Direction selective ganglion cells in the mammalian retina are strongly activated by motion in their preferred direction, but are suppressed by motion in the opposite, or null, direction. They report the direction of motion to higher brain centers or further visual processing, and they contribute to the control of eye movements and, potentially, to conscious vision. Direction selectivity of these ganglion cells is attributed to multiple pre- ad postsynaptic mechanisms. However, the implementation of these mechanisms at the synapse level is not fully understood. The goal of this proposal is to provide fundamental insights into th structure-function relationship of the synaptic circuitry that underlies direction selectivity. The proposed experiments will focus on synaptic inputs from the starburst amacrine cell, a critical interneuron that co-releases GABA and acetylcholine onto direction selective ganglion cells. We will first determine the properties of synaptic transmission and the functional wiring diagrams of the GABAergic and cholinergic circuits from starburst amacrine cells to direction selective ganglion cells, and will then identify the predominant synaptic mechanism underlying direction selectivity. We will take an innovative approach that combines genetic cell type-specific targeting, electrophysiology, fine resolution optogenetics and uncaging techniques to characterize and manipulate the synapse types of interest, and to correlate synaptic-level mechanisms with circuit function. This work will provide definitive answers to the outstanding questions that remain about the direction selective circuit. It will also contribute to the knowlede of the general principles that govern sensory processing. Moreover, this research will provide insight into the mechanism of chemical co-transmission in sensory systems and in higher brain structures.

Public Health Relevance

Our research goal is to understand how neurons in the mammalian retina compute the direction of image motion. The proposed research is relevant to public health because elucidating the mechanisms of normal visual function is the rational first step towards the ultimate goal of rescuing visual dysfunction in diseased states. Furthermore, the knowledge gained from the proposed study will have broader implications as it will address the general principles of sensory processing in the brain.

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 Chicago
Schools of Medicine
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Bleckert, Adam; Zhang, Chi; Turner, Maxwell H et al. (2018) GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells. Proc Natl Acad Sci U S A 115:E12083-E12090
Wei, Wei (2017) Compartmentalized dendritic signaling in a multitasking retinal interneuron. Proc Natl Acad Sci U S A 114:11268-11270
Koren, David; Grove, James C R; Wei, Wei (2017) Cross-compartmental Modulation of Dendritic Signals for Retinal Direction Selectivity. Neuron 95:914-927.e4
Shi, Xuefeng; Barchini, Jad; Ledesma, Hector Acaron et al. (2017) Retinal origin of direction selectivity in the superior colliculus. Nat Neurosci 20:550-558
Chen, Qiang; Pei, Zhe; Koren, David et al. (2016) Stimulus-dependent recruitment of lateral inhibition underlies retinal direction selectivity. Elife 5:
Pei, Zhe; Chen, Qiang; Koren, David et al. (2015) Conditional Knock-Out of Vesicular GABA Transporter Gene from Starburst Amacrine Cells Reveals the Contributions of Multiple Synaptic Mechanisms Underlying Direction Selectivity in the Retina. J Neurosci 35:13219-32