Distinct interneuronal dynamics selectively gate target-specific cortical projections in drug seeking.

Drug craving persists after prolonged abstinence, posing a major challenge in treating substance use disorders. The ventral medial prefrontal cortex (vmPFC) plays a critical role in impulsivity and decision-making, making it a promising target for mitigating drug craving by orchestrating downstream brain-wide activity. However, the dynamics of vmPFC sub-circuits during the progression of drug addiction remain unclear. Here, we uncover a circuit-level mechanism by which distinct vmPFC sub-circuits, defined by cell-type-specific interneurons and projection-specific cortical outputs, differentially modulate mesolimbic pathways to drive drug-seeking behavior. Our results reveal that distinct interneuron subtypes display unique activity dynamics and exert selective modulation over projection-specific cortical outputs. Notably, parvalbumin (PV)-positive interneurons exhibit target-specific synaptic remodeling with pyramidal neurons projecting to distinct downstream targets, which is crucial for modulating mesolimbic circuits and driving persistent cocaine seeking after abstinence. These findings provide compelling insights into vmPFC microcircuit mechanisms underlying substance use disorders.