Long-Term Changes in Axon Calibers after Injury: Observations on the Mouse Corticospinal Tract

White matter pathology is common across a wide spectrum of neurological diseases. Char-acterizing this pathology is important for both a mechanistic understanding of neurological diseases as well as for the development of neuroimaging biomarkers. Although axonal calibers can vary by orders of magnitude, they are tightly regulated and related to neuronal function, and changes in axon calibers have been reported in several diseases and their models. In this study, we utilize the impact acceleration model of traumatic brain injury (IA-TBI) to assess early and late changes in the axon diameter distribution (ADD) of the mouse corticospinal tract using Airyscan and electron mi-croscopy. We find that axon calibers follow a lognormal distribution whose parameters significantly change after injury. While IA-TBI leads to 30% loss of corticospinal axons by day 7 with a bias for larger axons, at 21 days after injury we find a significant redistribution of axon frequencies that is driven by a reduction in large-caliber axons in the absence of detectable degeneration. We postulate that changes in ADD features may reflect a functional adaptation of injured neural systems. More-over, we find that ADD features offer an accurate way to discriminate between injured and non-injured mice. Exploring injury-related ADD signatures by histology or new emerging neuroimaging modalities may offer a more nuanced and comprehensive way to characterize white matter pathology and may also have the potential to generate novel biomarkers of injury.