Microstructural and microglial changes after repetitive mild traumatic brain injury in mice
The first step to achieving objective diagnostic approaches is the development of appropriate preclinical models in which pathophysiological mechanisms are similar to those observed in humans and can be studied in depth. Previously, we have shown graded levels of neuropathology in mice subjected to repetitive mild closed head injury (rmCHI) as a result of varying the frequency, quantity, and severity of injuries, with more frequent injuries resulting in long‐term cognitive deficits (Meehan et al., 2012; Mannix et al., 2013; Kondo et al., 2015). Additionally, we demonstrated that mice subjected to rmCHI have impaired balance and spatial memory deficits that persist for 3 months after injury, concomitant with chronic astrocytosis and microgliosis (Mannix et al., 2014).
Glial activation and upregulation of inflammatory mediators such as tumor necrosis factor‐α (TNF‐α) have been linked directly to the pathophysiology and progression of TBI (Webster et al., 2015). Together with brain microstructure, regional and phenotypic glial activation data after repetitive mild TBI (rmTBI) may yield clinically relevant biomarkers and predictors of outcome. Furthermore, detailed analysis of complete sets of diffusion metrics (mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD], and fractional anisotropy [FA]) suggests that gliosis rather than cytotoxic edema is most consistent with changes in these parameters after acute mild TBI in humans (Croall et al., 2014). Therefore, the present investigation uses a combination of high‐resolution susceptibility‐weighted magnetic resonance imaging (SWI) and diffusion tensor imaging (DTI) in tandem with a temporal and regional evaluation of microglia and common molecular mediators of a neuroinflammatory microenvironment. We test the hypothesis that rmCHI in mice leads to significant diffusion abnormalities concomitant with anomalous white and gray matter microstructure, microgliosis, and increased cytokine production in both the acute and the subacute phases postinjury.