Functional dissection of a neuronal brain circuit mediating higher-order associative learning

A central feature characterizing the neural architecture of many species' brains is their capacity to form associative chains through learning. In elementary forms of associative learning, stimuli coinciding with reward or punishment become attractive or repulsive. Notably, stimuli previously learned as attractive or repulsive can themselves serve as reinforcers, establishing a cascading effect whereby they become associated with additional stimuli. When this iterative process is perpetuated, it results in higher-order associations. Here, we use odor conditioning in Drosophila and computational modeling to dissect the architecture of neuronal networks underlying higher-order associative learning. We show that the responsible circuit, situated in the mushroom bodies of the brain, is characterized by parallel processing of odor information and by recurrent excitatory and inhibitory feedback loops that empower odors to gain control over the dopaminergic valence-signaling system. Our findings establish a paradigmatic framework of a neuronal circuit diagram enabling the acquisition of associative chains.