Generalization of negative memories drives the development of psychological distress-related behaviors

Individuals with depression and anxiety often exhibit intensified and overgeneralized negative memories. However, the causal contribution of memory features, especially the relative roles of memory strengthening versus generalization in shaping subsequent affective disturbances, remains poorly understood. Here, we developed behavioral paradigms to dissociate memory generalization from strengthening and found that negative experiences leading to memory overgeneralization, but not those enhancing memory strength alone, triggered stress-related behaviors in mice. We identified the projection from medial prefrontal cortex (mPFC) to the bed nucleus of the stria terminalis (BNST) as a key circuit linking generalized memory to stress-related phenotypes. Single-cell calcium imaging revealed a significant overlap between the BNST-projecting mPFC (mPFC^BNST) neuronal ensemble encoding stress-related behaviors and that encoding generalized memory, but not memory strength. Circuit-specific transcriptomic profiling, chromophore-assisted light inactivation, and short hairpin RNA-mediated gene knockdown further demonstrated that actin cytoskeleton remodeling within the mPFC^BNST neurons, a molecular event underlying the formation of memory generalization, is essential for the emergence of stress-related behaviors. Collectively, these findings identify the generalization of negative memories as a principal driver of stress-related behaviors. More broadly, they provide mechanistic insight into how overgeneralized negative memories, a cognitive feature commonly observed in psychological disorders, may contribute to vulnerability to psychological distress, thereby offering a conceptual framework relevant to early identification and intervention in affective disorders.