Amygdala stress-responsive ensembles mediate distinct susceptibility to negative stress-induced remote depression in adolescent and adult mice

Adolescent stress increases susceptibility to adult depression, potentially by encoding negative memories in stress-responsive neuronal ensembles, though the mechanisms remain unclear. In this study, we use a social defeat stress model with Tet-off labeling to examine the effects of short-term stress during adolescence and adulthood on behavior and cellular changes. Adolescent stress generates denser, more excitable stress-responsive neuronal ensembles in the basolateral amygdala (BLA) compared to adult stress, suggesting persistent traces of early-life stress that heighten remote depression risk. Adolescent mice display underdeveloped, hypoactive parvalbumin (PV) interneurons in the BLA, further suppressed by microglial phagocytic activity. Bidirectional modulation of BLA stress-responsive neuronal ensembles or PV neurons significantly alters depression-like behaviors. Overall, our findings indicate that BLA stress-responsive neuronal ensembles mediate differences in depression susceptibility between adolescent and adult stressed mice, with microglial dysfunction impairing PV neuron inhibitory control. These insights offer potential targets for early intervention in adult depression.