In this application, an expert in the function of retinal circuitry proposes to investigate mechanisms of signal processing and adaptation within the rod pathway for night vision in the mammalian retina. Rod and cone bipolar cells are essential for night and day vision because they transmit and signals from photoreceptors in the outer retina for processing to the inner retina. Understanding how the rod pathway encodes information is a fundamental problem that applies to all sensory pathways, including cone bipolar pathways and cortical circuits. The rod bipolar makes a synaptic ribbon contact onto the A17 amacrine cell, which then makes a reciprocal inhibitory feedback contact onto the rod bipolar cell. Over the past decade, this synaptic connection has been studied by many laboratories, producing a wealth of biophysical details relevant to its function. However, the neurophysiological detail appears so complex that its functional role is difficult to grasp. Recent studies have discovered several mechanisms in the rod bipolar ribbon synapse that cause it to adapt to the background level and to contrast. However the feedback inhibition from the A17 amacrine cell is not thought to contribute to this adaptation. Several other signal processing mechanisms in the A17 have been identified that regulate its feedback. These mechanisms are fundamental and significant because they are similar to those found in many other neurons in the brain. We hypothesize that at night, a divisive receptive field surround from the A17 amacrine cell regulates synaptic release by the rod bipolar cell to improve its signal quality, and that the A17 regulates the laterl extent of the surround according to the background level. We propose to study the effect of amacrine feedback on the synaptic processing performed by the rod and cone bipolar cells. Using realistic computational models of retinal circuitry, we will delineate the possible roles of feedback and feedforward mechanisms involved at the rod bipolar - A17 reciprocal synapse.
In Aim 1, we will develop a detailed model of the presynaptic and postsynaptic biophysical mechanisms excluding the details of morphology. We will examine how the known mechanisms for modulating vesicle release by the rod bipolar ribbon can limit or enhance the information content of its signal.
Aim 2 will test the hypothesis that negative feedback to the rod bipolar cel generates a divisive spatial surround that enhances the contrast response to twilight signals. In this aim, we will take the model of feedback from Aim 1 and add details of the fine radiating dendrites of the A17 amacrine, including its voltage-gated sodium and potassium channels. Overall, the proposed research will improve our understanding of the signal processing at different background levels performed by visual pathways of the retina. As the rod and cone pathways are critical for vision, the research will improve our understanding of a range of eye diseases. Because these pathways are critical targets for stimulation by visual prostheses and genetic approaches to restoring vision loss from a range of eye diseases, the knowledge gained here will help to advance the development of such devices and treatments.

Public Health Relevance

To understand the cause of some types of eye disease that can cause blindness, one must understand the normal function of the visual pathways of the retina. We propose to study the function of inhibitory feedback in the retinal pathway for night vision. The results of our study will lead to a better understanding of the normal function of neurons in retinal pathways in night and day, and thus to a better understanding of how they contribute to a disease process, to allow eye doctors to better restore the normal function of the retina through prosthetic or other types of treatment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Greenwell, Thomas
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University of Pennsylvania
Schools of Medicine
United States
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Borghuis, Bart G; Ratliff, Charles P; Smith, Robert G (2018) Impact of light-adaptive mechanisms on mammalian retinal visual encoding at high light levels. J Neurophysiol 119:1437-1449
Howlett, Marcus H C; Smith, Robert G; Kamermans, Maarten (2017) A novel mechanism of cone photoreceptor adaptation. PLoS Biol 15:e2001210
Ding, Huayu; Smith, Robert G; Poleg-Polsky, Alon et al. (2016) Species-specific wiring for direction selectivity in the mammalian retina. Nature 535:105-10
Lipin, Mikhail Y; Taylor, W Rowland; Smith, Robert G (2015) Inhibitory input to the direction-selective ganglion cell is saturated at low contrast. J Neurophysiol 114:927-41
Smith, Robert G; Delaney, Kerry R; Awatramani, Gautam B (2014) Post-receptor adaptation: lighting up the details. Curr Biol 24:R608-10
Puthussery, Theresa; Venkataramani, Sowmya; Gayet-Primo, Jacqueline et al. (2013) NaV1.1 channels in axon initial segments of bipolar cells augment input to magnocellular visual pathways in the primate retina. J Neurosci 33:16045-59
Abbas, Syed Y; Hamade, Khaldoun C; Yang, Ellen J et al. (2013) Directional summation in non-direction selective retinal ganglion cells. PLoS Comput Biol 9:e1002969
Taylor, W R; Smith, R G (2012) The role of starburst amacrine cells in visual signal processing. Vis Neurosci 29:73-81
Trenholm, Stuart; Johnson, Kyle; Li, Xiao et al. (2011) Parallel mechanisms encode direction in the retina. Neuron 71:683-94
Taylor, W R; Smith, R G (2011) Trigger features and excitation in the retina. Curr Opin Neurobiol 21:672-8

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