Subconcussive Preconditioning Modifies Acute Microglial Response and Improves Cognitive Outcomes Post-Concussion

Subconcussive impacts are highly prevalent in contact sports and are thought to increase concussion risk. However, the specific conditions under which these subconcussive impacts influence concussion outcomes are uncertain, limiting our understanding of the mechanisms behind repetitive head trauma. Given that subconcussive impacts elicit a microglial response, we examined how subconcussive preconditioning affects microglial morphology and transcriptomic profile, as well as cognitive outcome after concussion. To investigate this question, we developed and validated a scalable, closed-head controlled cortical impact model. Using this approach, we found that although concussion elicited morphological features of hyper-surveillant microglia at 1 day post-injury, they resolved by 9 days post-injury, and subconcussive impacts only produced microglial changes at 9 days post-injury. When subconcussive impacts preceded a concussive impact (i.e., preconditioned concussion), no changes in microglial morphology appeared at either 1 day or 9 days after injury. Subconcussive preconditioning also upregulated microglial genes associated with inhibiting pro-inflammatory pathways and enhancing folate metabolism. Interestingly, subconcussive preconditioning eliminated concussion-associated cognitive deficits in novel object recognition and this cognitive protection was time dependent: preconditioning impacts were only protective if delivered within 2 min of concussion and had no effect if delivered over a 48-h window. These results suggest that some types of subconcussive impacts may offer protection against subsequent concussion and mitigate changes in microglial morphology and inflammatory responses. Understanding this timing window could inform strategies for minimizing cognitive impairments in athletes exposed to repetitive head trauma.