The goal of this proposal is to understand the synaptic mechanism and neuronal circuitry underlying complex visual processing in the mature mammalian retina, with a focus on the function and organization of individual synapses in the direction selective circuit. The proposed study is based on recent findings that identified critica synaptic interactions underlying the generation of direction selectivity. These findings suggested a previously unappreciated level of synaptic intricacy in the underlying neuronal circuit. They revealed the importance, as well as the possibility, to understand the mechanism of directional computation at a microcircuit level. In order to gain direct knowledge of the function and organization of the direction-selective microcircuits, a novel experimental approach is proposed here, which integrates two-photon imaging, dual patch-clamp recording, spot UV uncaging, and transgenic technology, so that neuronal connectivity and interactions at individual synaptic sites can be measured in an intact retinal network and correlated with the morphological and functional properties of the cells in the same experiment. The proposed experiments are designed to understand (1) the synaptic mechanism of cholinergic transmission in the mature retina, (2) the functional organization of individual cholinergic and GABAergic synapses between starburst amacrine and direction-selective ganglion cells, (3) the functional organization of GABAergic synapses between starburst amacrine cells, and (4) the synaptic interactions at bipolar cell axon terminals. Results from these experiments are expected to provide novel insights into the nature of dendritic and axonal computation at a synaptic level and in an intact retinal circuit. This approach may also provide a novel experimental paradigm for studying the function and connectivity at individual synapses in other CNS circuits.

Public Health Relevance

The proposed research is relevant to public health, because the results of the studies are expected to provide novel insights into the function of the human retina and the mechanism of nicotinic neurotransmission, which is important for a wide range of neural functions and diseases.

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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Yale University
Schools of Medicine
New Haven
United States
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Xu, Hong-Ping; Burbridge, Timothy J; Ye, Meijun et al. (2016) Retinal Wave Patterns Are Governed by Mutual Excitation among Starburst Amacrine Cells and Drive the Refinement and Maintenance of Visual Circuits. J Neurosci 36:3871-86
Lee, Seunghoon; Zhang, Yi; Chen, Minggang et al. (2016) Segregated Glycine-Glutamate Co-transmission from vGluT3 Amacrine Cells to Contrast-Suppressed and Contrast-Enhanced Retinal Circuits. Neuron 90:27-34
Zhou, Elton K; Xu, Hong-Ping (2015) GABAergic regulation of spontaneous spike patterns in the developing rabbit retina. Neurosci Lett 600:137-42
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Burbridge, Timothy J; Xu, Hong-Ping; Ackman, James B et al. (2014) Visual circuit development requires patterned activity mediated by retinal acetylcholine receptors. Neuron 84:1049-64
Chen, Minggang; Lee, Seunghoon; Park, Silvia J H et al. (2014) Receptive field properties of bipolar cell axon terminals in direction-selective sublaminas of the mouse retina. J Neurophysiol 112:1950-62
Lee, Seunghoon; Chen, Lujing; Chen, Minggang et al. (2014) An unconventional glutamatergic circuit in the retina formed by vGluT3 amacrine cells. Neuron 84:708-15
Ackman, James B; Burbridge, Timothy J; Crair, Michael C (2012) Retinal waves coordinate patterned activity throughout the developing visual system. Nature 490:219-25
Xu, Hong-ping; Furman, Moran; Mineur, Yann S et al. (2011) An instructive role for patterned spontaneous retinal activity in mouse visual map development. Neuron 70:1115-27

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