A Single Concussion in Juvenile Mice Leads to Sex Specific Acute Cerebral Vascular Dysfunction and Blood-brain Border Dysfunction

Background Traumatic brain injury (TBI) can induce alterations to the blood–brain border (BBB) that contributes to long-term neurological and behavioral deficits. The temporal progression of post-concussion BBB dysfunction during developmentally sensitive periods remains poorly understood. Therefore, we sought to characterize the temporal evolution of BBB disruption and cerebrovascular alterations acutely after concussion in juvenile mice. Methods Postnatal day 17 (PND17) C57BL/6J male and female mice were subjected to sham or single closed head injury with long-term disorders (CHILD). At 1h, 6h, 1d, 3d, and 7d post-injury, Evans blue (EB) dye was administered intravenously to evaluate BBB permeability, followed by vessel painting to visualize modified cerebrovascular angioarchitecture. MRI-based T2 relaxation mapping at 1dpi has been used for brain tissue properties, including edema. EB and vascular features were modeled to assess ability to discriminate between sham and CHI mice. Results A single early-life concussion induced hyper-acute (hours) structural and functional alterations in brain vasculature. CHILD in PND17 mice resulted in: 1) disruption of physiological functions and developmental trajectories, 2) reduced brain volumes and sex-dependent T2 relaxometry changes (elevated in females, reductions in males), and 3) hyper-acute BBB increases in permeability which correlated with cerebral vascular rarefaction. Notably, males exhibited more robust BBB and vascular perturbations than females, revealing sex-dependent trajectories of vascular response to CHILD. We also highlight differential vulnerability in vessel location with the smaller penetrating cortical vessels displaying greater susceptibility to alterations compared to larger, more resilient pial blood vessels. Modeling demonstrated that vascular features clustered together while trajectory analysis confirmed that female CHI mice were not consistent in their disease trajectory compared to male CHI. Additional analysis suggested that vascular features able to discriminate in a sex- and injury specific manner. Conclusions A single concussion is sufficient to induce hyper-acute BBB and cerebrovascular perturbations in juvenile mice, which may presage long-term deficits during development. Importantly, sex differences in vascular TBI responses evident at PND17 emphasize the need to consider sex as an important variable in future pediatric TBI research.