Microglia-Mediated Neuroprotection from Concussion
Subconcussive impacts are highly prevalent in contact sports and are thought to increase concussion likelihood. However, we do not precisely understand the conditions under which subconcussive impacts affect concussion recovery, limiting both our mechanistic understanding and resultant recovery monitoring strategies. Microglia are brain-resident immune cells and homeostatic regulators of brain function, playing a key role in cognitive outcome following neurological disease. Yet, we have few means of surveilling brain-specific inflammation. Emerging techniques using neuron-derived extracellular vesicles (EVs) may offer a measure of neuro-inflammatory processes. In this work, we consider how subconcussive impacts influence concussion recovery to understand how microglia can protect against concussion, and, in tandem, identify neuron-derived EV biomarkers for concussion diagnosis and recovery. To do so, we developed a closed-head controlled cortical impact method to deliver precise, scalable brain injuries to mice. We found that delivering two subconcussive impacts prior to a concussive impact (i.e., subconcussive preconditioning) within a two minute period, but not a 48-hour period, protected the brain against concussion and reduced memory deficits. We characterized microglial localization and morphology and found that subconcussive preconditioning diminished hypersurveillant microglial morphology. We next depleted microglia using PLX5622 and determined that microglia mediated the protective preconditioning effect. We next identified neuron-derived EV biomarkers for general concussion diagnosis as well as based on prior impact history. We identified inflammation- and diet-dependent concussion biomarkers and identified a panel of neuronal EV miRNAs associated with cognitive recovery. Together, these results demonstrate microglia’s role in governing variable concussion outcomes and their downstream effects on neuron-derived EV miRNAs. These findings not only expand our understanding of repetitive head injury to include a novel protective role, but also our understanding of neuron-derived EVs as containing a multicellular signature of neuroinflammation post-acutely. These results underscore the importance of surveilling inflammation as a means of predicting cognitive outcome following concussion. Future work should consider direct measures of surveilling brain inflammation, especially prospectively to assess concussion risk, and identify specific microglial pathways involved in neuroprotection against concussion.
Engineering, Neuroscience and Neurobiology
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