Molecular mechanisms underlying direction-selective circuit assembly and function in the mouse visual system

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PROJECT SUMMARY The elaboration of neural circuits involves a complex series of events, including neuronal differentiation, settling of neurons in appropriate locations, neural process outgrowth and pathfinding, target selection, synaptogenesis and synapse refinement. Development of direction-selective (DS) circuits in the mammalian visual system relies on precise execution of each of these steps, however we are only beginning to understand how these connections are established. The central goal of this proposal is to understand the molecular mechanisms that allow components of DS circuits to mediate appropriate visual system responses to image motion. DS responses depend critically on distinct classes of bipolar cells, starburst amacrine cells (SACs), and direction-selective retinal ganglion cells (DSGCs). The development of these neurons, including their differentiation and the regulation of their morphology and synaptic contacts, is integral to the generation of functional DS circuitry. Here, we propose leveraging our recent gene profiling and additional Preliminary Findings to address key unresolved questions in DS circuit wiring. Subtypes of DSGCs are tuned to motion in distinct preferred directions, and this is due to differences in asymmetric wiring of SACs onto the dendrites of these different DSGC subtypes; however, the underlying basis of this asymmetric SAC-DSGC wiring is unknown. We have identified genes that are differentially expressed in subtypes of DSGCs that are components of the Accessory Optic System (AOS): On-DSGCs (oDSGCs) that differ only in their preferred directional preference–in this case for dorsal vs. ventral object motion. Analysis of these differentially expressed (DE) genes has the potential to reveal underlying molecular mechanisms governing the development of these oDSGCs and the synaptic wiring that determines their directional tuning, since the central difference between dorsal-oDSGCs and ventral-oDSGCs is the polarity of their preferred directional tuning. This proposal is focused on testing the hypothesis that differential gene expression in oDSGCs of the accessory optic system (AOS) tuned to detect either upward or downward motion instructs the development of functional DS circuits.