Early Myelination Supports the Establishment of Consistent Handedness

ABSTRACT Lateralization of brain functions, such as handedness, is thought to enhance cortical efficacy by reducing redundancy and speeding up decision‐making. The corpus callosum (CC), one of the brain's largest myelinated tracts, is critical for interhemispheric connectivity and has been implicated in lateralization. However, it is unclear whether the myelination of transcallosal axons contributes causally to lateralized functions. Here, we assessed the impact of myelin integrity in the circuits that regulate paw laterality in mice. We hypothesized that myelin, an essential component of CC architecture and required for rapid axonal impulse conduction, is necessary for the establishment and maintenance of handedness. To test this, we behaviorally assessed paw preference by differentially controlling the degree, localization, and timing of hypomyelination in different mouse models. As expected, control mice were strongly lateralized and showed an equal distribution of paw preference directionality (right or left). In contrast, dysmyelinated ( Mbp shi/shi ) mice, which mastered the task without obvious impairments, exhibited reduced lateralization scores and were either ambidextrous or left‐pawed. Interestingly, neither congenital myelination reduction ( Mbp neo/neo ) nor forebrain‐specific disruption of developmental myelination had an effect on paw lateralization. Similarly, demyelination induced in adulthood had no impact on paw preference. We conclude that the presence of compact myelin during early brain development is essential for the establishment of handedness, in a manner that is likely independent of fine axonal conduction velocity control. We propose a model in which developmental myelination is timed to support the establishment of key functional aspects of brain function, such as lateralization.