AbstractThe involvement of brain glycogen in the progress of chronic stress-induced impairment of hippocampal astrocyte structural plasticity and depression-like behavior is yet to be clarified. The present study designed three experiments to determine the role of brain glycogen in the plasticity and behavioral consequences of chronic stress. Time course studies on brain glycogen, astrocytes, and behavioral responses to stress were conducted in Experiment 1. Chronic stress decreased the hippocampal glycogen levels, reduced astrocytic size and protrusion length in the hippocampus, and induced depression-like behavior. Glycogen synthase 1 mRNA in the hippocampus was silenced by lentiviral vector-based RNA interference (RNAi) in Experiment 2. This RNAi produced a lack of glycogen in the hippocampus, decreased the hippocampal astrocyte size, and induced depressive behavior in rats. The mechanisms of chronic stress-induced brain glycogen decrease were investigated in Experiment 3. Chronic stress promoted hippocampal glycogen breakdown and increased hippocampal glycogen synthesis. Results suggest that decreased glycogen content was associated with chronic stress-induced atrophy of hippocampal astrocyte size and depression-like behavior. Furthermore, the decrease of glycogen content in the hippocampus might be due to the compensation of glycogen synthesis for breakdown in an insufficient manner.