Treadmill exercise relieves cortical interneuron hyperactivation to prevent stress-induced anxiety-like behaviors in male mice

Physical exercise effectively relieves anxiety disorders, and the underlying mechanisms are mostly studied in the regulation of glutamatergic transmission. The potential role of the GABAergic inhibitory pathway, however, is largely underappreciated. The current study found that chronic restraint stress (CRS) induces hyperactivation of parvalbumin (PV)-expressing interneurons (INs) in the prelimbic (PrL) region of male C57BL/6 J mice, and 14-day treadmill exercise effectively reduces PV-IN activity. Such modulation of the inhibitory transmission restores synaptic structure and functions in cortical pyramidal neurons, and chemogenetic manipulation confirmed the necessary role of PV-IN modulation in exercise-mediated anxiolytic effects. Our work broadens the knowledge of cortical inhibitory circuits in exercise intervention against mental illness and provides more targets for the neuromodulation of anxiety disorders. Persistent treadmill exercise relieves anxiety-like behaviors in chronically restrained male mice via the relief of the hyperactivation of parvalbumin interneurons in the medial prefrontal cortex.