Project Summary Retinal ganglion cell (RGC) degeneration underlies vision loss following traumatic injuries and in optic neuropathies like glaucoma. Treating these conditions requires interventions that promote RGC neuroprotection and axon regeneration. While many such treatments have been identified in pre-clinical animal models, none promote recovery, and typically treatment effects are limited to a small subset of RGCs. To bridge the gap in understanding why treatments have incomplete effects, we took the approach of resolving how axonal injury affects distinct RGC types and how each RGC type responds to regenerative interventions. This approach revealed that RGC resilience and axon regeneration are highly cell type-dependent and associate with high RGC activity levels. In this proposal, we will explore the mechanistic connections between cell type-specific RGC activity, resilience, and axon regeneration. Neuronal activity mediates numerous cellular processes that could influence injury response including immediate early gene expression, cAMP signaling, and Ca2+ dynamics. Indeed, increasing RGC activity by neuromodulation promotes RGC survival and axon regeneration. However, we have limited insight into how these approaches will work across RGC cell types, which have distinct functional properties and participate in different neural circuits. Our experiments will employ cutting-edge multidisciplinary approaches to dissect the molecular and physiological effects of neuromodulatory treatments on different RGC types. We will first examine a signaling pathway mediated by Urocortin (UCN) and Corticotropin-releasing hormone (CRH), which we recently discovered to promote RGC resilience and axon regeneration after axonal injury. UCN/CRH are neuropeptides that increase neuronal excitability, but their function in RGCs and the mechanisms underlying their neuroprotective and regenerative effects are unresolved. We will investigate both the native roles of UCN/CRH in shaping RGC physiology and the effects of activating UCN/CRH signaling on mitigating RGC injury response. Next, we will test the effects of increasing or decreasing RGC activity on injury response by silencing RGC pre-synaptic inputs or by directly altering RGC membrane potential. Our work will be the first to characterize the combined effects of injury and activity across cell types of a diverse neuronal population. We will gain mechanistic insight into the connection between high RGC activity and selective resilience and axon regeneration after injury. Our studies have strong potential to improve approaches for the treatment of RGC degeneration and are also likely to elucidate generalizable principles mediating neuronal survival and axon regeneration that will have implications for other neurodegenerative conditions.