Hunger dampens a nucleus accumbens circuit to drive persistent food seeking.

To find food efficiently, a hungry animal engages in goal-directed behaviors that rely on nucleus accumbens (NAc) circuits. Synaptic alterations within these circuits underlie shifts in behavior across motivational states. Here, we show that hunger dampens an NAc to lateral hypothalamus (LH) circuit to promote persistent food seeking. BigLEN, a hunger-driven neuropeptide, acts through its receptor GPR171 to inhibit glutamate transmission onto NAc shell Drd1+ LH-projecting medium spiny neurons by suppressing cholinergic signaling. The antagonism of GPR171 in food-deprived animals reduces persistent unrewarded food-seeking behavior but does not alter effortful food seeking or overall food intake. The chemogenetic upregulation of the NAc to LH circuit reduces this persistent unrewarded responding in hungry animals. These results describe how hunger-driven neuromodulation targets a distinct dimension of motivated behavior by shaping information flow through anatomically defined circuit elements.