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The recollection of environmental cues associated with threat or reward allows animals to select the most appropriate behavioral responses. Neurons in the prelimbic (PL) cortex respond to both threat- and reward-associated cues. However, it remains unknown whether PL regulates threat-avoidance vs. reward-approaching responses when an animals’ decision depends on previously associated memories. Using a conflict model in which male Long–Evans rats retrieve memories of shock- and food-paired cues, we observed two distinct phenotypes during conflict: (1) rats that continued to press a lever for food ( Pressers ) and (2) rats that exhibited a complete suppression in food seeking ( Non-pressers ). Single-unit recordings revealed that increased risk-taking behavior in  Pressers  is associated with persistent food-cue responses in PL, and reduced spontaneous activity in PL glutamatergic (PL GLUT ) neurons during conflict. Activating PL GLUT  neurons in  Pressers  attenuated food-seeking responses in a neutral context, whereas inhibiting PL GLUT  neurons in  Non-pressers  reduced defensive responses and increased food approaching during conflict. Our results establish a causal role for PL GLUT  neurons in mediating individual variability in memory-based risky decision-making by regulating threat-avoidance vs. reward-approach behaviors.

Neural correlates and determinants of approach–avoidance conflict in the prelimbic prefrontal cortex