Malaise and memory: Circuit mechanisms of memory of post-ingestion effects

Arguably, one of the most important memories is the sensory hallmark of a food that made an animal sick as such food should be avoided in the future. Pathogens that enter the digestive system via food trigger an infection that leads to nausea and malaise. Interestingly, the onset of malaise commences usually several minutes if not hours after the food has been consumed suggesting that animals can associate post-ingestive effects with a previously occurring sensory experience such as taste or smell. Previous work suggested that Drosophila melanogaster can associate an odour with the intestinal malaise caused by pathogen infection. How this type of memory is encoded in the fly’s memory brain center, the mushroom body, and which neuronal mechanisms enable the necessary communication between gut and brain remains unclear. By contrast, the immune response triggered in the gut upon entry of such pathogens has been well characterized. Among the players are factors such as cytokines that have the capacity to travel from the gut to the brain. Therefore, it is conceivable that such factors are used to induce or modulate memory formation at the level of the mushroom bodies making this a very interesting system to understand a physiologically relevant form of memory from the level of a molecule up to a functional neural circuit.Using two bacterial strains to infect Drosophila by feeding (ECC15 and Pseudomonas entomophila (PE)), we aim at answering three main questions with this proposal: (i) What is the role of relative timing in pathogen infection and aversive food memories?, (ii) How does the mushroom body integrate and store the relevant information at the circuit level?, and (iii) Are these memories imprinted and carried from larval to adult stage as previously shown in C. elegans? Based on promising preliminary results, we will employ an integrative approach including immune- and microbiology, custom-build behavioural assays, optogenetics, high resolution split-Gal4 line genetics, and in vivo functional imaging, to answer these questions. Given the importance of being able to learn to avoid dangerous food sources, we anticipate that this work has important implications also for other animal species including humans. Furthermore, it will broaden the role of the mushroom body and contribute novel insights to its function as an integrator of internal state and distant sensory experiences.