NSF-BSF: Interaction of Cholinergic and Dopaminergic Modulation Underlying Associative Learning

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Learning and memory is supported by synaptic plasticity, which involves actions of multiple neuromodulators. Different neuromodulators often target the same brain areas and neurons to act either synergistically or antagonistically. Major obstacles to studying the effect of these interactions on the circuit activity and behavior have been the sheer complexity of the circuit and the presence of redundant receptor families of neuromodulators. This project will tackle these issues by utilizing a simple genetic model organism and provide mechanistic insights into how two major neuromodulator pathways interact with each other to induce synaptic plasticity. The results of this study will lead to a fundamental understanding of the key mechanisms of learning and memory that are generally applicable to multiple species. The project will also contribute to the STEM education for the general public through the outreach program, in which the principal investigator will host K-12 teachers for the summer internship. In addition, both US and Israeli laboratories will train undergraduate and graduate researchers and facilitate their scientific interactions through close collaboration across the countries.This project will use olfactory learning in Drosophila as a platform to study interactions between multiple neuromodulators. The focused brain area is the mushroom body (MB), a learning center of insects. Although dopamine has been known to play a central role in modulating olfactory signals in the MB, recent comprehensive ultrastructural study suggested the existence of abundant cholinergic interconnections between MB neurons. Despite the fact that acetylcholine is the main excitatory neurotransmitter in the insect brain, little is known about the role played by its G-protein-coupled muscarinic receptors in learning and memory. The objective of this study is to understand how dopamine and acetylcholine act in concert on the same set of neurons to exert their effects on learning. Sophisticated genetic tools, in vivo electrophysiology, two-photon functional imaging and behavioral assays will be employed to determine how muscarinic receptors modulate olfactory responses in the MB neurons and how they affect dopamine-induced synaptic plasticity. Since metabotropic glutamate receptors, which can be regarded as the mammalian counterpart of insect muscarinic receptors, are widespread in the brain and known to interact with other neuromodulators, the proposed research is expected not only to contribute to fundamental progress in the field of Drosophila learning and memory, but also to provide general insights into neuronal plasticity across multiple brain areas and species.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.