Morphological maturation and circuit integration of adult-born neurons are key to functional recovery after traumatic brain injury.

Abstract

Successful repair after brain injury requires a chain of events, including the generation, migration, and successful integration of adult-born neurons into preexisting circuits. In mammals, the capacity for neuronal regeneration is extremely limited and further declines with age, constraining recovery. Regeneration-competent vertebrates offer a unique opportunity to uncover mechanistic principles of seamless brain repair. We here introduce the African turquoise killifish, a naturally short-lived vertebrate in which tissue repair occurs at young but not old age. We established an integrative approach combining i) an optimized retroviral vector application to birthdate GFP-labeled dividing neural stem cells and their progeny, ii) targeted electrophysiology to quantify synaptic and intrinsic maturation of such neurons, and iii) a conditioned avoidance assay to track recovery of learned behavior in adult killifish. We applied this workflow to the dorsomedial telencephalon, a region homologous to the mammalian amygdala. We reveal that injury-induced adult-born neurons survive, mature, and integrate synaptically into preexisting circuits, and that this coincides with the recovery of learned avoidance behavior by two months postinjury. Only when newborn neurons display mature morpho-electric properties, including complex dendritic arborization and abundant dendritic spines, recovery of behavior is accomplished. That full functional recovery takes around 50 d, substantially longer than previously inferred from histological analyses alone, is a striking finding given the killifish's short lifespan. These findings establish the killifish as a powerful vertebrate model and introduce a scalable platform for experimentally manipulating neuronal maturation and integration in vivo, particularly in the context of aging and age-related regenerative decline.