Altered structural connectivity networks in a mouse model of complete and partial dysgenesis of the corpus callosum

Timothy J Edwards,Laura R Fenlon,Ryan J Dean,Jens Bunt,Elliott H Sherr,Linda J Richards

doi:10.1016/j.neuroimage.2020.116868

Timothy J Edwards, Laura R Fenlon + Show 4 more

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https://doi.org/10.1016/j.neuroimage.2020.116868

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Abstract

Corpus callosum dysgenesis (CCD) describes a collection of brain malformations in which the main fiber tract connecting the two hemispheres is either absent (complete CCD, or ‘agenesis of the corpus callosum’) or reduced in size (partial CCD). Humans with these neurodevelopmental disorders have a wide range of cognitive outcomes, including seemingly preserved features of interhemispheric communication in some cases. However, the structural substrates that could underlie this variability in outcome remain to be fully elucidated. Here, for the first time, we characterize the global brain connectivity of a mouse model of complete and partial CCD. We demonstrate features of structural brain connectivity that model those predicted in humans with CCD, including Probst bundles in complete CCD and heterotopic sigmoidal connections in partial CCD. Crucially, we also histologically validate the recently predicted ectopic sigmoid bundle present in humans with partial CCD, validating the utility of this mouse model for fine anatomical studies of this disorder. Taken together, this work describes a mouse model of altered structural connectivity in variable severity CCD and forms a foundation for future studies investigating the function and mechanisms of development of plastic tracts in developmental disorders of brain connectivity.

Highlights

The corpus callosum (CC) is the largest white matter tract in the mammalian brain
We anticipated that the BTBR x C57Bl/6 N2 (BTBR N2) cross, being enriched for potentially causative BTBR alleles for Corpus callosum dysgenesis (CCD), would display a corresponding increase in the proportion of mice with complete or partial CCD
The results of the diffusion MRI (dMRI) based tractography approach combined with histological validation demonstrate that the structural rewiring that occurs cannot be explained purely by the absence of callosal connections

Summary

Introduction

The corpus callosum (CC) is the largest white matter tract in the mammalian brain. It comprises spatially organized axonal projections that facilitate the bilateral integration of motor, sensory, and associative processes between the two cerebral hemispheres. Functions that involve the bilateral integration of information between hemispheres remain largely intact in CCD; a clear contrast to individuals who have had a callosotomy later in life (Paul et al, 2007) This has led many to question how structural connections are organized in the absence of callosal fibers. Tractography in individuals who possess a callosal remnant (partial CCD) has further demonstrated considerable variability in the combination of brain regions that this diminished structure connects Amongst these connections is the sigmoid bundle, an aberrant white matter tract that has been described in a minority of partial CCD individuals, which asymmetrically connects the frontal lobe to the contralateral parieto-occipital cortex via the CC remnant (Tovar-Moll et al, 2007; Wahl et al, 2009; Benezit et al, 2015). This is likely due to a combination of factors, not limited to: genetic heterogeneity, environmental influences and methodological challenges of studying in vivo structural connectivity in humans

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