Chemotherapy for cancer can result in a debilitating neurological syndrome that is due, in part, to damage to the brain’s white matter. We have been working to better understand this damage and to develop strategies for neuroregeneration. We have found that a commonly used chemotherapy called methotrexate causes long term depletion of the neural precursor population responsible for maintenance and plasticity of the white matter (oligodendrocyte precursor cells, OPC) by damaging the microenvironment of these precursor cells, i.e. the relationship of OPCs with other cells in the microenvironment. Having now uncovered some of the signaling pathways that are altered because of this microenvironmental damage, we are testing possible therapeutic strategies to address it and restore the OPC population following chemotherapy.