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Brain development is a protracted and tightly regulated sequence of events, including cell proliferation, differentiation, migration, synaptogenesis, maturation and apoptosis. Any perturbation of these timed processes might cause detrimental consequences for the adult brain, in particular for its structure and functionality. Ionising radiation is able to perturb brain development. Conclusive evidence for this was provided by the follow-up of in utero exposed atomic bomb survivors. Radiation exposure to the unborn child, taking place during corticogenesis, resulted in long-term neurological defects, such as an increased incidence of mental disability, growth retardation and microcephaly, as well as reduced IQ scores and school performance. Several experimental animal studies have been performed to characterise underlying mechanisms of these deficits, generally focusing on behavioural deficiencies and small brain size due to DNA damage, apoptosis and a defective cell migration, but have up to now failed to provide a coherent picture of radiation-induced injury to the brain. Illustrative hereto is the lack of understanding on the structure-function relationship and on the causal role of short-term effects in the induction of late sequelae. Importantly, no clear consensus exists on the possible effects of low doses of radiation (≤0.10 Gray (Gy)). An increased knowledge on putative low-dose effects would, however, be of major importance for the improvement of radiation protection strategies for expecting mothers and their unborn child.A first research line of this PhD dissertation was dedicated to unravel how the timing of irradiation during early neurogenesis affects further brain development and function. We evidenced that locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after in utero radiation exposure at embryonic day 11. Therefore, this developmental stage was chosen for further mechanistic analyses focusing on the cerebral cortex and the hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the preplate at 24 h post irradiation (PI), suggesting cell death occurrence in differentiating neurons rather than proliferating cells. As such, we challenged the generally assumed view of a higher radiosensitivity in dividing cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. Magnetic resonance imaging (MRI) showed that the ventricles were enlarged while N-acetyl aspartate (NAA) concentrations and fractional anisotropy (FA) were reduced in the cortex of the irradiated animals at an adult age, indicating a decrease in neuronal cell number and persistent neuroinflammation. In the juvenile hippocampus, we revealed a reduction in general neurogenic proliferation and in the number of Sox2-positive precursor cells. We proposed that both alterations in cortical morphology and hippocampal neurogenesis might contribute to the observed aberrant behaviour. Overall, this first study offered new insight into acute radiation-dependent effects on the embryonic brain, which could be further investigated in the following chapters.A more in-depth analysis of the early radiation effects in the neocortex was then carried out. This showed a dose-dependent G2/M arrest, induced by widespread DNA damage in 0.10- and 1.00-Gy-exposed cortices. A spatiotemporal examination of apoptotic cells in the irradiated mouse brain revealed more extensive and long-lasting apoptosis in the 1.00-Gy-irradiated embryos in comparison to the 0.10-Gy-exposed embryos. A notable novel finding was an altered doublecortin (DCX) expression pattern at 6 h PI in both dose groups, suggestive for a defective cell migration or aberrant neuron differentiation. Altogether, novel insights into the immediate effects of in utero irradiation were provided. These short-term effects might be important mediators in the development of prenatal irradiation-induced adult structural and functional deficits.Next, we investigated the long-term brain consequences of in utero exposure to radiation into more detail. A thorough investigation of the dose-response relationship of altered brain functionality and architecture following prenatal irradiation was achieved by a behavioural test battery and volumetric 3D T2-weighted MRI. We revealed dose-dependent changes in activity, social behaviour, anxiety-related exploration and spatio-cognitive performance. Of these, both emotionality and higher cognitive abilities were affected in mice exposed to 0.10 Gy. Microcephaly was uncovered from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, whole-brain volume, as well as relative ventricle and prefrontal cortex volume, were strongly correlated to altered behavioural parameters. Hence, an important contribution to a better understanding of the brain-behaviour relationship in prenatally irradiated mice was provided.Lastly, we performed an explorative study on ageing effects in the prenatally irradiated brain. Ageing did not provoke large radiation-induced alterations in brain structure and functionality, as revealed by longitudinal MRI and volumetric analyses or behavioural tests. However, a striking finding was that the volume of the hippocampus was significantly decreased in the 0.05-, 0.10- and 1.00-Gy-exposed 90-week-old animals. Therefore, gene expression profiling of the aged hippocampus was initiated. Subsequent pathway analysis disclosed that differentially expressed genes in the 1.00-Gy-irradiated hippocampus were involved in various processes, of which those relevant for brain ageing were of particular interest to us. Thus, we presented a first hint on subtle alterations in ageing due to intrauterine stress induced by an exposure to radiation.In conclusion, we uncovered some novel findings in both the early prenatal radiation response and in late in utero irradiation-induced outcome. A comprehensive analysis on the irradiation-induced brain structure-function relationship was provided, as well as a first detailed examination of early radiation injury useful to study the causal link between short- and long-term effects in the future. Furthermore, we presented an initial investigation on 'intrauterine programming of ageing'. Importantly, we were able to demonstrate radiation effects at low doses (0.05-0.10 Gy), which were previously assumed to be innocent.

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