Animals learn to associate otherwise neutral sensory cues with positive or negative contingencies and rely on those associations to make adaptive decisions. Flexible updating of these acquired associations as contingencies change is also important. Failure to update internal representations plays a causal role in some mental disorders, including schizophrenia and anxiety. While the neural substrates of acquiring and updating associations have been studied in mammalian models, the complexity of the mammalian brain has made it difficult to obtain precise cellular and synaptic mechanistic understanding. Drosophila flies exhibit flexible associative learning: they learn to avoid an odor paired with electric shock, and extinguish that learned association when the odor is later presented without shock. Flies have powerful genetic tools to allow precise manipulation and visualization of neural activity with cellular resolution in the mushroom body brain region (MB), where neural plasticity underlying learning occurs. Our long-term goal is to use Drosophila to gain mechanistic insight into how acquisition and extinction are implemented by synaptic microcircuits of the MB. Our novel hypothesis is that plasticity of dopamine neurons embedded in a recurrent synaptic microcircuit residing in the fly mushroom body underlies extinction of odor-shock associations. To test this hypothesis we employ in vivo Ca2+ imaging and optogenetics to visualize and manipulate dynamic changes in neural activity of specific genetically targeted MB cell types as a fly acquires and extinguishes an association between a neutral odor and aversive electric shock.
The proposed experiments will systematically dissect the mechanisms by which microcircuits encode and update associations during learning at a cellular resolution difficult to achieve in other model organisms. Because the molecular mechanisms and synaptic organization of learning are conserved, these studies will provide valuable new information applicable to mammalian learning. Because failure to update internal representations is involved in several mental disorders, having a detailed mechanistic understanding of how nervous systems perform these updates would inform translational and clinical approaches to healthy and disordered learning.
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