Food cue regulation of AGRP hunger neurons guides learning

Agouti-related peptide (AGRP)-expressing neurons are activated by fasting-this causes hunger(1-4), an aversive state that motivates the seeking and consumption of food(5,6). Eating returns AGRP neuron activity towards baseline on three distinct timescales: rapidly and transiently following sensory detection of food cues(6-8), slowly and longer-lasting in response to nutrients in the gut(9,10), and even more slowly and permanently with restoration of energy balance(9,11). The rapid regulation by food cues is of particular interest as its neurobiological basis and purpose are unknown. Given that AGRP neuron activity is aversive(6), the sensory cue-linked reductions in activity could function to guide behaviour. To evaluate this, we first identified the circuit mediating sensory cue inhibition and then selectively perturbed it to determine function. Here, we show that a lateral hypothalamic glutamatergic -> dorsomedial hypothalamic GABAergic (gamma-aminobutyric acid-producing)(12) -> AGRP neuron circuit mediates this regulation. Interference with this circuit impairs food cue inhibition of AGRP neurons and, notably, greatly impairs learning of a sensory cue-initiated food-acquisition task. This is specific for food, as learning of an identical water-acquisition task is unaffected. We propose that decreases in aversive AGRP neuron activity(6) mediated by this food-specific circuit increases the incentive salience(13) of food cues, and thus facilitates the learning of food-acquisition tasks.