Chemotherapy-induced cognitive deficit (“chemobrain”) is a major side effect of cancer treatment that frequently persists long into survivorship. There are no FDA-approved drugs for prevention or treatment of chemobrain, and the underlying mechanisms are poorly understood. This application aims at filling this void and responds to provocative question #9: What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae? Our previous work in models of ischemic brain damage demonstrated that nasally applied mesenchymal stem cells migrate into the brain to restore cognitive and sensorimotor dysfunction, by promoting endogenous repair mechanisms leading to restoration of brain structure and by suppression of neuro-inflammation. Our preliminary data show that cisplatin induces cognitive deficits in mice that are associated with decreased neurogenesis, abnormalities in white matter organization and dendritic spine integrity, and impaired mitochondrial respiration. Preliminary data indicate that mesenchymal stem cells (MSC) administered intranasally travel into the brain, restore the cognitive deficits and normalize mitochondrial function. Preliminary in vitro data indicates that MSC transfer healthy mitochondria to neurons damaged by cisplatin. Our working hypothesis is that cisplatin induces cognitive deficits by causing persistent mitochondrial damage leading to neuroinflammation, stem cell depletion, abnormalities in white matter organization and dendritic spine integrity, and impaired synaptic connectivity. We propose that nasally administered MSC reverse CICI by restoring mitochondrial function and suppressing neuroinflammation. To test our hypothesis we will pursue the following Specific Aims: Aim 1: Treat CICI by intranasal administration of MSCs; Aim 2: Determine whether nasally administered MSCs migrate into the brain to promote endogenous repair mechanisms; and Aim 3: Determine the mechanisms underlying the effect of cisplatin and MSC on the brain. This study is innovative because: a) we will be the first to fully analyze CICI in the mouse at the neuroimaging, cellular, mitochondrial and inflammatory levels; b) the potential to restore CICI by nasal administration of MSC has not been tested; c) the hypothesis that MSC transfer mitochondrial to damaged neurons in vivo has not been tested; c) successful completion of this study will identify key molecular mechanisms underlying chemobrain; and d) we will provide proof of principle that chemobrain can be repaired. This project is significant because chemobrain is a common side effect of cancer treatment that often persists into survivorship and reduces quality of life. We have already performed extensive safety studies in mice treated with MSC for ischemic brain damage. Successful completion of this project will provide the first step toward a treatment for brain damage and associated functional impairments caused by chemotherapy for tumors outside the nervous system or by other cancer treatments, including radiation therapy for brain tumors.