Progressive lifespan modifications in the corpus callosum following a single concussion in juvenile male mice monitored by diffusion MRI.

INTRODUCTION: The vulnerability of white matter (WM) in acute and chronic moderate-severe traumatic brain injury (TBI) has been established. In concussion syndromes, including preclinical rodent models, lacking are comprehensive longitudinal studies spanning the mouse lifespan. We previously reported early WM modifications using clinically relevant neuroimaging and histological measures in a model of juvenile concussion at one month post injury (mpi) who then exhibited cognitive deficits at 12mpi. For the first time, we assess corpus callosum (CC) integrity across the lifespan after a single juvenile concussion utilizing diffusion MRI (dMRI). METHODS: C57Bl/6 mice were exposed to sham or two severities of closed-head concussion (Grade 1, G1, speed 2 m/s, depth 1 mm; Grade 2, G2, 3 m/s, 3 mm) using an electromagnetic impactor at postnatal day 17. In vivo diffusion tensor imaging was conducted at 1, 3, 6, 12 and 18mpi and processed for dMRI parametric maps: fractional anisotropy (FA), axial (AxD), radial (RD) and mean diffusivity (MD). Hemispheric CC and regional CC data were extracted. To identify the biological basis of altered dMRI metrics, astrocyte and microglia in the CC were characterized at 1, 12 and 18 mpi by immunohistochemistry. RESULTS: Hemispheric CC analysis revealed altered FA and RD trajectories following juvenile concussion. Shams exhibited a temporally linear increase in FA with age while G1/G2 mice had plateaued FA values. G2 concussed mice exhibited high variance of dMRI metrics at 18mpi, which was attributed to the heterogeneity of TBI on the anterior CC. Regional analysis of dMRI metrics at the impact site unveiled significant differences between G2 and sham mice. The dMRI findings appear to be driven, in part, by loss of astrocyte morphology. CONCLUSION: For the first time, we demonstrate progressive perturbations to WM of male mice after a single juvenile concussion across their lifespan. The CC alterations were dependent on concussion severity with elevated sensitivity in the anterior CC that was related to astrocyte and microglial morphology changes. Our findings suggest that long-term monitoring of children with juvenile concussive episodes using dMRI is warranted, focusing on vulnerable WM tracts.