Abstract
BackgroundMild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs. The pathophysiology of mTBI is complex, with reports routinely correlating diffuse axonal injury (DAI) with prolonged morbidity. Progressive chronic neuroinflammation has also recently been correlated to morbidity, however, the potential association between neuroinflammatory microglia and DAI is not well understood. The majority of studies exploring neuroinflammatory responses to TBI have focused on more chronic phases of injury involving phagocytosis associated with Wallerian change. Little, however, is known regarding the neuroinflammatory response seen acutely following diffuse mTBI and its potential relationship to early DAI. Additionally, while inflammation is drastically different in rodents compared to humans, pigs and humans share very similar inflammatory profiles and responses.MethodsIn the current study, we employed a modified central fluid percussion model in micro pigs. Using this model of diffuse mTBI, paired with various immunohistological endpoints, we assessed the potential association between acute thalamic DAI and neuroinflammation 6 h following injury.ResultsInjured micro pigs displayed substantial axonal damage reflected in the presence of APP+ proximal axonal swellings, which were particularly prominent in the thalamus. In companion, the same thalamic sites displayed extensive neuroinflammation, which was observed using Iba-1 immunohistochemistry. The physical relationship between microglia and DAI, assessed via confocal 3D analysis, revealed a dramatic increase in the number of Iba-1+ microglial processes that contacted APP+ proximal axonal swellings compared to uninjured myelinated thalamic axons in sham animals.ConclusionsIn aggregate, these studies reveal acute microglial process convergence on proximal axonal swellings undergoing DAI, an interaction not previously recognized in the literature. These findings transform our understanding of acute neuroinflammation following mTBI and may suggest its potential as a diagnostic and/or a therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0405-6) contains supplementary material, which is available to authorized users.
Highlights
Mild traumatic brain injury is an all too common occurrence that exacts significant personal and societal costs
Using this model of central fluid percussion injury (cFPI), we demonstrated that diffuse Mild traumatic brain injury (mTBI) in the micro pig produced substantial diffuse axonal injury (DAI), within the thalamus, an area commonly affected in human TBI [49,50,51,52], without concomitant contusion or hematoma formation
In summary, we demonstrated that central fluid percussion injury in adult micro pigs precipitated substantial acute axonal injury in the thalamus that is ultrastructurally similar to acute DAI in humans
Summary
Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs. Mild traumatic brain injury (mTBI) is a common insult that exacts devastating personal and social costs [1,2,3,4]. One pathology that frequently follows mTBI is diffuse axonal injury (DAI), in which force-induced stress results in discrete areas of scattered axonal disruption that progress to disconnection. This results in a proximal axonal segment that remains connected to the neuronal soma and a distal segment that progresses to Wallerian degeneration [10,11,12,13]. Advanced neuroimaging and histological studies have firmly established a positive correlation between DAI and TBI-induced morbidity both clinically and experimentally [10, 14,15,16,17,18]
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