Abstract
Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. SARM1 protein is a central driver of axon degeneration through a conserved molecular pathway. Sarm1−/− mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of the SARM1 pathway as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Ultrastructural classification of pathology of individual axons, using electron microscopy, demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. Longitudinal MRI studies in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, Sarm1 KO mice exhibited beneficial effects in motor learning and sleep behavior. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.
Highlights
Traumatic brain injury (TBI) results in long term disability in more severe cases and can cause persistent symptoms even in patients who receive a “mild” diagnosis [42, 67, 72]
Sarm1 knockout protects against corpus callosum (CC) atrophy and axon‐myelin pathology in chronic TBI The potential for Sarm1 inactivation to provide long term axon protection and/or to mitigate post-traumatic neurodegeneration was first evaluated using transmission electron microscopy (EM) (Fig. 1)
As previously characterized in this concussive TBI model [52, 61], TBI results in damaged axons that are dispersed among adjacent intact axons and may exhibit demyelination in Sarm1 WT mice (Fig. 1h)
Summary
Traumatic brain injury (TBI) results in long term disability in more severe cases and can cause persistent symptoms even in patients who receive a “mild” diagnosis [42, 67, 72]. TBI may lead to post-traumatic neurodegeneration and increase the risk for co-morbid. In patients with moderate-severe TBI, diffuse axonal injury has been shown to predict the extent of post-traumatic neurodegeneration, based on MRI volumetric and diffusion tensor imaging (DTI) data [30]. DTI tractography demonstrated disrupted fiber tract continuity in anterior CC regions after concussions while broad areas of disrupted tracts were found throughout the CC in patients with MRI findings of diffuse axonal injury [38]. Ex vivo MRI of a patient who died 26 days after TBI demonstrated that white matter tract disruptions detected by DTI correlated with neuropathological identification of axonal injury [69]
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