Post-chemotherapy induced cognitive impairment, also called “chemobrain,” affects large numbers of cancer patients and survivors, and is characterized by subjectively reported and objectively measured cognitive deficits following cancer chemotherapy. These deficits can last for up to several years and significantly impact the quality of life of affected patients. Recent findings have indicated that declines in neurogenesis, particularly by neural stem cells (NSCs) in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), contribute to cognitive dysfunction following treatment with a number of different chemotherapy agents. Our preliminary data indicate that the glycosaminoglycan hyaluronan (HA) is reduced in the dentate gyri of mice treated with a common chemotherapy agent, 5-fluorouracil (5-FU). Disruption of HA in the SGZ leads to increased NSC proliferation and increased numbers of neuronal progenitors whose maturation is delayed in the granule cell layer of the dentate gyrus. Similarly, mice lacking the major transmembrane HA receptor CD44 demonstrate increased NSC proliferation in the SGZ and delayed neuronal progenitor cell maturation in the dentate gyrus. These mice also demonstrate cognitive deficits related to altered hippocampal function. These data support the novel hypothesis that chemotherapy can alter the HA-based hippocampal extracelluar matrix either by increasing hyaluronidase activity or decreasing HA synthesis, leading to the disruption of HA in the SGZ. This disruption would initially lead to increased NSC proliferation and delayed or aberrant neuronal differentiation, and the eventual exhaustion of NSCs and reduced neurogenesis. Our aim in the current application is to test this hypothesis in a rodent model of chemotherapy with the long-term goal of developing strategies that can enhance or protect neurogenesis during cancer therapies. Our specific aims are: (1) To test the hypothesis that chemotherapy leads to the induction of hyaluronidases and the accumulation of specific HA digestion products in the hippocampus; and (2) To test the hypothesis that chemotherapy-induced HA digestion leads to aberrant adult neurogenesis. All together, these studies have the potential to reveal a novel mechanism by which hippocampal neurogenesis is disrupted in individuals with chemobrain and will begin to test the efficacy of interfering with hyaluronidase activity as a means of enhancing neurogenesis in cancer patients undergoing chemotherapy.