tünde Molnár, Oleg Yarishkin, Peter Barabas, Anthony Iuso, Bryan W. Jones, Robert Marc, Tam Phuong, and David Krizaj.

Bonus, we got the cover!  The image was created by Tam Phuong.

 

Significance: Store-operated Ca2+ signaling represents a major signaling pathway and source of cytosolic Ca2+ in astrocytes. Here, we show that the store-operated response in Müller cells, radial glia that perform key structural, signaling, osmoregulatory and mechanosensory functions within the retina, is mediated through synergistic activation of TRPC and Orai channels. The endfoot disproportionately expresses the depletion sensor STIM1, contains an extraordinarily high density of ER cisternae that shadow neuronal, astrocyte, vascular and axonal structures, interface with mitochondria but also originates SOCE-induced transcellular Ca2+ waves that propagate glial excitation into the proximal retina. These results identify a molecular mechanism that underlies complex interactions between the plasma membrane and calcium stores and contributes to radial glial function, regulation and response to mechanical stress.

Abstract: The endoplasmic reticulum (ER) is at the epicenter of astrocyte Ca2+ signaling. We sought to identify the molecular mechanism underlying store-operated calcium entry (SOCE) that repletes ER Ca2+ stores in mouse Müller cells. Store depletion, induced through blockade of sequestration transporters in Ca2+-free saline, induced synergistic activation of canonical transient receptor potential (TRPC1) and Orai channels. Store-operated TRPC1 channels were identified by their electrophysiological properties, pharmacological blockers and ablation of the Trpc1 gene. ICRAC (Ca2+ release-activated) currents were identified by ion permeability, voltage-dependence and sensitivity to selective Orai antagonists Synta66 and GSK7975A. Depletion-evoked calcium influx was initiated at the Müller endfoot and apical process, triggering centrifugal propagation of Ca2+ waves into the cell body. EM analysis of the endfoot compartment showed high-density ER cisternae that shadow retinal ganglion cell (RGC) somata and axons, protoplasmic astrocytes, vascular endothelial cells and ER-mitochondrial contacts at the vitreal surface of the endfoot. The mouse retina expresses transcripts encoding both Stim and all known Orai genes; Müller glia predominantly express STIM1 whereas STIM2 is mainly confined to the outer plexiform and retinal ganglion cell layers. Elimination of TRPC1 facilitated Müller gliosis induced by the elevation of intraocular pressure (IOP), suggesting that TRPC channels might play a neuroprotective role during mechanical stress. These findings expand the current knowledge about store-operated signaling in astroglia, as well as calcium signaling pathways in Müller astroglia and functional roles these cells play in retinal physiology and pathology.

Seasonal And Post-Trauma Remodeling Of The Ground Squirrel Retina

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We have a new publication out, Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina authored by Dana Merriman, Ben Sajdak, Wei Li and Bryan W. Jones.

Abstract:

With a photoreceptor mosaic containing ∼85% cones, the ground squirrel is one of the richest known mammalian sources of these important retinal cells. It also has a visual ecology much like the human’s. While the ground squirrel retina is understandably prominent in the cone biochemistry, physiology, and circuitry literature, far less is known about the remodeling potential of its retinal pigment epithelium, neurons, macroglia, or microglia. This review aims to summarize the data from ground squirrel retina to this point in time, and to relate them to data from other brain areas where appropriate. We begin with a survey of the ground squirrel visual system, making comparisons with traditional rodent models and with human. Because this animal’s status as a hibernator often goes unnoticed in the vision literature, we then present a brief primer on hibernation biology. Next we review what is known about ground squirrel retinal remodeling concurrent with deep torpor and with rapid recovery upon re-warming. Notable here is rapidly-reversible, temperature-dependent structural plasticity of cone ribbon synapses, as well as pre- and post-synaptic plasticity throughout diverse brain regions. It is not yet clear if retinal cell types other than cones engage in torpor-associated synaptic remodeling. We end with the small but intriguing literature on the ground squirrel retina’s remodeling responses to insult by retinal detachment. Notable for widespread loss of (cone) photoreceptors, there is surprisingly little remodeling of the RPE or Müller cells. Microglial activation appears minimal, and remodeling of surviving second- and third-order neurons seems absent, but both require further study. In contrast, traumatic brain injury in the ground squirrel elicits typical macroglial and microglial responses. Overall, the data to date strongly suggest a heretofore unrecognized, natural checkpoint between retinal deafferentiation and RPE and Müller cell remodeling events. As we continue to discover them, the unique ways by which ground squirrel retina responds to hibernation or injury may be adaptable to therapeutic use.

Development Of Animal Models Of Local Retinal Degeneration

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Henri Lorach, Jennifer Kung, Corinne Beier, Yossi Mandel, Roopa Dalal, Philip Huie, Jenny Wang, Sengjun Lee, Alexander Sher, Bryan W. Jones, and Daniel Palanker have a new publication, Development of Animal Models of Local Retinal Degeneration (the IOVS direct link is here).

Many of the models of retinal degeneration we explore are genetic.  This project was designed to explore two other alternative approaches to retinal degeneration that are non-genetic and capable of producing highly localized retinal degeneration with precise onset time.

 

Webvision Chapter: Retinal Degeneration, Remodeling and Plasticity

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We have published a new chapter in Webvision, Retinal Degeneration, Remodeling and Plasticity that covers the history of the study of retinal degenerations and some of the implications for vision rescue.  Authors are Bryan W. Jones, Rebecca L. Pfeiffer and Robert E. Marc.  It will, like other Webvision chapters evolve over time, which is the whole point of Webvision, but we hope it will generate some discussion.

Ultrastructural Connectomics Reveals The Entire Chemical And Electrical Synaptic Cohort Of An ON Cone Bipolar Cell In The Inner Plexiform Layer Of The Rabbit Retina

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This abstract was presented at the 2014 Society for Neuroscience meeting in Washington D.C. by J. Scott Lauritzen, Crystal L. Sigulinsky, Danny P. Emrich, Joshua M. Dudleston, Noah T. Nelson, Rebecca L. Pfeiffer, Nathan R. Sherbotie, John V. Hoang, Jefferson R. Brown, Carl B. Watt, James R. Anderson, Bryan W. Jones and Robert E. Marc.

Purpose: Despite large-scale efforts aimed at mapping the mammalian nervous system, the entire synaptic cohort of a single mammalian neuron of any class has never been mapped. To this end we reconstructed all chemical and electrical synaptic partners of a single ON cone bipolar cell (ON CBC) in the inner plexiform layer (IPL) of the rabbit retina. We then searched all members of the same cell class for repeating network motifs and explored postsynaptic cell sampling topologies from this bipolar cell (BC).

Methods: Cells in retinal connectome 1 (RC1) were annotated with Viking viewer, and explored via graph visualization of connectivity and 3D rendering (Anderson et al., 2011 J Microscopy). Small molecule signals in RC1, e.g. GABA, glycine, and L-glutamate, combined with morphological reconstruction and connectivity analysis allow robust cell classification. The default resolution of RC1 is 2.18nm/pixel, however goniometric recapture at 0.273 nm/pixel was performed as needed for synapse verification.

Results: ON CBC 593 is one of 20 BCs of this class in RC1, the axonal arbors of which tile with gap junctions between nearest neighbors at their distal axonal tips. ON CBC 593 contains 194 ribbons, 274 postsynaptic densities, 20 gap junctions, and 66 conventional synapses, for a total of 554 synaptic connections. Twenty ganglion cells sample the glutamatergic output. ON CBC 593 is presynaptic to 262 amacrine cell (AC) processes, and is postsynaptic to 228 AC processes. Of these, 33% form reciprocal connections. We approximate that ON CBC 593 forms synapses with 50 distinct ACs. ON CBC 593 is routinely pre- and postsynaptic to within-class, cross-class, feedback, and feedforward inhibition motifs, including 1 instance of OFF-ON crossover inhibition. ON CBC 593 forms 12 gap junctions with at least 2 AII ACs, 7 with 5 ON CBCs, and 1 with itself. We searched for repeating network motifs across all ON CBCs of this class in RC1. Thus far, 80% of these form in-class inhibitory motifs, and 75% form cross-class inhibitory motifs. All ACs and GCs discovered to contact multiple branches of ON CBC 593 form synapses on every branch.

Conclusions: An individual bipolar cell is inherently multi-kinetic, receiving inhibition driven by all ON CBC classes, sharing these signals via gap junctions with ON CBCs of the same class, and driving inhibition of all ON CBC classes. This constitutes a substrate for multi-channel coordination throughout the IPL, and predicts multi-kinetic BC responses. The results establish a normative framework against which members of the same and different classes may be compared, and foster interpretation of BC physiological behavior under different stimulus regimes.

A Multi-Scale Computational Model For The Study Of Retinal Prosthetic Stimulation

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We have a new publication in IEEE, A Multi-Scale Computational Model For The Study Of Retinal Prosthetic Stimulation.  Authors are: Kyle Loizos, Gianluca Lazzi, J. Scott Lauritzen, James R. Anderson, Bryan W. Jones and Robert E. Marc.

Abstract: An implantable retinal prosthesis has been developed to restore vision to patients who have been blinded by degenerative diseases that destroy photoreceptors. By electrically stimulating the surviving retinal cells, the damaged photoreceptors may be bypassed and limited vision can be restored. While this has been shown to restore partial vision, the understanding of how cells react to this systematic electrical stimulation is largely unknown. Better predictive models and a deeper understanding of neural responses to electrical stimulation is necessary for designing a successful prosthesis. In this work, a computational model of an epi-retinal implant was built and simulated, spanning multiple spatial scales, including a large-scale model of the retina and implant electronics, as well as underlying neuronal networks.

 

Retinal Prosthetics, Optogenetics and Photoswitches

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We have a new publication, Retinal Prosthetics, Optogenetics and Photoswitches in ACS Chemical Neuroscience.  Authors are:  Robert E. Marc, Rebecca L. Pfeiffer, and Bryan W. Jones.

Abstract:

Three technologies have emerged as therapies to restore light sensing to profoundly blind patients suffering from late-stage retinal degenerations: (1) retinal prosthetics, (2) optogenetics, and (3) chemical photoswitches. Prosthetics are the most mature and the only approach in clinical practice. Prosthetic implants require complex surgical intervention and provide only limited visual resolution but can potentially restore navigational ability to many blind patients. Optogenetics uses viral delivery of type 1 opsin genes from prokaryotes or eukaryote algae to restore light responses in survivor neurons. Targeting and expression remain major problems, but are potentially soluble. Importantly, optogenetics could provide the ultimate in high-resolution vision due to the long persistence of gene expression achieved in animal models. Nevertheless, optogenetics remains challenging to implement in human eyes with large volumes, complex disease progression, and physical barriers to viral penetration. Now, a new generation of photochromic ligands or chemical photoswitches (azobenzene-quaternary ammonium derivatives) can be injected into a degenerated mouse eye and, in minutes to hours, activate light responses in neurons. These photoswitches offer the potential for rapidly and reversibly screening the vision restoration expected in an individual patient. Chemical photoswitch variants that persist in the cell membrane could make them a simple therapy of choice, with resolution and sensitivity equivalent to optogenetics approaches. A major complexity in treating retinal degenerations is retinal remodeling: pathologic network rewiring, molecular reprogramming, and cell death that compromise signaling in the surviving retina. Remodeling forces a choice between upstream and downstream targeting, each engaging different benefits and defects. Prosthetics and optogenetics can be implemented in either mode, but the use of chemical photoswitches is currently limited to downstream implementations. Even so, given the high density of human foveal ganglion cells, the ultimate chemical photoswitch treatment could deliver cost-effective, high-resolution vision for the blind.

Synapse Classification And Localization In Electron Micrographs

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We have a new publication, Synapse Classification And Localization In Electron Micrographs in Pattern Recognition Letters.  Authors are: Vignesh Jagadeesh, James Anderson, Bryan W. Jones, Robert Marc, Steven Fisher and B.S. Manjunath.

Abstract:  Classification and detection of biological structures in Electron Micrographs (EM) is a relatively new large scale image analysis problem. The primary challenges are in modeling diverse visual characteristics and development of scalable techniques. In this paper we propose novel methods for synapse detection and localization, an important problem in connectomics. We first propose an attribute based descriptor for characterizing synaptic junctions. These descriptors are task specific, low dimensional and can be scaled across large image sizes. Subsequently, techniques for fast localization of these junctions are proposed. Experimental results on images acquired from a mammalian retinal tissue compare favorably with state of the art descriptors used for object detection.

Robust Segmentation based Tracking using an Adaptive Wrapper for Inducing Priors

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We have published another manuscript, Robust Segmentation based Tracking using an Adaptive Wrapper for Inducing Priors.  This manuscript describes the work on adaptive tracing and proposes an algorithm that adapts a generic tracing algorithm to an application of interest.  In our specific case, it is boundaries of cells in high frequency space in transmission electron microscopy images.  But the approach in this paper is applicable to biological, medical, remote sensing and surveillance data as well utilizing priors specific to the application.  The co-authors on the paper are: Vignesh Jagadeesh, James Anderson, Bryan W. Jones, Robert E. Marc, Steven K Fisher and B.S Manjunath.