ABSTRACT Traumatic injury to the adult human brain results in life-long loss of function. By contrast, the adult zebrafish brain has a striking ability to efficiently regenerate after injury. The molecular mechanisms controlling this phenomenon are unclear and understudied. Understanding the events that lead to activation and migration of stem cells during zebrafish brain regeneration is challenged by imprecise injury models, complexity of the brain regions traditionally studied and limited platforms for live imaging. This proposed research will establish the zebrafish olfactory bulb (OB) as a model for brain regeneration. The OB has a great capacity for regeneration and neuroplasticity, contains large and morphologically distinct axons, controls behavioral outputs, and is anatomically and functionally conserved among vertebrates. The specific aims of this proposal seek to (1) genetically ablate regions of the zebrafish OB and dissect dynamics of cell biology during regeneration via live imaging; (2) identify the transcriptional programs that control the activation and progression of neuronal progenitors along separate lineages during brain regeneration; and (3) identify and interrogate signaling pathways required for brain regeneration. Ultimately, the biological events discovered in this proposal may be potential targets for therapeutic strategies in human brain injury and stroke.