Behaviorally relevant sex differences are often associated with structural differences in the brain and many diseases are sexually dimorphic in prevalence and progression. Characterizing sex differences is imperative to gaining a complete understanding of behavior and disease which will, in turn, allow for a balanced approach to scientific research and the development of therapies. In this study, we generated novel tissue probability maps (TPMs) based on 30 male and 30 female in vivo C57BL/6 mouse brain magnetic resonance images and used voxel-based morphometry (VBM) to analyze sex differences. Females displayed larger anterior hippocampus, basolateral amygdala, and lateral cerebellar cortex volumes, while males exhibited larger cerebral cortex, medial amygdala, and medial cerebellar cortex volumes. Atlas-based morphometry (ABM) revealed a statistically significant sex difference in cortical volume and no difference in whole cerebellar volume. This validated our VBM findings that showed a larger cerebral cortex in male mice and a pattern of dimorphism in the cerebellum where the lateral portion was larger in females and the medial portion was larger in males. These results are consonant with previous ex vivo studies examining sex differences, but also suggest further regions of interest.

Background

Gray matter (GM) atrophy in brain is one of the best predictors of long-term disability in multiple sclerosis (MS), and recent findings have revealed that localized GM atrophy is associated with clinical disabilities. GM atrophy associated with each disability mapped to a distinct brain region, revealing a disability-specific atlas (DSA) of GM loss.

Objective

To uncover the mechanisms underlying the development of localized GM atrophy.

Methods

We used voxel-based morphometry (VBM) to evaluate localized GM atrophy and Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) to evaluate specific pathologies in mice with experimental autoimmune encephalomyelitis (EAE).

Results

We observed extensive GM atrophy throughout the cerebral cortex, with additional foci in the thalamus and caudoputamen, in mice with EAE compared to normal controls. Next, we generated pathology-specific atlases (PSAs), voxelwise mappings of the correlation between specific pathologies and localized GM atrophy. Interestingly, axonal damage (end-bulbs and ovoids) in the spinal cord strongly correlated with GM atrophy in the sensorimotor cortex of the brain.

Conclusion

The combination of VBM with CLARITY in EAE can localize GM atrophy in brain that is associated with a specific pathology in spinal cord, revealing a PSA of GM loss.