Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice

Advances in the management of pediatric brain tumors have increased survival rates in children, but their quality of life is impaired due to cognitive deficits that arise from irradiation. The pathogenesis of these deficits remains unknown, but may involve reduced neurogenesis within the hippocampus. To determine the acute radiosensitivity of the dentate subgranular zone (SGZ), 21-day-old C57BL/J6 male mice received whole brain irradiation (2-10 Gy), and 48 h later, tissue was assessed using immunohistochemistry. Proliferating SGZ cells and their progeny, immature neurons, were decreased in a dose-dependent fashion. To determine if acute changes translated into long-term alterations in neurogenesis, mice were given a single dose of 5 Gy, and 1 or 3 months later, proliferating cells were labeled with 5-bromo-2'-deoxyuridine (BrdU). Confocal microscopy was used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes. X-rays significantly reduced the production of new neurons at both time points, while glial components showed no change or small increases. Measures of activated microglia and infiltrating, peripheral monocytes indicated that reduced neurogenesis was associated with a chronic inflammatory response. Three months after irradiation, changes in neurogenesis were associated with spatial memory retention deficits determined using the Morris water maze. Behavioral training and testing increased the numbers of immature neurons, most prominently in irradiated animals. These data provide evidence that irradiation of young animals induces a long-term impairment of SGZ neurogenesis that is associated with hippocampal-dependent memory deficits. (C) 2004 Elsevier Inc. All rights reserved.