Physical exercise mediates a cortical FMRP-mTOR pathway to improve resilience against chronic stress in adolescent mice.

Aerobic exercise effectively relieves anxiety disorders via modulating neurogenesis and neural activity. The molecular mechanism of exercise-mediated anxiolysis, however, remains incomplete. On a chronic restrain stress (CRS) model in adolescent mice, we showed that 14-day treadmill exercise profoundly maintained normal neural activity and axonal myelination in the medial prefrontal cortex (mPFC), in association with the prevention of anxiety-like behaviors. Further interrogation of molecular mechanisms revealed the activation of the mechanistic target of the rapamycin (mTOR) pathway within mPFC under exercise training. At the upstream of mTOR, exercise-mediated brain RNA methylation inhibited the expression of Fragile X mental retardation protein (FMRP) to activate the mTOR pathway. In summary, treadmill exercise modulates an FMRP-mTOR pathway to maintain cortical neural activity and axonal myelination, contributing to improved stress resilience. These results extended our understanding of the molecular substrate of exercise-mediated anxiolytic effect during adolescent period.