Structural covariance of brain region volumes is associated with both structural connectivity and transcriptomic similarity.

An organizational pattern seen in the brain, termed structural covariance, is the statistical association of pairs of brain regions in their anatomical properties. These associations, measured across a population as covariances or correlations usually in cortical thickness or volume, are thought to reflect genetic and environmental underpinnings. Here, we examine the biological basis of structural volume covariance in the mouse brain. We first examined large scale associations between brain region volumes using an atlas-based approach that parcellated the entire mouse brain into 318 regions over which correlations in volume were assessed, for volumes obtained from 153 mouse brain images via high-resolution MRI. We then used a seed-based approach and determined, for 108 different seed regions across the brain and using mouse gene expression and connectivity data from the Allen Institute for Brain Science, the variation in structural covariance data that could be explained by distance to seed, transcriptomic similarity to seed, and connectivity to seed. We found that overall, correlations in structure volumes hierarchically clustered into distinct anatomical systems, similar to findings from other studies and similar to other types of networks in the brain, including structural connectivity and transcriptomic similarity networks. Across seeds, this structural covariance was significantly explained by distance (17% of the variation, up to a maximum of 49% for structural covariance to the visceral area of the cortex), transcriptomic similarity (13% of the variation, up to maximum of 28% for structural covariance to the primary visual area) and connectivity (15% of the variation, up to a maximum of 36% for structural covariance to the intermediate reticular nucleus in the medulla) of covarying structures. Together, distance, connectivity, and transcriptomic similarity explained 37% of structural covariance, up to a maximum of 63% for structural covariance to the visceral area. Additionally, this pattern of explained variation differed spatially across the brain, with transcriptomic similarity playing a larger role in the cortex than subcortex, while connectivity explains structural covariance best in parts of the cortex, midbrain, and hindbrain. These results suggest that both gene expression and connectivity underlie structural volume covariance, albeit to different extents depending on brain region, and this relationship is modulated by distance.

Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. The majority of RTT cases are caused by de novo mutations in methyl-CpG-binding protein 2 (MECP2), and several mouse models have been created to further understand the disorder. In the current literature, many studies have focused their analyses on the behavioral abnormalities and cellular and molecular impairments that arise from Mecp2 mutations. However, limited efforts have been placed on understanding how Mecp2 mutations disrupt the neuroanatomy and networks of the brain. METHODS: In this study, we examined the neuroanatomy of male and female mice from the Mecp2tm1Hzo, Mecp2tm1.1Bird/J, and Mecp2tm2Bird/J mouse lines using high-resolution magnetic resonance imaging (MRI) paired with deformation-based morphometry to determine the brain regions susceptible to Mecp2 disruptions. RESULTS: We found that many cortical and subcortical regions were reduced in volume within the brains of mutant mice regardless of mutation type, highlighting regions that are susceptible to Mecp2 disruptions. We also found that the volume within these regions correlated with behavioral metrics. Conversely, regions of the cerebellum were differentially affected by the type of mutation, showing an increase in volume in the mutant Mecp2tm1Hzo brain relative to controls and a decrease in the Mecp2tm1.1Bird/J and Mecp2tm2Bird/J lines. CONCLUSIONS: Our findings demonstrate that the direction and magnitude of the neuroanatomical differences between control and mutant mice carrying Mecp2 mutations are driven by the severity of the mutation and the stage of behavioral impairments.