Adolescent Mice Demonstrate a Distinct Pattern of Injury after Repetitive Mild Traumatic Brain Injury.
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abstract
Recently, there has been increasing interest in outcomes after repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions). While most of the scientific attention has focused on elite athlete populations, the sequelae of rmTBI in children and young adults have not been well-studied. Prior TBI studies have suggested that developmental differences in response to injury, including differences in excitotoxicity and inflammation, could result in differences in functional and histopathologic outcomes after injury. The purpose of this study is to compare outcomes in adolescent (5-week old) versus adult (4-month old) mice in a clinically relevant model of rmTBI. We hypothesized that functional and histopathologic outcomes after rmTBI would differ in developing adolescent brains compared to mature adult brains. Male adolescent and adult (C57Bl/6) mice were subjected to a weight drop model of rmTBI (n=10-16/group). Loss of consciousness (LOC) after each injury was measured. Functional outcomes were assessed including tests of balance (rotorod), spatial memory (Morris water maze), and impulsivity (elevated plus maze). After behavioral testing, brains were assessed for histopathological outcomes including microglial immunolabeling and N-methyl-D-aspartate (NMDA) receptor subunit expression. Injured adolescent mice had longer LOC than injured adult mice compared to their respective sham controls. Compared with sham mice, adolescent and adult mice subjected to rmTBI had impaired balance, increased impulsivity and worse spatial memory that persisted up to 3 months after injury, and the effect of injury was worse in adolescent versus adult mice in terms of spatial memory. Three months after injury, adolescent and adult mice demonstrated increased IBA1 immunolabeling compared to sham controls. Compared to sham controls, NR2b expression in the hippocampus was reduced by approximately 20% in both adolescent and adult injured mice. The data suggest that injured adolescent mice may show a distinct pattern of functional deficits after injury that warrant further mechanistic studies.
