Neuroprotective Kynurenine Pathway Effects of Exercise on Depression after Adolescent Concussion - PROJECT SUMMARY Nearly 1 in 5 adolescents report having sustained a concussion, and ~40% experience symptoms lasting >1 month. Post-injury disruption to neural circuits involved in mood and emotional regulation can lead to psychological sequelae (e.g., depression). Symptoms may reflect both injury pathophysiology and/or psychosocial stressors. Adolescents with concussion face a disproportionately higher risk of psychological symptoms than their peers who have not sustained a concussion. Although aerobic exercise aids recovery, current guidance is generic and mechanisms linking exercise to psychological outcomes remain unclear. Importance of the Research. We will determine if the kynurenine (KYN) pathway (KP), a pathway at the intersection of inflammation, neurotransmission, and brain function, is associated with the therapeutic effects of aerobic exercise on post-concussion depressive symptoms. After concussion, inflammation shifts KP metabolism toward neurotoxicity (↑quinolinic acid [QuinA], ↓KYN acid [KynA]), a profile linked to mood disorders. Aerobic exercise upregulates skeletal muscle KYN aminotransferases, diverting circulating KYN toward KynA, reducing brain exposure to QuinA. By integrating KP metabolites with exercise metrics, inflammatory markers, and depressive symptoms, we will establish a precision rehabilitation framework for adolescent concussion. Research Strategy. We seek to (1) determine whether aerobic exercise volume and intensity after adolescent concussion modify KP metabolism, producing a more neuroprotective profile (↑KynA/QuinA, ↓KYN) during recovery and (2) evaluate whether KP profiles predict onset or worsening of depressive symptoms and identify adolescents responsiveness to exercise-based recovery guidance. These aims will generate an integrated biological and behavioral profile of recovery that integrates molecular biomarkers of KP metabolism, aerobic exercise behaviors, inflammatory and injury markers, and psychological outcomes. This framework will delineate individualized contributors to post-concussion depressive symptoms, identify adolescents who are most/least responsive to exercise rehabilitation, and establish biologically grounded strategies for precision intervention. Rigor and Feasibility. Our investigative team brings expertise in concussion, exercise physiology, biomarkers, and adolescent mental health. We will leverage existing infrastructure from the ongoing parent trial, which includes longitudinal outcomes data, serum samples, actigraphy-based activity tracking, and validated symptom assessments. Our collaborative, multi-site RCT design ensures rigor, reproducibility, and feasibility. Impact. Results will inform biomarker-driven interventions, enable identification of adolescents most vulnerable to post-concussion depression, and guide individualized exercise prescriptions. By advancing biomarker-guided, personalized approaches to reduce post-concussion depressive symptom burden, this study will provide the basis for effective strategies to reduce long-term morbidity and improve adolescent recovery and well-being.
