A major research challenge for neurobiology is to understand the neural mechanisms that give rise to an extreme diversity of parallel visual pathways and ultimately the contributions that these pathways make to our perception of motion, form and color. For motion perception the cell types, circuits and synaptic mechanisms that mediate selectivity to the direction of moving stimuli have been intensively studied in the non-primate mammal for decades and over a dozen distinct direction selective pathways are recognized in the mouse retina together with growing evidence for similarly diverse underlying neural mechanisms. The great complexity of the visual pathways found in the mouse is mirrored in the primate, yet surprisingly the abundant direction selective ganglion cells have not been previously identified. The broad long-term objective of this new research program is to elucidate for the first time the cell types, circuits, synaptic organization and underlying cellular mechanisms for direction selectivity in the macaque monkey retina, as an ideal model for human visual processing centered around the fovea. Our proposed research plan arises from a series of discoveries that opens a door to the first detailed study of both the visual physiology and synaptic organization of direction selective circuitry in the macaque retina. In preliminary studies we have identified the primate ON-OFF direction selective ganglion cell as the recursive bistratified type and have developed new methods that permit systematic targeting of this cell type for analysis. The synaptic physiology and directional tuning of this ganglion cell type are the focus of Aim 1 where we test the hypothesis that directional selectivity in the primate is radially aligned with respect to the fovea. Second, we have developed reliable methods for targeting the starburst amacrine cell type, the key retinal interneuron in the direction selective circuit, for both physiological analysis and connectomic circuit reconstruction for the first time. Preliminary data reveal novel features of starburst receptive field structure, directional tuning and connectivity providing the focus for Aim 2 where we test new hypotheses for the cellular origins of direction selectivity and its synaptic transfer to ganglion cells. Finally, we have discovered direction selectivity in the poly-axonal spiking A1 amacrine cell type and evidence for a functional link to ON-OFF direction selective ganglion cells. The focus of Aim 3 therefore is to test the hypotheses that the A1 cells unique axonal component provides synaptic input to both starburst and ON-OFF direction selective ganglion cells, and determine the role of the A1 cells unique dendro-axonal structure in direction selectivity. In sum the broad aim is to characterize the directional tuning properties of these three cell types, and to use connectomics for the first time to determine the underlying synaptic interactions that create direction selectivity in the primate retina. Outcomes will thus have a specific impact on understanding of mechanisms motion processing in human vision and more broadly on growing applications of the primate model for the development of tools and methods for vision restoration.

Public Health Relevance

The perception of motion is critical for normal human vision yet the cells, circuits and mechanisms that give rise to selectivity for movement direction have never been identified in the primate retina. The proposed project arises from the discovery of direction selective ganglion cells and associated novel circuitry in the macaque monkey retina and applies state of the art connectomic and functional imaging methods to advance understanding of the primate direction selective circuit for the first time. Outcomes will have significance for advancing understanding of motion processing in human vision and impact on the development of tools for cellular imaging and vision restoration in the unique primate retinal model.

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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Wright, Charles Baker
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University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
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