Priming neuronal regeneration: early adaptive mechanisms in zebrafish CNS injury

The zebrafish (Danio rerio) exhibits a remarkable capacity to regenerate the central nervous system following injury, restoring both tissue architecture and neural function. This review focuses on the earliest phases of the injury response, when conserved damage signals are first sensed, integrated, and translated into trajectories that bias tissue outcomes toward regeneration or persistent degeneration. We examine how early molecular cues, including damage-associated molecular patterns, inflammatory signals, calcium, and redox dynamics are differentially interpreted in zebrafish compared to mammals, leading to distinct cellular and tissue-level responses. Within this early signaling landscape, emerging evidence indicates that neuronal activity and neurotransmitter plasticity constitute a neuron-specific regulatory layer fundamental to the regulation of early injury responses and the initiation of regenerative programs. Rather than cataloging downstream regenerative mechanisms, we emphasize the importance of early temporal coordination of these injury-derived signals, which establishes permissive or non-permissive regulatory states. Overall, this review positions the zebrafish as a powerful vertebrate model for identifying general principles of early signal integration and temporal control that govern regenerative competence, providing a conceptual framework that may inform strategies to enhance repair in the injured mammalian CNS.