Biology subjects

Georges, A. P.

Publications and source records attributed to Georges, A. P..

2 recordsLinked to original sources

bioRxiv2025

Microglia modulate concussion biomarkers and cognitive recovery in male mice

There is a critical unmet need for concussion biomarkers that predict cognitive recovery. Existing TBI biomarkers largely capture acute cellular damage rather than the multicellular repair processes that determine long-term outcome, and whether microglia causally shape divergent trajectories remains unclear. Here, we used PLX5622 to deplete microglia and other CSF1R-dependent myeloid cells in a male mouse model comparing concussion alone to concussion preconditioned by prior subconcussive impacts. Microglial depletion had no effect on cognitive outcome after concussion alone, but introduced a significant novel object recognition deficit specifically when concussion was preconditioned, revealing a history-dependent role for microglia in recovery. To identify the molecular substrates of this divergence, we profiled brain-derived GluA1/2+ extracellular vesicle (EV) miRNAs and single-nuclei transcriptomes from the injured brain. Diagnostic and injury-history EV miRNA biomarkers discriminated between concussion subtypes in microglia-intact animals but lost this discriminative power after depletion, indicating that these neuron-enriched biomarkers are influenced by microglia-dependent biology rather than injury alone. snRNA-seq further revealed that microglial depletion selectively induced transcriptional programs related to oligodendrocyte maturation after unconditioned concussion, a candidate substrate for this microglia-dependence. Finally, we identified a serum EV miRNA panel that estimated cognitive recovery across injury conditions. Together, these findings identify a history-dependent role for microglia in concussion outcome and characterize brain-derived EVs as a potentially promising tool for surveilling the neuroinflammatory processes influencing recovery.

bioengineering↗

bioRxiv2025

Subconcussive preconditioning prevents microglial morphology changes and improves cognitive outcomes in mice

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, and microglial morphology offers insight into function, we examined how subconcussive preconditioning affects microglial morphology and 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 features of hypersurveillant microglia at 1 day post-injury, they resolve 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 or 9 days after injury. 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 minutes of concussion, and had no effect if delivered over a 48-hour window. These results suggest that some types of subconcussive impacts may offer protection against subsequent concussion and mitigate changes in microglial morphology. Understanding this timing window could inform strategies for minimizing cognitive impairments in athletes exposed to repetitive head trauma.

bioengineering↗