Exercise engages a mechanically activated astrocyte state linking muscle activity to hippocampal plasticity

Physical exercise promotes brain health in part through muscle-derived factors that enter the brain, but how peripheral signals are translated into neural responses remain unclear. Here, we identify astrocyte contraction as a previously unrecognized physiological response to exercise signals that may contribute to adult hippocampal neurogenesis. In vivo, voluntary running rapidly induced nuclear localization of the mechanically sensitive transcriptional regulator Yes-associated protein (YAP), and increased non-muscle myosin II phosphorylation in hilar astrocytes in mice, consistent with acute contraction. Using an in vitro platform with ultrasensitive force sensors, we found that factors released by contracting skeletal muscles activated astrocytes which in turn increased contraction that was necessary and sufficient for their proliferation and expansion. Activated astrocytes subsequently released soluble factors that modulated neuronal network tension and promoted immature neuron abundance. These findings identify astrocyte contractility as a physiological transducer of exercise-derived muscle signals and establish cellular force generation as a potential mechanism regulating neuroplasticity.