Reverse translational approaches to population neuroimaging: using rodent models to interpret genetic associations with MRI

Thesis

Mouse models play an essential role in advancing research in humans. The genetic similarity between humans and mice means we can measure and compare equivalent phenotypes across species. More importantly, through invasive studies which we cannot conduct in humans, mouse models can provide a mechanistic insight into the molecular and cellular drivers of the phenomena of interest.

This thesis proposes to investigate key findings from the UK Biobank population neuroimaging studies using mouse models. Researchers have identified novel links between imaging-derived phenotypes and genetics. Key results of these studies showed associations between genetic variants in the VCAN and BCAN genes and multi-modal MRI metrics in white matter. VCAN and BCAN encode extracellular matrix proteins. The biological drivers of these associations are not obvious, in that we do not expect the extracellular matrix to have a strong influence on the identified MRI signals.

To investigate the biological mechanisms driving the observed MRI signal changes, we conducted multi-modal ex-vivo MRI and histology studies in Vcan and Bcan mouse models.

We first developed new MRI and histology protocols, neither of which were established at the start of our studies. We implemented new multi-modal ex-vivo MRI protocols and post-processing pipelines, working in a new Bruker 7T scanning facility. We subsequently optimised immunohistochemistry processing and staining protocols to yield high-quality, multi-stain histology data. This data is registered to MRI using bespoke tools and pipelines developed in-house and processed to extract quantitative metrics which can be directly linked to MRI metrics at the MRI voxel level.

Our ex-vivo MRI results showed that some of the Vcan and Bcan homozygous mice exhibited differences in MRI phenotypes compared to wild-type controls. In particular, male homozygous Bcan mice showed consistent MRI phenotypes across multiple metrics when compared to male wild-types. These findings confirmed that changes in the Vcan and Bcan genes lead to changes in brain imaging phenotypes. Our preliminary histology analyses reveal some emerging trends in the histology data. In male Bcan mice, we observed differences in neurofilament content which would be consistent with the observed changes in MRI metrics. These trends may prove informative once we have completed the histological analysis on the full cohorts.

Authors: Tisca, C

• DOI: 10.5287/ora-xqnjgjd6e
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: MRI-histology; mouse models; UK Biobank; microstructural MRI; preclinical MRI; GWAS
• Subjects: Histology; Magnetic resonance imaging; Genetics