Anderson, E. D.; Augustin, D.; Georges, A. P.; Kim, T.; Issadore, D. A.; Meaney, D. F.

There is a critical unmet need for concussion biomarkers for injury prognosis and cognitive recovery. Existing traumatic brain injury (TBI) biomarkers are largely focused on acute cellular damage and reactivity, rather than the cellular repair mechanisms that contribute to differential concussion outcomes. Neuron-derived extracellular vesicles (EVs) are an emerging alternative to traditional protein biomarkers, providing a brain-specific molecular signature that can inform mechanistic insights and subsequent therapeutic intervention. Although neuroinflammation plays a key role in injury repair and cognitive recovery, its influence on neuronal EV signatures is unknown. In this work, we examine the role of inflammation in subacute neuronal EV biomarkers for differential concussion recovery in male mice. In particular, we identify general diagnostic biomarkers for concussion using miRNAs from neuronal EVs in blood serum, and then subtyped concussion based on prior injury history. Using PLX5622 to diminish the brain\'s inflammatory response, we find that acute inflammation significantly contributes to differential cognitive recovery post-concussion and can enhance or impede recovery based on injury history. Furthermore, we find that removing microglia prior to injury eliminates diagnostic biomarkers of concussion. Finally, we identify a general panel of EV-derived miRNA biomarkers associated with cognitive recovery across all experimental conditions. Together, we not only identify putative biomarkers for post-acute concussion diagnosis, injury history, and cognitive recovery, but also define a novel role for neuron-derived EVs in indirectly surveilling brain inflammation. Broadly, these findings could inform efforts to subtype concussion patients and identify more precise recovery profiles for individual concussion patients.