Cancer chemotherapy can be lifesaving but frequently results in long-term cognitive deficits. This project seeks to establish a regenerative strategy for chemotherapy-induced cognitive dysfunction by harnessing the potential of the interactions between active neurons and glial precursor cells that promote myelin plasticity in the healthy brain. In the first year of this award, we have made on-track progress towards establishing a working experimental model system of chemotherapy-induced neurotoxicity that faithfully models the human disease both in terms of the cellular damage as well as functional deficits in cognition. Using this model, we have found that the oligodendroglial precursor cell population depletion following chemotherapy is due not only to a direct effect of the chemotherapy on the OPCs, but also due to alterations in the microenvironmental milieu of the brain that normally maintains this population of cells. We have also been able to identify several therapeutic candidate molecules that we will be studying in the coming years of the project to ascertain which of these candidates are sufficient to promote OPC population repletion and neuro-regeneration after chemotherapy exposure.