Dopamine receptor regulation of learning and forgetting

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Program overview: Animals must balance limited memory storage capacity with continuous learning in complex and changing environments. Therefore, the ability to forget, i.e., to alter or remove information in the brain, is an advantage allowing cognitive flexibility and the conservation of memory resources. Indeed, studies in both invertebrates and mammals indicate that there are biological systems to regulate forgetting. Interestingly, dopamine (DA) plays a dual role in both learning and forgetting in Drosophila. While learning has been a major focus of neuroscience in the past, the study of forgetting remains a promising and undiscovered area of research. The long-term goal of my research program is to elucidate the neurobiology that regulates forgetting and to understand how neurons determine whether a memory stays or goes. For this research program, I will use advanced methodologies including behavioral memory assays, neurogenetics, advanced proteomics, and in vivo synaptic physiology. Recent progress and short-term goals: In Drosophila, I have discovered that dopamine neurons play a critical and dual role in both memory formation and forgetting. Remarkably, dopamine differentially modulates memory through two dopamine receptors; acting through Dop1R1(R1) to form memories, and through Dop1R2(R2) to cause forgetting. Recently I have developed a proximity labeling proteomics approach to identify signaling systems that engage these receptors and shed light on their distinct signaling networks. Furthermore, recently it was shown that forgetting is mediated through R2 coupling to the G protein Gaq, but it remains unclear if forgetting is mediated by the canonical pathway downstream of Gaq involving the endoplasmic reticulum organelle. Over the next 5 years, my trainees and I will use multilevel approaches and state-of-the-art techniques to investigate three short-term goals: (i) Identify and compare R1 and R2 proximal proteins in native memory circuits in living flies, (ii) Dissect memory relevance of dopamine receptor proximal proteins, and (iii) Characterize ER Ca2+ signaling mechanisms regulating R2-mediated forgetting. Significance: This study is centered around elucidating how information is encoded, maintained, and forgotten in the brain. This question is central to understanding animal cognition and thus an active and critical area of research in neuroscience. With a focus on the neurobiology of forgetting, this study stands out by contributing to an exciting and novel area of research. Using an innovative combination of cutting-edge tools, this study will significantly expand our understanding of the cellular systems that control dopamine-mediated memory systems, and how downstream signaling through an important organelle, the ER, controls memory storage. In the long-term, this programme will lay the foundational ideas and approaches for further expansion of our knowledge of memory systems in the future.