Micron-resolution fiber mapping in histology independent of sample preparation

Detailed knowledge of the brain's nerve fiber network is crucial for understanding its function in health and disease. However, mapping fibers with high resolution remains prohibitive in most histological sections because state-of-the-art techniques are incompatible with their preparation. Here, we present a micron-resolution light-scattering-based technique that reveals intricate fiber networks independent of sample preparation for extended fields of view. We uncover fiber structures in both label-free and stained, paraffin-embedded and deparaffinized, newly-prepared and archived, animal and human brain tissues - including whole-brain sections from the BigBrain atlas. We identify altered microstructures in demyelination and hippocampal neurodegeneration, and show key advantages over diffusion magnetic resonance imaging, polarization microscopy, and structure tensor analysis. We also reveal structures in non-brain tissues - including muscle, bone, and blood vessels. Our cost-effective, versatile technique enables studies of intricate fiber networks in any type of histological tissue section, offering a new dimension to neuroscientific and biomedical research.