Acute Stress Drives Adaptive Anxiety via Excitatory-Inhibitory Imbalance in the Prefrontal-Amygdala Circuit in Male...

Acute stress rapidly reshapes brain function to promote adaptive behavioral responses. Although dysfunction of the medial prefrontal cortex (mPFC)-amygdala circuit is well established in chronic stress-related anxiety, its role in acute adaptive anxiety remains unresolved. Here, using an acute restraint stress (ARS) model in male mice, we identified temporally restricted, projection-specific recruitment of dorsomedial prefrontal cortex (dmPFC) circuitry that regulates acute anxiety-like behavior. ARS selectively increased the activity of dmPFC projection neurons (PNs) at 2 h, but not 24 h post-stress, with minimal ventromedial prefrontal cortex engagement. This transient activation was confined to basolateral amygdala-projecting neurons (dmPFC^→BLA PNs) in layer II/III and layer V. Mechanistically, ARS enhanced excitatory synaptic transmission without altering inhibition, shifting the excitation-inhibition balance toward excitation in dmPFC^→BLA PNs. Functionally, inhibiting this circuit attenuated ARS-induced anxiety-like behavior, whereas activating it in unstressed mice recapitulated an anxiogenic state.