title: Defining the biomechanical and biological threshold of murine mild traumatic brain injury using CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration).
abstract: CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a recently described animal model of traumatic brain injury (TBI) that primarily produces diffuse axonal injury (DAI) characterized by white matter inflammation and axonal damage. CHIMERA was specifically designed to reliably generate a variety of TBI severities using precise and quantifiable biomechanical inputs in a nonsurgical user-friendly platform. The objective of this study was to define the lower limit of single impact mild TBI (mTBI) using CHIMERA by characterizing the dose-response relationship between biomechanical input and neurological, behavioral, neuropathological and biochemical outcomes. Wild-type male mice were subjected to a single CHIMERA TBI using six impact energies ranging from 0.1 to 0.7J, and post-TBI outcomes were assessed over an acute period of 14days. Here we report that single TBI using CHIMERA induces injury dose- and time-dependent changes in behavioral and neurological deficits, axonal damage, white matter tract microgliosis and astrogliosis. Impact energies of 0.4J or below produced no significant phenotype (subthreshold), 0.5J led to significant changes for one or more phenotypes (threshold), and 0.6 and 0.7J resulted in significant changes in all outcomes assessed (mTBI). We further show that linear head kinematics are the most robust predictors of duration of unconsciousness, severity of neurological deficits, white matter injury, and microgliosis following single TBI. Our data extend the validation of CHIMERA as a biofidelic animal model of DAI and establish working parameters to guide future investigations of the mechanisms underlying axonal pathology and inflammation induced by mechanical trauma.
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: dnamjoshi@gmail.com.
authors.forename: Dhananjay R
authors.initials: DR
authors.lastname: Namjoshi
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: chengwh@mail.ubc.ca.
authors.forename: Wai Hang
authors.initials: WH
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: asmab@mail.ubc.ca.
authors.forename: Asma
authors.initials: A
authors.lastname: Bashir
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: wanna@mail.ubc.ca.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilkinson
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: stukas@mail.ubc.ca.
authors.forename: Sophie
authors.initials: S
authors.lastname: Stukas
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: krismmartens@gmail.com.
authors.forename: Kris M
authors.initials: KM
authors.lastname: Martens
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: tom@mech.ubc.ca.
authors.forename: Tom
authors.initials: T
authors.lastname: Whyte
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: zola830@gmail.com.
authors.forename: Zelalem A
authors.initials: ZA
authors.lastname: Abebe
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: kurt.mcinnes@gmail.com.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: McInnes
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, Vancouver, British Columbia, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: cripton@mech.ubc.ca.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cripton
authors.affiliation: Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada; International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: wcheryl@mail.ubc.ca.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D001696:Biomechanical Phenomena / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001924:Brain Concussion / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D020833:Diffuse Axonal Injury / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL
keywords: Animal model of traumatic brain injury; Behavior; Biomechanics; CHIMERA; Closed head injury; Neuropathology; Traumatic brain injury