Our long-term goal is to understand how retinal circuits perform the computations underlying healthy vision. The immediate goal of this proposal is to understand how retinal circuits adjust their properties to the contrast of a visual scene. Contrast adaptation is important for visual processing across eye fixations and between different environments: it increases sensitivity at low contrast to improve the signal-to-noise ratio, and it decreases sensitivity at high contrast to prevent response saturation. Presently, we know relatively little about the cellular and synaptic basis for contrast adaptation in the mammalian retina. This proposal comprises two specific aims that will generate novel insights into the synaptic mechanisms underlying contrast adaptation by integrating synapse- and circuit-level analyses of retinal signaling. In one approach, responses to contrast stimulation of photoreceptors will be recorded in specific types of retinal interneurons identified by genetic expression of fluorescent proteins and visualized by two-photon laser-scanning microscopy. In a second approach, we will use optogenetic control of subtypes of interneurons to examine transmission at specific synapses. Using these complementary approaches, Specific Aim 1 will determine the mechanisms for contrast adaptation in dim light by probing a specialized pathway for rod vision.
Specific Aim 2 will determine the mechanisms for contrast adaptation at brighter light levels by probing parallel pathways for cone vision. Relevance to Public Health: Understanding how contrast adaptation is implemented by retinal synapses and circuits generates fundamental information about the neural basis of vision and informs the design of retinal prosthetics and the study of animal models of human retinal diseases. A goal of vision research is the development of gene-based therapies for treating blindness caused by photoreceptor degeneration (e.g., retinitis pigmentosa). A promising therapy of this sort is the generation of light sensitivity in retinal interneurons using virally-mediated expression of channelrhodopsin-2 (ChR2), a light-gated cation channel. We will express ChR2 in interneurons to study synaptic interactions in retinal circuits;by design, we will compare photoreceptor- and ChR2-mediated circuit outputs. Thus, we will generate critical information about the range of visual signals that could be encoded by a retina in which ChR2 is the only light sensor. We address three goals of the Retinal Diseases Program in the National Plan for Eye and Vision Research: 1) determining potential therapeutic strategies for treatment of retinitis pigmentosa, 2) increasing understanding of post-photoreceptor adaptation (i.e., gain control in neural circuits), and 3) increasing understanding of how inter-cellular interactions in neural networks generate signals that are interpretable as visual images.

Public Health Relevance

Our proposed studies on the cellular basis of contrast adaptation in 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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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Greenwell, Thomas
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University of Maryland College Park
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College Park
United States
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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
Cui, Yuwei; Wang, Yanbin V; Park, Silvia J H et al. (2016) Divisive suppression explains high-precision firing and contrast adaptation in retinal ganglion cells. Elife 5:
Demb, Jonathan B; Singer, Joshua H (2016) Mind the Gap Junctions: The Importance of Electrical Synapses to Visual Processing. Neuron 90:207-9
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 (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
Ke, Jiang-Bin; Wang, Yanbin V; Borghuis, Bart G et al. (2014) Adaptation to background light enables contrast coding at rod bipolar cell synapses. Neuron 81:388-401
Cembrowski, Mark S; Logan, Stephen M; Tian, Miao et al. (2012) The mechanisms of repetitive spike generation in an axonless retinal interneuron. Cell Rep 1:155-66
Demb, Jonathan B; Singer, Joshua H (2012) Intrinsic properties and functional circuitry of the AII amacrine cell. Vis Neurosci 29:51-60
Wang, Yanbin V; Weick, Michael; Demb, Jonathan B (2011) Spectral and temporal sensitivity of cone-mediated responses in mouse retinal ganglion cells. J Neurosci 31:7670-81

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