Impaired Hippocampal Neurogenesis Is Involved In Cognitive Dysfunction Induced By Cranial Radiation Therapy

【Objective】 To investigate the changes of hippocampal neurogenesis and cognitivedysfunction induced by cranial radiation therapy.【Methods】C57BL/6J mice at age of10days were subjected to10Gy whole brainirradiation dose with6MV X-ray to develop irradiation-induced brain injury model.Morris water maze is designed to estimate spatial learning and memory. At differenttime following irradiation brain tissue was removed to stain with hematoxylin-eosinfor the pathological result. DCX and PCNA immunohistochemical staining marks thelevel of neurogenesis in the hippocampus. ED1immunohistochemical staining marksthe activation of microglia. The TUNEL assay is used technique for the assessment ofapoptotic neuron death in situ in the hippocampus. γ-H2AX immunofluorescenthistochemical staining labels the formation of DSB. Real-time PCR is supplied toinspect the expression of TNF-and IL-1β mRNA. Enzyme Linked ImmunosorbentAssay(ELISA) is tested for the concentration of TNF-in the plasma.【Results】Pathological studies demonstate interstitial edema, inflammatory cellinfiltration, cell degeneration, necrosis, apoptosis in the acute phase, but in the chronic phase show edema subsiding, reduction of inflammatory cells, cytothesis in thedentate gyrus of the hippocampus. IHC studies reveal at different time followingirradiation decreased number of DCX-positive cells and PCNA-positive cellscompared with the controlled group. ED1-positive cells increase significantly.TUNEL-positive cells begin to appear in the in the dentate gyrus of the hippocampus6hours after irradiation, subsequently the number reach the highest level48hoursafter irradiation. The formation of γ-H2AX foci gets at the top0.5hour afterirradiation, later reduces. After irradiation, the expression of TNF-and IL-1βmRNA is higher than the controlled group. The concentration of TNF-in the plasmain the irradiated group is higer than the controlled group3hours after irradiation, andmaximized1week after irradiation. Morris water maze tests show the latency nosignificant differences between the irradiated group and the controlled group on thefirst three days, but demonstrate that the latency in the the irradiated group is longerthan the controlled group with a significant differences on Day4, Day5, Day6.【Conclusions】Developing irradiation-induced brain injury model by cranialradiation therapy, we find that inhibition of hippocampal neurogenesis and activationof microglia may be connected closely to cognitive dysfunction induced by cranialradiation therapy.