CRCNS US-France Research Proposal: Collaborative Research: Encoding reward expectation in Drosophilia

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Animals develop an understanding of their environment through learning that specific cues in the environment are reliably paired with and consequently predict important outcomes, such as access to food or the presence of danger. The concept of outcome expectation based on these predictions has been influential in the development of studies of associative learning in mammals. These analyses have had a profound impact on understanding of outcome-related behavior in humans, including monetary rewards and the consequences of traumatic experiences, and for pathologies of the reward systems in the brain. The neural underpinnings of outcome expectation are particularly challenging to study in mammals because of the requirement for exquisite cellular, temporal, and genetic specificity of experimental manipulations. The fruit fly Drosophila melanogaster has been a valuable model for investigating the genetic and neural bases that underlie learning and memory, including learning of cue-outcome associations. The recent development of work with identified neurons and their detailed connections in the fly brain makes the larval and adult fruit fly brains ripe as models for advancing understanding of neural bases for outcome expectation learning in mammals. Using the powerful experimental approaches available in the fruit fly model system and resources guided by computational modeling, the team of researchers investigate complex memory representations in Drosophila. This project also provides interdisciplinary training for postdoctoral researchers, and graduate and undergraduate students, development of new K-12 biology classroom material, and collaboration with Arizona State University’s award-winning Ask-A-Biologist program.Early and most current studies of learning and memory in the fruit fly (Drosophila melanogaster) use basic behavior conditioning protocols to study learning in controlled laboratory settings. The ability to transgenically manipulate many of the brain neurons in the fruit fly with exquisite specificity, and the recent knowledge of the synaptic ‘connectome’ of the fruit fly brain, makes these animals almost unique as a comprehensive model for studies of learning, memory and motivated behavior. Within this context, the investigators propose that studies of learning and memory will be greatly enhanced by using more sophisticated means for evaluating memory representations, and by combining those studies with information from the connectome guided by computational modelling. To that end, the investigators examine the function of reinforcement pathways in relation to the absence of expected reinforcement. Specifically, the investigators study the memory representations in fruit flies when an expected consequence of a conditioned stimulus fails to occur. Through a series of experiments, they test the prediction that in Drosophila when a conditioned stimulus is associated with a failed expectation of an appetitive food reinforcement, the conditioned stimulus will acquire aversive value, and vice versa for a failed expectation of an aversive reinforcer. The investigators combine these studies with manipulations of reinforcement pathways in the central nervous system identified and selected based on the recently released fly brain connectome. The experimental work is iteratively knitted in with established computational models.A companion project is being funded by the French National Research Agency (ANR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.