title: Adult neurogenesis transiently generates oxidative stress.
abstract: An increasing body of evidence suggests that alterations in neurogenesis and oxidative stress are associated with a wide variety of CNS diseases, including Alzheimer's disease, schizophrenia and Parkinson's disease, as well as routine loss of function accompanying aging. Interestingly, the association between neurogenesis and the production of reactive oxidative species (ROS) remains largely unexamined. The adult CNS harbors two regions of persistent lifelong neurogenesis: the subventricular zone and the dentate gyrus (DG). These regions contain populations of quiescent neural stem cells (NSCs) that generate mature progeny via rapidly-dividing progenitor cells. We hypothesized that the energetic demands of highly proliferative progenitors generates localized oxidative stress that contributes to ROS-mediated damage within the neuropoietic microenvironment. In vivo examination of germinal niches in adult rodents revealed increases in oxidized DNA and lipid markers, particularly in the subgranular zone (SGZ) of the dentate gyrus. To further pinpoint the cell types responsible for oxidative stress, we employed an in vitro cell culture model allowing for the synchronous terminal differentiation of primary hippocampal NSCs. Inducing differentiation in primary NSCs resulted in an immediate increase in total mitochondria number and overall ROS production, suggesting oxidative stress is generated during a transient window of elevated neurogenesis accompanying normal neurogenesis. To confirm these findings in vivo, we identified a set of oxidation-responsive genes, which respond to antioxidant administration and are significantly elevated in genetic- and exercise-induced model of hyperactive hippocampal neurogenesis. While no direct evidence exists coupling neurogenesis-associated stress to CNS disease, our data suggest that oxidative stress is produced as a result of routine adult neurogenesis.
authors.affiliation: CNS, Astellas Research Institute of America LLC, Skokie, Illinois, United States of America. noah.walton@us.astellas.com
authors.forename: Noah M
authors.initials: NM
authors.lastname: Walton
authors.forename: Rick
authors.initials: R
authors.lastname: Shin
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tajinda
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Heusner
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kogan
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyake
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003561:Cytarabine; D004247:DNA / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D003561:Cytarabine; D004247:DNA