title: Impact of Low-Dose Ionizing Radiation on Cognitive Abilities in the Mouse : Assessment of Radiation Sensitivity during Pre- and Postnatal Brain Development
Creators: name: Klink, Axel
Publisher: name: UNSPECIFIED
Year: 2021

description: In our modern society various sources of radiation are omnipresent. Sectors like nuclear power generation, long distance air travel and medical radiation diagnostics rank among the most prominent. Especially, the amount of medically necessary radiation is increasing and represents a major source of exposure in the general population. Therefore, radiation protection and the epidemiology of radiation have gained in importance. The risk possibly arising from exposure to low-dose radiation is still part of intensive and ongoing debates, demonstrating that current results are still controversial. Consequently, further studies on the effects of low-dose radiation are of great social relevance. Systemic studies within animals could provide additional information about radiation impact on behaviour and neurogenesis within the hippocampus, thus contributing to a better understanding of radiation induced sequelae and improving current risk assessment. This thesis evaluates the effects of low-dose ionizing radiation (LDIR, defined as ≤ 0.5 Gy) on murine behaviour and neurogenesis. Chapter I and II deal with irradiations at specific time points during prenatal (E14.5) and early postnatal (P10) brain development and provide results on the long-term sensitivity to low-dose radiation. Chapter III deals with low-dose irradiation during different learning phases at an early adult stage (two months) and provides results on the short-term sensitivity to low-dose radiation. Chapter IV deals with the long-term effects of low-dose irradiation at E14.5 or P10 on neurogenesis. Chapter V provides an overarching comparison of all time points of irradiation. Mice performed a set of behavioural tasks including the Rotarod performance test for the analysis of motor function and coordination, the Elevated-Zero-Maze for evaluation of anxiety and exploration, and the Morris Water Maze for the analysis of spatial learning and memory abilities. Furthermore, naïve mice were irradiated at E14.5 or P10 and analyzed immunohistologically at the age of two months. Here, the focus was on quantification of DCX+ neural progenitor cells in the neurogenic niche of the dentate gyrus. Substantial dose-dependent effects during MWM testing were detected after irradiation at the time points E14.5 and P10, but not after irradiations in two months old mice compared to Sham controls. Impairment of MWM performance was characterized by decreasing efficiencies in spatial searching and disturbed reference memory with increasing irradiation dose. The comparison of E14.5 and P10 revealed only slight differences, so that a similar sensitivity to low-dose irradiation was ascribed to both time points. Immunohistological analysis revealed that irradiation with 0.5 Gy reduced the number of DCX+ progenitor cells in the adult dentate gyrus of naïve mice after both the embryonic and the early postnatal irradiation. However, a significant cell loss was only observed in mice irradiated at E14.5 compared to the P10. My data show that the neurogenic niche in the dentate gyrus reacts very sensitive to radiation exposure, even if doses are low. The alterations in neurogenesis are certainly associated with learning and memory deficits. As the observed impact on neurogenesis was differently pronounced in naïve animals irradiated at E14.5 or P10, whereas the observed cognitive effects were quite similar, the reduced number of progenitor cells within the hippocampal network was probably not the only relevant trigger for cognitive impairment. It is conceivable that migration of progenitor cells and synaptogenesis which are crucial steps during murine brain development at E14.5 and P10, respectively, add an extra layer of complexity to radiation-induced sequelae that should be also taken into consideration in the human brain.