Dissociable contributions of the amygdala and ventral hippocampus to stress-induced changes in defensive behavior

Background Severe stress can produce multiple persistent changes in defensive behavior relevant to psychiatric illness. While much is known about the circuits supporting stress-induced associative fear, how stress-induced circuit plasticity supports non-associative changes in defensive behavior remains unclear. Methods Mice were exposed to an acute severe stressor, and subsequently, both associative and non-associative defensive behavioral responses were assessed. A mixture of local protein synthesis inhibition, pan-neuronal chemogenetic inhibition, and projection-specific chemogenetic inhibition were utilized to isolate the roles of the basolateral amygdala (BLA) and ventral hippocampus (vHC) to the induction and expression of associative and non-associative defensive behavioral changes. Results Stress-induced protein synthesis in the BLA was necessary for enhancements in stress sensitivity but not enhancements in anxiety-related behaviors, whereas protein synthesis in the vHC was necessary for enhancements in anxiety-related behavior but not enhancements in stress sensitivity. Like protein synthesis, neuronal activity of the BLA and vHC were found to differentially support the expression of these same defensive behaviors. Additionally, projection-specific inhibition of BLA-vHC connections failed to alter these behaviors, indicating that these defensive behaviors are regulated by distinct BLA and vHC circuits. Lastly, contributions of the BLA and vHC to stress sensitivity and anxiety-related behavior were independent of their contributions to associative fear. Conclusions Stress-induced plasticity in the BLA and vHC were found to support dissociable non-associative behavioral changes, with BLA supporting enhancements in stress sensitivity and vHC supporting increased anxiety-related behavior. These findings demonstrate that independent BLA and vHC circuits are critical for stress-induced defensive behaviors, and that differential targeting of BLA and vHC circuits may be needed in disease treatment. ### Competing Interest Statement The authors have declared no competing interest.