Sex-dependent differences in behavior and hippocampal neurogenesis after irradiation to the young mouse brain

Cranial radiotherapy in the treatment of pediatric malignancies may lead to cognitive deficits, and girls suffer more severe deficits than boys. However, most experimental studies are performed on male animals only. Our aim was to investigate possible long-term gender differences in response to cranial irradiation (IR). Basal neurogenesis in non-irradiated mice was higher in females but this was not apparent until the animals were adult. Male and female C57BL/6J mice received a single dose of 8 Gy to the whole brain on postnatal day 14 and were killed 6 h or 4 months later. Proliferation in the subgranular zone of the dentate gyrus in the hippocampus, as judged by the number of phosphohistone H3-positive cells, was reduced by half 6 h after IR in both males and females. The reduced proliferation was still obvious 4 months after IR. Consequently, the continuous addition of new neurons to the granule cell layer (GCL) during brain growth was reduced in irradiated mice, and the reduction was more pronounced in females. This resulted in hampered growth of the GCL, reduced bromodeoxyuridine incorporation in adulthood, and severely reduced adult neurogenesis, as judged by the number of doublecortin-positive cells in the GCL. In an open-field test, locomotor activity was increased in both males and females after IR and anxiety levels were increased, more so in females. In an IntelliCage test, place learning was impaired by IR in females but not males.