Critical analysis of translational potential of rodent models of white matter pathology across a wide spectrum of human diseases.

Rodents are the most commonly used laboratory animals in medical research. However, significant evolutionary divergences between humans and rodents, particularly in the complexity of white matter connectome, which are fundamentally shaped by myelin as their major structural component, pose critical challenges in modeling the human neurological diseases. Given the divergences and central roles of myelin in pathology, a thorough reevaluation of the rodent models used in contemporary research is critical, alongside the careful selection, optimization, or de novo development of models that faithfully recapitulate human white matter disorders. In this review, we summarize the strengths and limitations of existing rodent models, emphasizing their contributions to understanding demyelinating pathologies across autoimmune, neurodegenerative, vascular, perinatal, traumatic, infectious and genetic diseases. We also overview white mater disease models using other species and human stem cells. Subsequently we discuss critical interspecies differences in white matter biology that may limit translational relevance, while highlighting how rodent models enhance our comprehension of various pathological conditions. Lastly, we outline strategies to refine rodent models through advanced genetic engineering, humanized microenvironments, and multimodal phenotyping, with the goal of progressively improving existing them to increase their preclinical translational potentials.