Increased Brain IL‐1b and Fatigue Following Downhill Running: Role of Brain Macrophages

Brain cytokines, induced by inflammatory challenges have been linked to sickness behaviors, including fatigue. However, the brain cytokine response to exercise is not well understood. Previous data show that exaggerated fatigue following downhill vs uphill running is associated with increased brain IL‐1β concentration. PURPOSE This study was designed to investigate brain macrophages in the increased IL‐1β response to downhill running via a macrophage depletion technique (clodronate‐filled liposomes (CLOD)) that selectively targets perivascular and meningeal macrophages. METHODS Male C57BL/6 mice (n=110) were assigned to UP‐SAL, UP‐CLOD, DWN‐SAL, DWN‐CLOD, CON‐SAL & CON‐CLOD groups. Mice were given 10μL ICV injections of clodronate or saline‐filled liposomes. 96hr later, mice were run at 22 m/min and −14% or +14% grade, for 150‐min. Fatigue was assessed 12–24hr later via voluntary wheel running (Exp. 1) or treadmill running to fatigue (Exp. 2). Brain IL‐1β concen. was determined at 24hr (Exp. 3). RESULTS CLOD had no effect on wheel running (Exp 1), but did delay treadmill running fatgue in both uphill (158 ± 8 vs. 124 ± 10 min) and downhill runners (126 ± 15 vs. 65 ± 8 min) compared to SAL (Exp 2). CLOD reduced IL‐1β in the cortex of downhill runners (0.86 ± 0.06 vs 1.05 ± 0.1 pg/100ug total protein) and cerebellum of both uphill (3.5 ± 0.2 vs. 4.1 ± 0.18 pg/100ug total protein) and downhill runners (3.7 ± 0.4 vs. 4.5 ± 0.38 pg/100ug total protein) compared to SAL, but this effect didn't reach statistical significance (p=0.2). CONCLUSION These results support a role of brain macrophages in some forms of fatigue, but the precise relationship between brain macrophages, IL‐1β and central fatigue remain to be determined.