A neural mechanism for learning from delayed postingestive feedback

Animals learn the value of foods on the basis of their postingestive effects and thereby develop aversions to foods that are toxic^{1, 2, 3, 4, 5, 6, 7, 8, 9–10} and preferences to those that are nutritious^{11, 12–13}. However, it remains unclear how the brain is able to assign credit to flavours experienced during a meal with postingestive feedback signals that can arise after a substantial delay. Here we reveal an unexpected role for the postingestive reactivation of neural flavour representations in this temporal credit-assignment process. To begin, we leverage the fact that mice learn to associate novel^14,15, but not familiar, flavours with delayed gastrointestinal malaise signals to investigate how the brain represents flavours that support aversive postingestive learning. Analyses of brain-wide activation patterns reveal that a network of amygdala regions is unique in being preferentially activated by novel flavours across every stage of learning (consumption, delayed malaise and memory retrieval). By combining high-density recordings in the amygdala with optogenetic stimulation of malaise-coding hindbrain neurons, we show that delayed malaise signals selectively reactivate flavour representations in the amygdala from a recent meal. The degree of malaise-driven reactivation of individual neurons predicts the strengthening of flavour responses upon memory retrieval, which in turn leads to stabilization of the population-level representation of the recently consumed flavour. By contrast, flavour representations in the amygdala degrade in the absence of unexpected postingestive consequences. Thus, we demonstrate that postingestive reactivation and plasticity of neural flavour representations may support learning from delayed feedback.