Cellular and Molecular Mechanisms that Direct Visual System Connectivity

A wide range of cellular and molecular mechanisms direct the formation of neural circuits in the mammalian visual system, and these are critical for behavioral responses to visual input. We have investigated the establishment of connections among retinal neurons and also between retinal ganglion cells (RGCs), the sole output neurons of the retina, and their targets in the brain. Based on the expression and function of certain guidance cues and their receptors, we have defined molecules and mechanisms critical for the establishment of the laminar (layered) organization of pre- and post-synaptic components of connections in the retina, and also for RGC axon targeting to visual system nuclei in the brainstem. This has led us to investigate particular classes of connections: those that mediate direction-selective (DS) responses to image motion, and also connectivity essential for non-image forming visual system functions.

As a result of a novel, focused, gene profiling effort we have identified genes selectively expressed in direction-selective ganglion cells (DSGCs) tuned to upward or downward motion. These include transcription factors, secreted proteins, receptors, and a range of cell surface molecules. Mice harboring mutations in several of these genes are deficient in vertical, but not horizontal, motion detection, and some of these mutations also affect DSGC dendritic morphology. We are currently investigating at all levels how these proteins affect DS circuit connectivity and the unique directional tuning preferences of DSGCs. Related studies are also directed towards investigating similar issues for non-image forming RGCs. Finally, our visual system work also motivates research directed towards promoting optic nerve regeneration following injury or degeneration.