Project Summary/Abstract Healthy vision requires the function of parallel cellular and synaptic pathways in the neural retina. Circuits constructed from diverse cell types provide the anatomical and physiological basis for encoding diverse visual scenes. Indeed, visual inputs to the mouse retina are converted to electrical signals by photoreceptors (1 rod, 2 cone types), integrated by interneurons (1 horizontal, ~15 bipolar, ~60 amacrine cell types), and relayed to the brain by retinal ganglion cells (>40 types) whose axons form the optic nerve. In a surgical model of nerve injury, called the optic nerve crush (ONC), the axons of retinal ganglion cells (RGCs) are damaged. In response to ONC, 70-80% of RGCs die within two weeks. The death of RGCs is biased, however, and depends on the RGC type. A group of resilient RGC types persists and survives for weeks following the crush, whereas other susceptible RGC types die within a few days. A long-term goal of the ONC model is to rescue injured RGCs and enable regrowth of axons to target brain regions and restore functional vision. The field has identified transcriptomic and tissue-level mechanisms that promote RGC survival. Furthermore, RGC survival and axon regeneration are enhanced by RGC electrical activity (e.g., action potential firing). However, there is a major gap in our understanding of (1) how activity of different RGC types is affected following ONC; (2) how changes in activity align with the resilient/susceptible category of RGC types; and (3) whether there are cellular or synaptic mechanisms that are affected by ONC and prohibit the ability to enhance activity in certain RGC types following injury. I will therefore utilize electrophysiological and confocal microscopy techniques to directly address my hypothesis that dysfunction and reduced firing in RGCs post optic nerve crush depends on the RGC type and reflects a combination of synaptic and cell-intrinsic mechanisms. I will measure the anatomy and physiology of specific RGC types that are either resilient or susceptible to ONC and determine the contributions of either synaptic or intrinsic mechanisms to RGC hypoactivity after ONC. Understanding these mechanisms will generate insights into how naturally-occurring diseases that affect the optic nerve, such as glaucoma, cause dysfunction and death of RGCs and could contribute to the design of rational therapies.

Project Narrative Visual injury and disease affect millions of patients annually, but there is still much to learn about the mechanisms that impair visual processing in these conditions. Here, I will determine the chronic effects of an acute injury on distinct subpopulations of retinal ganglion cells, the retina’s output neurons that signal the brain. The results of the proposed experiments could contribute to understanding human diseases that affect the optic nerve, including glaucoma.