title: Persistent Impact of In utero Irradiation on Mouse Brain Structure and Function Characterized by MR Imaging and Behavioral Analysis.
abstract: Prenatal irradiation is known to perturb brain development. Epidemiological studies revealed that radiation exposure during weeks 8-15 of pregnancy was associated with an increased occurrence of mental disability and microcephaly. Such neurological deficits were reproduced in animal models, in which rodent behavioral testing is an often used tool to evaluate radiation-induced defective brain functionality. However, up to now, animal studies suggested a threshold dose of around 0.30 Gray (Gy) below which no behavioral alterations can be observed, while human studies hinted at late defects after exposure to doses as low as 0.10 Gy. Here, we acutely irradiated pregnant mice at embryonic day 11 with doses ranging from 0.10 to 1.00 Gy. A thorough investigation of the dose-response relationship of altered brain function and architecture following in utero irradiation was achieved using a behavioral test battery and volumetric 3D T2-weighted magnetic resonance imaging (MRI). We found dose-dependent changes in cage activity, social behavior, anxiety-related exploration, and spatio-cognitive performance. Although behavioral alterations in low-dose exposed animals were mild, we did unveil that both emotionality and higher cognitive abilities were affected in mice exposed to ≥0.10 Gy. Microcephaly was apparent from 0.33 Gy onwards and accompanied by deviations in regional brain volumes as compared to controls. Of note, total brain volume and the relative volume of the ventricles, frontal and posterior cerebral cortex, cerebellum, and striatum were most strongly correlated to altered behavioral parameters. Taken together, we present conclusive evidence for persistent low-dose effects after prenatal irradiation in mice and provide a better understanding of the correlation between their brain size and performance in behavioral tests.
authors.affiliation: Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN)Mol, Belgium; Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, Faculty of Science, Katholieke Universiteit LeuvenLeuven, Belgium.
authors.forename: Tine
authors.initials: T
authors.lastname: Verreet
authors.affiliation: Faculty of Medicine, Molecular Small Animal Imaging Center, Katholieke Universiteit LeuvenLeuven, Belgium; Department of Electrical Engineering (ESAT/PSI), Katholieke Universiteit Leuven and Medical Image Research Center, University Hospital LeuvenLeuven, Belgium.
authors.forename: Janaki Raman
authors.initials: JR
authors.lastname: Rangarajan
authors.affiliation: Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN) Mol, Belgium.
authors.forename: Roel
authors.initials: R
authors.lastname: Quintens
authors.affiliation: Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN) Mol, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Verslegers
authors.affiliation: Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, Katholieke Universiteit Leuven Leuven, Belgium.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Lo
authors.affiliation: Biomedical MRI Unit, Department of Imaging and Pathology, Faculty of Medicine, Katholieke Universiteit Leuven Leuven, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Govaerts
authors.affiliation: Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN) Mol, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Neefs
authors.affiliation: Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN) Mol, Belgium.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Leysen
authors.affiliation: Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN) Mol, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Baatout
authors.affiliation: Department of Electrical Engineering (ESAT/PSI), Katholieke Universiteit Leuven and Medical Image Research Center, University Hospital Leuven Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Maes
authors.affiliation: Faculty of Medicine, Molecular Small Animal Imaging Center, Katholieke Universiteit LeuvenLeuven, Belgium; Biomedical MRI Unit, Department of Imaging and Pathology, Faculty of Medicine, Katholieke Universiteit LeuvenLeuven, Belgium.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, Katholieke Universiteit Leuven Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, Faculty of Science, Katholieke Universiteit Leuven Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.affiliation: Laboratory of Molecular and Cellular Biology, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN) Mol, Belgium.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Benotmane
keywords: MRI; brain development; cognition; microcephaly; radiation exposure; sociability