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

Abstract

Traumatic brain injury (TBI) is a major public health issue, with recent increased awareness of the potential long-term sequelae of repetitive injury. While TBI is common, objective diagnostic tools with sound neurobiological predictors of outcome are lacking. Indeed, such tools could help identify those at risk for more severe outcomes after repetitive injury and improve understanding of biological underpinnings to provide important mechanistic insights. We tested the hypothesis that acute and subacute pathological injury, including the microgliosis that results from repeated, mild closed head injury, is reflected in susceptibility-weighted magnetic resonance imaging (SWI) and diffusion-tensor imaging (DTI) microstructural abnormalities. Using a combination of high-resolution magnetic resonance imaging (MRI), stereology and qPCR, we studied the pathophysiology of male mice that sustained 7 consecutive mild traumatic brain injuries over 9 days in acute (24 hour) and subacute (1 week) time periods. Repetitive mild closed head injury induced focal cortical microhemorrhages and impaired axial diffusivity at one week post-injury. These microstructural abnormalities were associated with a significant increase in microglia. Notably, microgliosis was accompanied by a change in inflammatory microenvironment, defined by robust spatiotemporal alterations in tumor necrosis factor alpha (TNFα) receptor mRNA. Together, these data contribute novel insight on the fundamental biological processes associated with repeated mild brain injury concomitant with subacute imaging abnormalities in a clinically relevant animal model of repeated mild TBI. These findings suggest new diagnostic techniques can be used as biomarkers to guide the use of future protective or reparative interventions.

Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior

“…74 A recent study of acute repetitive closed head TBI in mice also reported changes in RNA expression indicating activation of microglia in the cortex along with changes in ex vivo DTI AD. 75 Therefore, repetitive concussive or subconcussive impacts may lead to a microglial reaction in the cortex that could be detected noninvasively with continued advances in the clinical application of diffusion imaging approaches. This cortical microglial reaction could have significant functional implications for behavioral deficits and cognitive impairment given the emerging roles of microglia in synaptic pruning and neurodegenerative disease.…”

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

“…Production of inflammatory cytokines is also linked with glial cell activation following injury, and was commonly assessed in these studies. Depending on the cytokine variety, mTBI caused a rapid inflammation response that was shown to peak at 1 (Khuman et al, ), 2 (Namjoshi et al, ), 7 (Robinson et al, ) days post‐impact, with a prolonged sub‐acute profile (Bai et al, ; Mei, Zheng, Tan, Wang, & Situ, ). When chronic time points were assessed, reactive astrocytes and activated microglia persisted, appearing at 6 months (Mannix et al, ) and 3 months (Mannix et al, ).…”

Prenatal alcohol exposure potentiates chronic neuropathic pain, spinal glial and immune cell activation and alters sciatic nerve and DRG cytokine levels

“…Cellular lysate protein concentrations were determined by Quickstart ™ Bradford protein assay (BioRad, Hercules, CA, USA). Sciatic nerve cytokine expression levels were then determined using a V-PLEX ™ immunoassay (MesoScale Discovery, Gaithersburg, MD, detailed below) panel for identification of the cytokines and chemokines: TNFα, IL-1β, IL-6, IL-10 and CXCL1, as previously validated [63,77]. IL-10 levels in L4-L6 DRGs were also measured using MesoScale Discovery immunoassay platform.…”