High-throughput light-sheet 3D microscopy of whole rodent brain microstructure for integration with MRI
Year: 2026
Type: preprint
Abstract: Whole-brain cellular mapping is essential for understanding how differences in cellular architecture shape brain organisation and function. Magnetic Resonance Imaging (MRI) provides whole-brain coverage in humans and animal models but is only indirectly sensitive to cellular features. Integrating MRI with whole-brain microscopy is therefore critical for interpreting existing microstructural MRI metrics and developing new, more specific ones. Here, we present a scalable cross-resolution framework that integrates 3D light-sheet microscopy (LSM) of intact rodent brains with diffusion MRI (dMRI) to bridge cellular and macroscopic brain imaging. By combining active electrotransport-based tissue clearing and immunolabelling with accelerated LSM acquisitions, we achieve whole-brain multiplexed mapping of neuronal and glial populations in intact rodent brains on timescales comparable to conventional histology and 2D microscopy. This throughput enables LSM and MRI integration at scale, linking macroscopic MRI contrasts to microscopic cellular features within the same tissue. We apply this framework across eight genetically diverse mouse strains to develop predictive models of 3D microscopy-derived cellular features from multi-shell dMRI-derived contrasts. We demonstrate that data-driven combinations of state-of-the-art dMRI contrasts predict neuronal and astrocytic features better than individual contrasts, across all animals. Our novel approach enables 3D microscopy to guide the development and interpretation of microstructural MRI measures that are ultimately translatable to the living human brain.
Authors: Jenna M. Hanmer, Francesco D’Antonio, Jose-Pedro Manzano-Patron, Stephania Assimopoulos, Sydney C. Wood, Mohamed Tachrount, Qijia Shen, Martin Craig, Cyril Lai, Graham J. Hickman, Edalat Radfar, Kim I. Chisholm, Tracy D. Farr, Alan Jasanoff, Anna Hoerder-Suabedissen, Zoltan Molnar, Clemence Ligneul, Cristiana Tisca, Saad Jbabdi, Amy F.D. Howard, Karla L. Miller, Elizabeth de Guzman, Jason P. Lerch, Stamatios N. Sotiropoulos
Institutions: University of Nottingham, University of Oxford, Wellcome Centre for Integrative Neuroimaging, MRC Weatherall Institute of Molecular Medicine, Nottingham Trent University, University of Birmingham, University of Edinburgh, Massachusetts Institute of Technology, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay - Etablissement de Fontenay-aux-roses, Molecular Imaging Research Center, Imperial College London, University of Toronto, Hospital for Sick Children
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221728874