Preemptive Stimulation of AgRP Neurons in Fed Mice Enables Conditioned Food Seeking under Threat

The decision to engage in food-seeking behavior depends not only on homeostatic signals related to energy balance [1] but also on the presence of competing motivational drives [2] and learned cues signaling food availability [3]. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus are critical for homeostatic feeding behavior. Selective ablation or silencing of AgRP neurons causes anorexia [4, 5], whereas selective stimulation in fed mice promotes feeding and learned instrumental actions to obtain food reward [5-8]. However, it remains unknown whether AgRP neuron stimulation is sufficient to drive food-seeking behavior in the continued presence of a competing motivational drive, such as threat avoidance, or whether it can drive discrimination between learned sensory cues associated with food reward and other outcomes. Here we trained mice to perform a sensory discrimination task involving appetitive and aversive visual cues. Food-restricted mice exhibited selective operant responding to food-predicting cues but largely failed to avoid cued shocks by moving onto a safety platform. The opposite was true following re-feeding. Strikingly, AgRP neuron photostimulation did not restore operant responding in fed mice when initiated within the threat-containing arena, but did when initiated in the home cage, prior to arena entry. These data suggest that the choice to pursue certain behaviors and not others (e.g., food seeking versus shock avoidance) can depend on the temporal primacy of one motivational drive relative to the onset of a competing drive.