Divergent prefrontal cortex circuits regulate cued food seeking under distinct metabolic or emotional states

Flexibly adjusting food-seeking behaviour in response to food-associated cues and internal states is crucial for animals' survival. However, the neural mechanisms that modulate cued food-seeking behaviour during varying metabolic (i.e., hungry vs. satiated) and emotional (i.e., safe vs. threatened) states remain elusive. Here, we show that the encoding of metabolic or threat states in projection-defined neurons in the prelimbic cortex (PL) mediates cued food-seeking responses in rats. Using microendoscopic imaging, we demonstrate that neural population dynamics in PL consistently represent food cues, task-relevant behaviours, and internal state changes by recruiting distinct subsets of cue-responsive neurons at each state. Single-unit recording and loss-of-function experiments reveal that activity in divergent PL projections to the anterior paraventricular nucleus of the thalamus (aPVT) or the nucleus accumbens (NAc) promotes either hedonic feeding during satiation or food-seeking suppression during threat, respectively. Together, our findings uncover a mechanism by which divergent PL circuits regulate cued food-seeking under distinct metabolic or emotional states.