The central nervous system (CNS) is a terminally differentiated tissue, where any insult carries a heightened risk - yet the tissue response to these insults is variable and can range from irreversible destruction to almost complete recovery. The rules that instruct these divergent outcomes are still unknown. The aim of this CRC is therefore to understand the biology of the multicellular response that determines recovery after CNS injury. We will study how highly coordinated interactions that span different cell types and scales influence the structural and functional outcome after acute CNS injuries. We will investigate distinct damage and reconstitution constellations caused by inflammatory, traumatic, metabolic or ischemic insults and dissect the mechanisms that determine the balance between reconstitution and scarring in the nervous tissue. The aim of the proposal is (i) to define the immunological, glial and neuronal checkpoints that faithfully predict the outcome of CNS injuries, and (ii) to develop intervention strategies targeting these checkpoints that guide an injured CNS tissue towards reconstitution. The initial focus is set on the analysis of distinct damage models and the cellular interactions, subcellular alterations and molecular signals that determine recovery. Next, we aim to map out the common pathways and general rules that determine the reversibility of CNS injury e.g. by further expanding the analyzed disease spectrum and including computational modelling strategies. These studies will lay the foundation for the design of novel treatments strategies that harness the endogenous repair potential to promote tissue restitution and limit scarring.