Spatial heterogeneity in myelin sheathing impacts signaling reliability and susceptibility to injury.

Abstract

Axons in the mammalian brain show significant diversity in myelination motifs, displaying spatial heterogeneity in sheathing along individual axons and across brain regions. However, its impact on neural signaling and susceptibility to injury remains poorly understood. To address this, we leveraged cable theory and developed model axons replicating the myelin sheath distributions observed experimentally in different regions of the mouse central nervous system. We examined how the spatial arrangement of myelin affects propagation and predisposition to conduction failure in axons with cortical versus callosal myelination motifs. Our results indicate that regional differences inmyelination significantly influence conduction timing and signaling reliability. Sensitivity of action potential propagation to the specific positioning, lengths, and ordering of myelinated and exposed segments reveals non-linear and path-dependent conduction. Furthermore, myelination motifs impact signaling vulnerability to demyelination, with callosal motifs being particularly sensitive to myelin changes. These findings highlight the crucial role of myelinating glia in brain function and disease.Significance Statement This study highlights the importance of spatial heterogeneity of myelin sheathing in shaping nerve axonal conduction. Using model axons that faithfully replicate myelin distributions observed in the mouse central nervous system, our results revealed the impact of myelin patterns on the timing and reliability of neural signaling. Contrary to the conventional view in which uniform and equally spaced myelin segments imply linear conduction, our findings show that axonal conduction is a path-dependent, non-linear process influenced by the specific distribution of myelinated and unmyelinated segments. Membrane potential propagation along model axons in the corpus callosum was found to be more vulnerable to myelin changes compared to those in the cortex, especially post-myelin injury, emphasizing the role of sheath locations in both health and disease.