Abstract
Microglial activation is a pathological hallmark of traumatic brain injury (TBI). Following brain injury, activated microglia/macrophages adopt different phenotypes, generally categorized as M-1, or classically activated, and M-2, or alternatively activated. While the M-1, or pro-inflammatory phenotype is detrimental to recovery, M-2, or the anti-inflammatory phenotype, aids in brain repair. Recent findings also suggest the existence of mixed phenotype following brain injury, where activated microglia simultaneously express both M-1 and M-2 markers. The present study sought to determine microglial activation states at early time points (6–72 h) following single or repeated concussive injury in rats. Closed-head concussive injury was modeled in rats using projectile concussive impact injury, with either single or repeated impacts (4 impacts, 1 h apart). Brain samples were examined using immunohistochemical staining, inflammatory gene profiling and real-time polymerase chain reaction analyses to detect concussive injury induced changes in microglial activation and phenotype in cortex and hippocampal regions. Our findings demonstrate robust microglial activation following concussive brain injury. Moreover, we show that multiple concussions induced a unique rod-shaped microglial morphology that was also observed in other diffuse brain injury models. Histological studies revealed a predominance of MHC-II positive M-1 phenotype in the post-concussive microglial milieu following multiple impacts. Although there was simultaneous expression of M-1 and M-2 markers, gene expression results indicate a clear dominance in M-1 pro-inflammatory markers following both single and repeated concussions. While the increase in M-1 markers quickly resolved after a single concussion, they persisted following repeated concussions, indicating a pro-inflammatory environment induced by multiple concussions that may delay recovery and contribute to long-lasting consequences of concussion.
Highlights
The prevalence of closed-head concussive injury is high in both military and civilian population
Animal research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals, and adhered to the principles specified in the Guide for the Care and Use of Laboratory Animals, National Research Council (NRC) Publication, 2011 edition
While resting microglia has a ramified morphology, activation is characterized by a hypertrophied, bushy phenotype
Summary
The prevalence of closed-head concussive injury is high in both military and civilian population. Athletes with a history of repeated concussions show late-life memory problems, psychiatric illness and increased risk of progressive neurodegenerative diseases such as Alzheimer’s disease, and chronic traumatic encephalopathy (CTE) [4,5,6,7]. We have developed a rat model for closed-head mTBI called projectile concussive impact (PCI) injury that mimics several aspects of human concussive injury [9,10,11]. Using this injury model, we have demonstrated acute increases in inflammatory cytokines, persistent gliosis, chronic functional neurological impairments, and white matter thinning following single or repetitive hits [9]
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