| Summary: | Magnetic Resonance Imaging (MRI) has transformed neuroscience by enabling the measurement of brain structure, function, physiology, chemical composition, and connectivity. Yet, despite its sensitivity to microscopic biophysical tissue changes (e.g., from development, ageing, plasticity, or pathology), MRI's macroscopic (millimetre-scale) resolution and indirect nature limit specificity and pose challenges to interpretation. To address this, prior studies have combined MRI with histology, which has microscopic resolution and higher specificity. However, classical histology is inherently two-dimensional and tissue sectioning introduces distortions, making data fusion with MRI challenging. In contrast, advanced 3D techniques like light sheet microscopy preserve the full complexity of brain architecture but are typically restricted to small optically transparent samples, such as the cleared mouse brain.
This thesis introduces a novel multiscale imaging framework for the larger rat brain, integrating whole-brain 3D light-sheet microscopy (10um isotropic) with 3D ex-vivo anatomical and diffusion MRI (100-200um). Due to the larger size and higher lipid content of the rat brain, new tissue processing techniques were developed, including advanced tissue clearing protocols and electric field-enhanced immunolabelling. These innovations enable high-resolution 3D imaging of cellular structures that would otherwise be compromised in histology. Furthermore, by preserving the 3D anatomy of the tissue, alignment of microscopy images with MRI becomes less challenging, enabling detailed characterisation of white and grey matter across scales and modalities.
The methods introduced in this thesis advance multiscale brain imaging, offering enhanced insights into neuroanatomy at the cellular level. This work also lays the foundation for improving the specificity of the MRI contrasts and developing novel in vivo imaging techniques to explore brain connectivity and microstructure.
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