SCK•CEN

Studiecentrum voor kernenergie SCK•CEN (Belgium, abderrafi Benotmane)

Website: www.sckcen.be

 

Contribution to CEREBRAD

In the CEREBRAD project, SCK-CEN investigates gene expression changes from in utero irradiated mice at early (2h, 24h, 1 week) and late (1 month, 6 months) time points post-irradiation. An initial p53-regulated transcriptional response was observed, which was blunted after 24h. Genes that were upregulated after one week were significantly enriched in brain-related processes such as neurotransmission and axon formation, suggesting that at this time point the brains of irradiated mice are compensating for the earlier loss of cells due to apoptosis. One month after irradiation, minor changes could be observed. However, after 6 months, the group could clearly indicate the initiation of epigenetic mechanisms (DNA methylation, microRNAs), which may  be responsible for the long-term cognitive and behavioural defects which were observed in these animals. In all, the results demonstrated by this group show that radiation-induced gene expression changes in the brain are highly dynamic and occur in waves at different time points after radiation exposure.

SCK-CEN has also been involved in behavioural testing and MR (magnetic resonance) imaging of mice irradiated in utero with different doses between 0.0 and 1.0 Gy, while focusing on specific brain regions. Their data revealed altered spontaneous 23h cage activity and reduced anxiety-related behavior in irradiated animals, which showed a dose-dependent trend. Moreover, irradiated mice showed aberrant cognitive behavior, tested in the Morris water maze (a circular pool in which mice have to find the hidden platform by using spatial memory cues). When analyzing the strategies used by the animals to find the platform, cognitive differences were already noticed at a dose of 0.1 Gy. These data indicate that the hippocampus might be one of the most affected brain regions by prenatal radiation exposure.

In the same animals, also MR imaging has been performed. 3D ventricle scans (T2 maps) of all animals were analyzed and indicated a decreased brain volume in combination with a comparable ventricle volume for irradiated mice. These morphological alterations only occur at higher doses, suggesting that behavioral defects observed in mice irradiated with low doses of X-rays are due to more subtle changes in neuronal development, which will be studied in the future.

  

Time-dependent dynamism in the number of differentially expressed genes in response to low (0.1 Gy) and moderate (1.0 Gy) doses of ionizing radiation.

 

(1) Picture of the circular pool and hidden platform used in the Morris water maze test. Mice gradually learn to find the platform, at the end of all tests they can swim in a straight line to it. (2) Animals can use different strategies to find the hidden platform: (A) spatial strategies, (B) non-spatial strategies and (C) repititive looping. When mice learn to find the platform, they change strategie, from repititive looping and non-spatial to a spatial strategy. 

 

(A) Brain volume changes assessed by MR imaging in control animals and 4 irradiation conditions. The brain volume is reduces in irradiated animals. (B) The ventricular volume for the same mice does not seem to change. (C) When the ventricular volume is normalized by the brain volume, the highest irradiation dose (1.0 Gy) shows a significant increase in normalized volume.