The broad goal of our research program is to understand how neural circuit function depends on the intrinsic properties of component cells and synapses. The specific goal of this proposal is to determine how synaptic inhibition in inner-retinal circuits shapes responses observed in retinal ganglion cells (GCs), the retinal output channels. This proposal is focused on inhibition in a well-studied inner-retinal circuit: the rod bipolar (RB) cell pathway of the mouse retina, which comprises two central neurons, the ON RB and the AII amacrine cell (AC). The AII distributes the RB signal to several retinal output channels, most significantly the ON ? and OFF ? and ? GCs, and in the past project period, we identified two novel ACs (nNOS-1 and Rpb4) that provide synaptic inhibition to the RB-AII network. Both of these ACs receive input from the type 6 ON cone bipolar (CB) cell, and the properties of the type 6 CB are thought to generate the contrast-sensitivity and well-characterized nonlinear receptive field of the ON ? GC. Therefore, we advance the hypothesis that local contrast in the visual scene best engages these novel inhibitory circuits and that the response properties of nNOS-1 and Rpb4 ACs should be evident in the responses of AIIs and downstream ON ? and OFF ? GCs. Our goal is to elucidate cellular properties and responses to physiological stimuli at various stages in the RB pathway to understand the functions of these novel inner retinal circuits. The two specific aims proposed will generate an understanding of how variations in the visual scene modulate signal coding within individual retinal output channels:
Aim 1 tests the hypothesis that nNOS-1 ACs exhibit a non-classical receptive field surround that is manifested in the responses of downstream neurons in the retinal circuit;
Aim 2 expands our combined anatomical and physiological analyses to resolve how distinct inhibitory circuits converge on GCs and permit coding of unique components of the visual scene. Relevance to Public Health: Understanding how visual stimulus coding is implemented by retinal synapses informs the design of retinal prosthetics and the study of animal models of human retinal diseases. The proposed work clarifies how visual signal processing is modulated at three stages in the retinal network and addresses two goals of the Retinal Diseases Program in the National Plan for Eye and Vision Research: one, it builds on knowledge gained from retinal neuroscience to understand how retinal networks process visual images, and two, it works toward identifying the post photoreceptor neural components of adaptation.

Public Health Relevance

The proposed studies concerning the mechanisms governing visual stimulus coding by synaptic interactions in the mammalian retina will generate fundamental information about the neural basis of vision. This will facilitate the evaluation of retinal circuits in mouse models of human retinal diseases and the assessment of treatment strategies in these models. Additionally, our proposed studies using the light- gated cation channel, channelrhodopsin-2, could contribute to the development of gene-based therapies for treating human blindness arising from pathologies, like retinitis pigmentosa, that cause photoreceptor degeneration.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wright, Charles Baker
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University of Maryland College Park
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College Park
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Park, Silvia J H; Pottackal, Joseph; Ke, Jiang-Bin et al. (2018) Convergence and Divergence of CRH Amacrine Cells in Mouse Retinal Circuitry. J Neurosci 38:3753-3766
Graydon, Cole W; Lieberman, Evan E; Rho, Nao et al. (2018) Synaptic Transfer between Rod and Cone Pathways Mediated by AII Amacrine Cells in the Mouse Retina. Curr Biol 28:2739-2751.e3
Mortensen, Lena S; Park, Silvia J H; Ke, Jiang-Bin et al. (2016) Complexin 3 Increases the Fidelity of Signaling in a Retinal Circuit by Regulating Exocytosis at Ribbon Synapses. Cell Rep 15:2239-2250
Demb, Jonathan B; Singer, Joshua H (2016) Mind the Gap Junctions: The Importance of Electrical Synapses to Visual Processing. Neuron 90:207-9
Pallotto, Marta; Watkins, Paul V; Fubara, Boma et al. (2015) Extracellular space preservation aids the connectomic analysis of neural circuits. Elife 4:
Firl, Alana; Ke, Jiang-Bin; Zhang, Lei et al. (2015) Elucidating the role of AII amacrine cells in glutamatergic retinal waves. J Neurosci 35:1675-86
Demb, Jonathan B; Singer, Joshua H (2015) Functional Circuitry of the Retina. Annu Rev Vis Sci 1:263-289
Choi, Hannah; Zhang, Lei; Cembrowski, Mark S et al. (2014) Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina. J Neurophysiol 112:1491-504
Margolis, David J; Gartland, Andrew J; Singer, Joshua H et al. (2014) Network oscillations drive correlated spiking of ON and OFF ganglion cells in the rd1 mouse model of retinal degeneration. PLoS One 9:e86253
Stafford, Benjamin K; Manookin, Michael B; Singer, Joshua H et al. (2014) NMDA and AMPA receptors contribute similarly to temporal processing in mammalian retinal ganglion cells. J Physiol 592:4877-89

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