Ultra-high-resolution mapping of myelin and g-ratio in a panel of Mbp enhancer-edited mouse strains using microstructural MRI

•The role of MBP gene expression on white matter myelin elaboration was identified.•We validated a model-free reconstruction method for robust brain MWF mapping.•The findings were augmented with detailed, tract-wise measures of AWF.•Our hypomyelinated mouse models act as a tool for calibrated myelin-sensitive MRI. Non-invasive myelin water fraction (MWF) and g-ratio mapping using microstructural MRI have the potential to offer critical insights into brain microstructure and our understanding of neuroplasticity and neuroinflammation. By leveraging a unique panel of variably hypomyelinating mouse strains, we validated a high-resolution, model-free image reconstruction method for whole-brain MWF mapping. Further, by employing a bipolar gradient echo MRI sequence, we achieved high spatial resolution and robust mapping of MWF and g-ratio across the whole mouse brain. Our regional white matter-tract specific analyses demonstrated a graded decrease in MWF in white matter tracts which correlated strongly with myelin basic protein gene (Mbp) mRNA levels. Using these measures, we derived the first sensitive calibrations between MWF and Mbp mRNA in the mouse. Minimal changes in axonal density supported our hypothesis that observed MWF alterations stem from hypomyelination. Overall, our work strongly emphasizes the potential of non-invasive, MRI-derived MWF and g-ratio modeling for both preclinical model validation and ultimately translation to humans.