Adolescent Mice Demonstrate a Distinct Pattern of Injury after Repetitive Mild Traumatic Brain Injury

Abstract

Recently, there has been increasing interest in outcomes after repetitive mild traumatic brain injury (rmTBI) (e.g., sports concussions). Although 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 histopathological 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 histopathological outcomes after rmTBI would differ in developing adolescent brains compared with 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 with 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 than in adult mice in terms of spatial memory. Three months after injury, adolescent and adult mice demonstrated increased ionized calcium binding adaptor 1 (IbA1) immunolabeling compared with sham controls. Compared with sham controls, NMDA receptor subtype 2B (NR2B) expression in the hippocampus was reduced by ∼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 warrants further mechanistic studies.

Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent versus adult male mice

“…Our findings are consistent with those in a model of repeat closed head injury, where memory deficits (measured by performance in the Morris Water Maze task) were more severe in adolescent mice compared to adults (Mannix et al, ). Our results in adult mice contrast with results from other adult weight‐drop models, though.…”

Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent vs adult mice

“…26,27 Our findings are consistent with those in a model of repeat closed head injury, where memory deficits (measured by performance in the Morris Water Maze task) were more severe in adolescent mice compared to adults. 37 Our results in adult mice contrast with results from other adult weight-drop models, though. In one study, there were deficits in novel object recognition that were present 3 days after injury and, although improving over time, were still present 28 days postinjury.…”

Metabolic and Structural Imaging at 7 Tesla After Repetitive Mild Traumatic Brain Injury in Immature Rats

“…We and others have shown that repeat insults after a mTBI worsen traumatic axonal injury and neurobehavioral deficits in adult and pediatric models ( Prins et al., 2010 ; Donovan et al., 2014 ; Fidan et al., 2016 ; Mannix et al., 2017 ; Yu et al., 2017 ). Consistent with this, our DTI data showed that rmTBI exacerbated the changes in FA and other diffusivity indices when compared to a single episode of mTBI.…”