PAG-dependent defensive strategy selection: From stress-induced rigidity to adaptive flexibility

Adaptive survival requires flexibly choosing passive or active defenses as threat intensity varies. Many studies have described the execution of defensive behaviors, but the flexibility of mice to choose defensive strategies is poorly understood. Here, we demonstrate that auditory cues of different intensities (60 dB and 80 dB) elicit passive (freezing) and active (escape) defensive behaviors in mice, mimicking the flexibility to choose appropriate defensive behaviors when faced with varying degrees of threat. Single prolonged stress (SPS) mice exhibited dysregulated defensive behavior selection, showing a maladaptive tendency to freeze when facing imminent threats. Chemogenetic inhibition of the dorsal periaqueductal gray (dPAG) and ventrolateral periaqueductal gray (vlPAG) coordinates selective shifts in defensive behavior. These results imply that interactions between the dPAG and vlPAG may support flexible defensive strategy selection and influence behavioral output, highlighting PAG circuitry as a candidate target for improving adaptive responses in stress-related disorders.