Abstract
BackgroundTraumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement. Rodents continue to be the most widely used species for preclinical TBI research. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, however, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. Here we describe a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. In this study, we characterized head kinematics as well as functional, neuropathological, and biochemical outcomes up to 14d following repeated TBI (rTBI) in adult C57BL/6 mice using CHIMERA.ResultsHead kinematic analysis showed excellent repeatability over two closed head impacts separated at 24h. Injured mice showed significantly prolonged loss of righting reflex and displayed neurological, motor, and cognitive deficits along with anxiety-like behavior. Repeated TBI led to diffuse axonal injury with extensive microgliosis in white matter from 2-14d post-rTBI. Injured mouse brains also showed significantly increased levels of TNF-α and IL-1β and increased endogenous tau phosphorylation.ConclusionsRepeated TBI using CHIMERA mimics many of the functional and pathological characteristics of human TBI with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-55) contains supplementary material, which is available to authorized users.
Highlights
Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment
Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) repeated TBI (rTBI) induces widespread microgliosis and increases proinflammatory cytokine levels Using Iba-1 immunohistochemistry, we observed significantly increased microglial activation throughout several white matter tracts including the olfactory nerve layer, corpus callosum, optic tracts, and brachium of superior colliculus of injured brains compared to the sham controls as assessed using both fractal analysis and microglial density (Figures 5 and 6)
As the biomechanical input parameters are highly adjustable across impact energy, velocity, and directional parameters, CHIMERA offers a wide dynamic range of precisely controllable inputs to reproduce specific conditions that occur in human impact TBI
Summary
Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. TBI resulting from high-contact sports such as boxing, American football, ice hockey, soccer, and rugby account for almost 21% of all head injuries among children and adolescents, for mTBI [8]. In these situations, the skull experiences an impact resulting in brain deformation and resulting injury that most often occurs without skull fracture. The growing awareness that mTBI may have long-lasting and severe consequences [13,14,15,16] highlights the urgency to understand much more about the acute and long-term consequences of brain injury
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