Microstructural and microglial changes after repetitive mild traumatic brain injury in mice

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Every year in the United States, approximately 2.5 million people seek emergency medical treatment for a traumatic brain injury (TBI; Faul and Coronado, 2015). Although TBI is a growing major public health issue (Marin et al., 2014), diagnostic tools and readily available neurobiological predictors of outcomes for TBI are lacking (Bruce et al., 2015). The requirement for objective assessment criteria is amplified by the increasing concern over the consequences of repetitive trauma, especially if a second injury is sustained before complete recovery. Prior studies have suggested a temporal window of vulnerability after TBI, but without empirical measures of injury clinicians have limited tools to help guide critical management decisions seeking to prevent the sequelae of repetitive injury. Currently, computerized tomography scans and magnetic resonance imaging (MRI) with standard T1 and T2 sequences are the most frequently employed TBI diagnostic modalities, but the diagnostic and prognostic yield of these standard techniques is increasingly minor in the context of mild TBI. To stratify appropriate clinical resources and ensure the best treatment and followup care, objective diagnostic studies and biomarkers of injury must be identified and validated (Bruce et al., 2015). This is especially vital in the case of mild TBI, in which clinical management is often based on subjective symptom reporting.
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.

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