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Variability and heritability of mouse brain structure: Microscopic MRI atlases and connectomes for diverse strains.

ABSTRACT: Genome-wide association studies have demonstrated significant links between human brain structure and common DNA variants. Similar studies with rodents have been challenging because of smaller brain volumes. Using high field MRI (9.4 T) and compressed sensing, we have achieved microscopic resolution and sufficiently high throughput for rodent population studies. We generated whole brain structural MRI and diffusion connectomes for four diverse isogenic lines of mice (C57BL/6J, DBA/2J, CAST/EiJ, and BTBR) at spatial resolution 20,000 times higher than human connectomes. We measured narrow sense heritability (h²) I.e. the fraction of variance explained by strains in a simple ANOVA model for volumes and scalar diffusion metrics, and estimates of residual technical error for 166 regions in each hemisphere and connectivity between the regions. Volumes of discrete brain regions had the highest mean heritability (0.71 ± 0.23 SD, n = 332), followed by fractional anisotropy (0.54 ± 0.26), radial diffusivity (0.34 ± 0.022), and axial diffusivity (0.28 ± 0.19). Connection profiles were statistically different in 280 of 322 nodes across all four strains. Nearly 150 of the connection profiles were statistically different between the C57BL/6J, DBA/2J, and CAST/EiJ lines. Microscopic whole brain MRI/DTI has allowed us to identify significant heritable phenotypes in brain volume, scalar DTI metrics, and quantitative connectomes.

SUBMITTER: Wang N

PROVIDER: S-EPMC8442986 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGenetic variation in a population has an influence on the manifestation of monogenic as well as multifactorial disorders, with the underlying genetic contribution dependent on several interacting variants. Common laboratory mouse strains used for modelling human disease lack the genetic variability of the human population. Therefore, outcomes of rodent studies show limited relevance to human disease. The functionality of brain vasculature is an important modifier of brain diseases. Importantly, the restrictive interface between blood and brain-the blood-brain barrier (BBB) serves as a major obstacle for the drug delivery into the central nervous system (CNS). Using genetically diverse mouse strains, we aimed to investigate the phenotypic and transcriptomic variation of the healthy BBB in different inbred mouse strains.MethodsWe investigated the heterogeneity of brain vasculature in recently wild-derived mouse strains (CAST/EiJ, WSB/EiJ, PWK/PhJ) and long-inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, DBA/2J, NOD/ShiLtJ) using different phenotypic arms. We used immunohistochemistry and confocal laser microscopy followed by quantitative image analysis to determine vascular density and pericyte coverage in two brain regions-cortex and hippocampus. Using a low molecular weight fluorescence tracer, sodium fluorescein and spectrophotometry analysis, we assessed BBB permeability in young and aged mice of selected strains. For further phenotypic characterization of endothelial cells in inbred mouse strains, we performed bulk RNA sequencing of sorted endothelial cells isolated from cortex and hippocampus.ResultsCortical vessel density and pericyte coverage did not differ among the investigated strains, except in the cortex, where PWK/PhJ showed lower vessel density compared to NOD/ShiLtJ, and a higher pericyte coverage than DBA/2J. The vascular density in the hippocampus differed among analyzed strains but not the pericyte coverage. The staining patterns of endothelial arteriovenous zonation markers were similar in different strains. BBB permeability to a small fluorescent tracer, sodium fluorescein, was also similar in different strains, except in the hippocampus where the CAST/EiJ showed higher permeability than NOD/ShiLtJ. Transcriptomic analysis of endothelial cells revealed that sex of the animal was a major determinant of gene expression differences. In addition, the expression level of several genes implicated in endothelial function and BBB biology differed between wild-derived and long-inbred mouse strains. In aged mice of three investigated strains (DBA/2J, A/J, C57BL/6J) vascular density and pericyte coverage did not change-expect for DBA/2J, whereas vascular permeability to sodium fluorescein increased in all three strains.ConclusionsOur analysis shows that although there were no major differences in parenchymal vascular morphology and paracellular BBB permeability for small molecular weight tracer between investigated mouse strains or sexes, transcriptomic differences of brain endothelial cells point to variation in gene expression of the intact BBB. These baseline variances might be confounding factors in pathological conditions that may lead to a differential functional outcome dependent on the sex or genetic polymorphism.

Project description:BACKGROUND:The human brain is complex and interconnected structurally. Brain connectome change is associated with Alzheimer's disease (AD) and other neurodegenerative diseases. Genetics and genomics studies have identified molecular changes in AD; however, the results are often limited to isolated brain regions and are difficult to interpret its findings in respect to brain connectome. The mechanisms of how one brain region impacts the molecular pathways in other regions have not been systematically studied. And how the brain regions susceptible to AD pathology interact with each other at the transcriptome level and how these interactions relate to brain connectome change are unclear. METHODS:Here, we compared structural brain connectomes defined by probabilistic tracts using diffusion magnetic resonance imaging data in Alzheimer's Disease Neuroimaging Initiative database and a brain transcriptome dataset covering 17 brain regions. RESULTS:We observed that the changes in diffusion measures associated with AD diagnosis status and the associations were replicated in an independent cohort. The result suggests that disease associated white matter changes are focal. Analysis of the brain connectome by genomic data, tissue-tissue transcriptional synchronization between 17 brain regions, indicates that the regions connected by AD-associated tracts were likely connected at the transcriptome level with high number of tissue-to-tissue correlated (TTC) gene pairs (P?=?0.03). And genes involved in TTC gene pairs between white matter tract connected brain regions were enriched in signaling pathways (P?=?6.08?×?10-9). Further pathway interaction analysis identified ionotropic glutamate receptor pathway and Toll receptor signaling pathways to be important for tissue-tissue synchronization at the transcriptome level. Transcript profile entailing Toll receptor signaling in the blood was significantly associated with diffusion properties of white matter tracts, notable association between fractional anisotropy and bilateral cingulum angular bundles (Ppermutation?=?1.0?×?10-2 and 4.9?×?10-4 for left and right respectively). CONCLUSIONS:In summary, our study suggests that brain connectomes defined by MRI and transcriptome data overlap with each other.

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Variability and heritability of mouse brain structure: Microscopic MRI atlases and connectomes for diverse strains.

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