This proposal is based on the new technologies of connectomics, which uses automated transmission electron microscope (ATEM) imaging and computational molecular phenotyping (CMP) to build connectomes: complete maps of retinal networks, with molecular tags.
All aims use ATEM imaging and CMP.
Aim 1. Generate10 terabyte (TB) retinal connectomes for the C57Bl/6J and the YFP-synaptophysin C57Bl/6J mouse (B6.Cg-Tg(Thy1-YFP/Syp)10Jrs/J). The connectomes will span the photoreceptor and ganglion cell (GC) layers in a canonical volume from central retina. Significance. The Mouse C57Bl/6J and Thy1-YFP/Syp retinal connectomes will be nomograms for studying the neurogenetics of mammalian retinal networks and analyzing the mechanisms driving retinal remodeling. Pathologic remodeling in retinal degenerations is the primary barrier to all late stage therapeutic interventions. Understanding the cellular participants and altered architectures in remodeling is central to informing new approaches to vision restoration. Importantly, CMP of YFP signals provide a nearly complete TEM compliant molecular segmentation of retinal cell classes in the mouse.
Aim 2. Generate a 100 TB connectome for the baboon Papio Anubis retina. . The reference primate retinal connectome will be based an excitation-mapped baboon parafoveal retina, spanning the photo- receptor to ganglion cell layers in a canonical volume. Significance. This work allows analysis of how primate retinal networks evolved high resolution pure-cone channels and trichromacy, blending net- works with pre-existing photopic and scotopic channels. We will test the hypotheses that the (1) new synaptic motifs discovered in rabbit connectome RC1 are present in primates and (2) nested feedback / feed forward and crossover architectures are present in midget pathway.
Aim 3. Generate a 100 (TB) connectome for the adult male human retina. The human connectome will be a discontinuous canonical sample centered on the foveola with parafoveal and extramacular satellites, spanning the photoreceptor and ganglion cell layers. Significance. The human connectome will provide the ultimate network model for analysis of normal human vision and remodeling triggered by retinitis pigmentosa (RP) and macular degenerations. Remodeling in the human retina is more aggressive and complex than the mouse retina, with severe network revision in cone decimating zones and extreme bipolar cell rewiring and reprogramming in cone sparing zones of RP.

Public Health Relevance

This proposal is based on use of the new technology of connectomics to build the first complete maps of retinal nerve cell networks. These maps will provide the ultimate framework for understanding normal human vision and events underlying retinal disease, especially the rewiring consequences of degenerations and AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002576-36
Application #
8389865
Study Section
Special Emphasis Panel (ZRG1-BDPE-N (09))
Program Officer
Greenwell, Thomas
Project Start
1993-03-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
36
Fiscal Year
2013
Total Cost
$569,322
Indirect Cost
$155,920
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Jones, Bryan W; Pfeiffer, Rebecca L; Ferrell, William D et al. (2016) Retinal Remodeling and Metabolic Alterations in Human AMD. Front Cell Neurosci 10:103
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Loizos, Kyle; RamRakhyani, Anil Kumar; Anderson, James et al. (2016) On the computation of a retina resistivity profile for applications in multi-scale modeling of electrical stimulation and absorption. Phys Med Biol 61:4491-505
Pfeiffer, Rebecca L; Marc, Robert E; Kondo, Mineo et al. (2016) Müller cell metabolic chaos during retinal degeneration. Exp Eye Res 150:62-70
Molnár, Tünde; Yarishkin, Oleg; Iuso, Anthony et al. (2016) Store-Operated Calcium Entry in Müller Glia Is Controlled by Synergistic Activation of TRPC and Orai Channels. J Neurosci 36:3184-98
Jones, B W; Pfeiffer, R L; Ferrell, W D et al. (2016) Retinal remodeling in human retinitis pigmentosa. Exp Eye Res 150:149-65
Lauritzen, J Scott; Sigulinsky, Crystal L; Anderson, James R et al. (2016) Rod-cone crossover connectome of mammalian bipolar cells. J Comp Neurol :
Woodell, Alex; Jones, Bryan W; Williamson, Tucker et al. (2016) A Targeted Inhibitor of the Alternative Complement Pathway Accelerates Recovery From Smoke-Induced Ocular Injury. Invest Ophthalmol Vis Sci 57:1728-37
Jiang, Li; Wei, Yuxiao; Ronquillo, Cecinio C et al. (2015) Heterotrimeric kinesin-2 (KIF3) mediates transition zone and axoneme formation of mouse photoreceptors. J Biol Chem 290:12765-78
Lorach, Henri; Kung, Jennifer; Beier, Corinne et al. (2015) Development of Animal Models of Local Retinal Degeneration. Invest Ophthalmol Vis Sci 56:4644-52

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