Using gene expression atlases in animal imaging to develop hypotheses on transcriptomic changes

Introduction: Animal models are powerful tools to study the molecular underpinnings of genes associated with psychiatric disorders. However, especially when studying psychiatric disorders, approaches that translate findings derived from these models to human brains become pivotal. Structural neuroimaging provides a viable path for translational research. We here report changes in grey matter and fiber-tract architecture in a 16p11.2 del/+ mouse model. 16p11.2 hemideletions are copy number variants (CNVs) exhibiting a high association with psychiatric and neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) [1]. Since these disorders show a strong sex-bias with males about four times more often affected than females, we also investigated sex-specific effects of the genotype. Moreover, we used the Allen Mouse Brain Atlas (http://mouse.brain-map.org/) [2] to investigate, whether altered brain regions were associated with distinct gene expression patterns. Methods: We performed magnetic resonance imaging (MRI), including a diffusion weighed sequence, ex vivo. Mice were sacrificed at 70-days of age. Age/sex matched wild type and 16p11 del/+ mice (wildtype male =7, del/+ male =4, wildtype female =5, del/+female =5). MR images were analyzed using Voxel-Based Morphometry for T1-weighted sequences [3] and FSL tools (http://www.fmrib.ox.ac.uk/fsl/) for tract-based spatial statistics [4,5] for the DTI data sets. We used a modified versions for the post-mortem mouse brain of these standard protocols. Moreover, all available in situ hybrdization (ISH) maps of the genes involved in the hemideletion were downloaded from the Allen Mouse Brain Atlas (http://mouse.brain-map.org/) [2] (Figure 1). Nissl-stained images were 3D-reconstructed and aligned to Waxholm space. Resulting deformation fields were used on the ISH maps to also align them to Waxholm space. After alignment, we analyzed, whether gene expression patterns significantly differed between the altered brain regions and the the whole brain. Results: We found pronounced sex-specific changes in male animals with increased FA in medial fiber tracts, especially in those proximate to the striatum (Figure 2). Moreover, we were able to identify genes that show high expression patterns in brain regions with male-specific structural changes. Our data suggest that translational structural imaging approaches in general and the use of gene expression atlases might help to develop observer-independent hypotheses regarding the molecular underpinnings of brain structure changes in psychiatric disorders. Conclusions: Changes of striatal neuroanatomy have been previously described in 16p11 del/+ mice[6], while sex-specific effects have not yet been elucidated. Our findings of sex-specific fiber tract changes point to striatal deficits and match behavioral and molecular changes found specifically in male 16p11 del/+ mice.We here have demonstrated that animal models of CNVs can be used to characterize brain structure changes and that gene expression atlasses can be used to generate observer-indeprendent hypotheses on molecular pathways involved that can be later experimentally tested