title: 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.
authors.affiliation: 1 Division of Emergency Medicine, Boston Children's Hospital , Boston, Massachusetts.|2 Harvard Medical School , Boston, Massachusetts.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Mannix
authors.affiliation: 1 Division of Emergency Medicine, Boston Children's Hospital , Boston, Massachusetts.
authors.forename: Justin
authors.initials: J
authors.lastname: Berkner
authors.affiliation: 3 Department of Pharmacy, The Third Affiliated Hospital, Guangzhou Medical University , Guangzhou, Guangdong Province, People's Republic of China .
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Mei
authors.affiliation: 1 Division of Emergency Medicine, Boston Children's Hospital , Boston, Massachusetts.
authors.forename: Sasha
authors.initials: S
authors.lastname: Alcon
authors.affiliation: 1 Division of Emergency Medicine, Boston Children's Hospital , Boston, Massachusetts.
authors.forename: Jumana
authors.initials: J
authors.lastname: Hashim
authors.affiliation: 2 Harvard Medical School , Boston, Massachusetts.|4 Department of Neurosurgery, Boston Children's Hospital , Boston, Massachusetts.
authors.forename: Shenandoah
authors.initials: S
authors.lastname: Robinson
authors.affiliation: 5 Department of Pediatrics and Neuroscience, Office of Pediatric Research, University of New Mexico , Albuquerque, New Mexico .
authors.forename: Lauren
authors.initials: L
authors.lastname: Jantzie
authors.affiliation: 1 Division of Emergency Medicine, Boston Children's Hospital , Boston, Massachusetts.|2 Harvard Medical School , Boston, Massachusetts.|6 The Micheli Center for Sports Injury Prevention, Boston Children's Hospital , Boston, Massachusetts.|7 Sports Concussion Clinic, Division of Sports Medicine, Boston Children's Hospital , Boston, Massachusetts.
authors.forename: William P
authors.initials: WP
authors.lastname: Meehan
authors.affiliation: 1 Division of Emergency Medicine, Boston Children's Hospital , Boston, Massachusetts.|2 Harvard Medical School , Boston, Massachusetts.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qiu
mesh_terms: D000367:Age Factors; D000818:Animals; D001924:Brain Concussion / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D014474:Unconsciousness / Q000209:etiology / Q000378:metabolism
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: TBI; age; pediatric brain injury