Project Summary One of the barriers to therapeutic neural regeneration in humans is the absence of neural stem cells in most regions of the adult brain. Nonetheless, it would be advantageous to induce regeneration from resident cells. In addition, progress in the field would be accelerated if neural regeneration from resident cells could be investigated using a genetic model organism. Toward this end, we have developed a novel adult neurogenesis model in the Drosophila melanogaster central brain. We find that despite the absence of known neural progenitors, cells in the adult Drosophila central brain proliferate following injury, giving rise to both new neurons and new glial cells. Further, the new neurons project both axons and dendrites to specific target regions. We also observe functional recovery of behavioral deficits, suggesting that the new neurons integrate appropriately into neural circuits. Our results are paradigm-shifting because they suggest that resident brain cells can mediate neural regeneration. Here, we propose to utilize the model to investigate the signaling pathways and cellular mechanisms that regulate adult neurogenesis. Based on compelling preliminary data, our central hypothesis is that adult-born neurons are responsible for functional recovery from brain injury and that these neurons arise separately from adult-born glia. This hypothesis is supported by multiple lines of evidence from our ongoing work. We have identified, and are now investigating, genes uniquely upregulated during neural regeneration. The work proposed here will provide critical data about the molecular mechanisms that underlie that adult neurogenesis. Our work is innovative and has translational relevance because it shifts the focus of neural regeneration away from stem cell transplants and toward resident cell populations and it may lead to the identification of therapeutic targets for the stimulation of brain regeneration in humans.