AgRP neuron activity promotes associations between sensory and nutritive signals to guide flavor preference

Objective: The learned associations between sensory cues (e.g., taste, smell) and nutritive value (e.g., calories, post-ingestive signaling) of foods powerfully influences our eating behavior [1], but the neural circuits that mediate these associations are not well understood. Here, we examined the role of agouti-related protein (AgRP)-expressing neurons – neurons which are critical drivers of feeding behavior [2; 3] – in mediating flavor-nutrient learning (FNL). Methods: Because mice prefer flavors associated with AgRP neuron activity suppression [4], we examined how optogenetic stimulation of AgRP neurons during intake influences FNL, and used fiber photometry to determine how endogenous AgRP neuron activity tracks associations between flavors and nutrients. Results: We unexpectedly found that tonic activity in AgRP neurons during FNL potentiated, rather than prevented, the development of flavor preferences. There were notable sex differences in the mechanisms for this potentiation. Specifically, in male mice, AgRP neuron activity increased flavor consumption during FNL training, thereby strengthening the association between flavors and nutrients. In female mice, AgRP neuron activity enhanced flavor-nutrient preferences independently of consumption during training, suggesting that AgRP neuron activity enhances the reward value of the nutrient-paired flavor. Finally, in vivo neural activity analyses demonstrated that acute AgRP neuron dynamics track the association between flavors and nutrients in both sexes. Conclusions: Overall, these data (1) demonstrate that AgRP neuron activity enhances associations between flavors and nutrients in a sex-dependent manner and (2) reveal that AgRP neurons track and rapidly update these associations. Taken together, our findings provide new insight into the role of AgRP neurons in assimilating sensory and nutritive signals for food reinforcement.