Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury

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.

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

“…61 Those reports involve a single TBI, are limited in the number of phospho-epitopes they describe, and are using animal models of higher severity than the model we describe herein. Acute increases in phospho-tau after rmTBI have been reported in wild-type mice at 12, 24, and 48 hours after two mTBIs, 38 but again this mouse model is more severe than our rmTBI model, with more extensive white matter damage through the corpus callosum. There has been one report of accelerated hyperphosphorylated tau staining, accompanied by an increase in Gallyas silver staining, in aged human tau mice exposed to 5 rmTBIs over a 9-day period and euthanized 21 days after the final injury.…”

“…These activated microglia can also be found in the lateral geniculate nucleus of the thalamus. The optic nerve and tract have now been shown to be damaged in diverse injury models, including blast injury, 42,43 rmTBI, 38,41,44 and FPI, 45,46 suggesting that the visual system could be studied as an indicator of exposure to trauma. It is unclear why the visual system is susceptible to different types of injury, but the vulnerability of the optic tract to rmTBI may stem from the position of the optic nerve below the brain.…”

Repeated mild traumatic brain injury: potential mechanisms of damage

“…The impact results in unrestricted movement of the head and body as the animal readily penetrates the material upon impact and free falls onto a padded cushion below. Various other models have been developed to increase rotational acceleration 75 and employ momentum-exchange principles in a frontal impact model 76,77 through the use of a pendulum striker 78,79 as well as projectiles. 80,81 Mechanical input parameters and subsequent outcomes can be more variable in closed-head models incorporating rotational head movement.…”

“…57 Further, acute cytoskeletal abnormalities and intra-axonal organelle compaction detected by ultrastructural analysis, that persist long-term in white matter tracts, is temporospatially coincident with a prominent microglial response following 2 CCI mTBIs, 56 with similar outcomes in a model featuring rotational acceleration. 75 Activated microglia form extended cytoplasmic processes in direct contact with injured axons to form a potential barrier between the healthy and injured tissue, suggesting that microglial activation is a response to the axonal damage.…”

Sex and regional differences in microglia morphology and complement receptor 3 are independent of constitutive neuroinflammatory protein concentrations in healthy mice

“…Fractal analysis has been widely used as a morphometric analysis tool (Barreto et al, 2014;Fernandez-Arjona et al, 2017;Karperien et al, 2013;Karperien and Jelinek, 2015;Namjoshi et al, 2014;Orlowski et al, 2003;Soltys et al, 2001;Soltys et al, 2005) and added as a plugin to ImageJ for convenient use (Karperien, 1999(Karperien, -2013. In contrast with the skeleton analysis, fractal analysis is carried out on single cell and is therefore complementary to skeleton analysis.…”