Dopamine receptor regulation of learning and forgetting

项目概述：动物必须在复杂多变的环境中平衡有限的记忆存储能力和持续学习能力。因此，遗忘的能力，即改变或删除大脑中的信息，是一种优势，允许认知灵活性和记忆资源的保存。事实上，对无脊椎动物和哺乳动物的研究表明，存在调节遗忘的生物系统。有趣的是，多巴胺（DA）在果蝇的学习和遗忘中起着双重作用。虽然学习在过去一直是神经科学的一个主要焦点，但对遗忘的研究仍然是一个有前途的、未被发现的研究领域。我的研究项目的长期目标是阐明调节遗忘的神经生物学，并了解神经元如何决定记忆是保留还是消失。在这个研究项目中，我将使用先进的方法，包括行为记忆分析、神经遗传学、先进的蛋白质组学和体内突触生理学。近期进展和短期目标：在果蝇中，我发现多巴胺神经元在记忆形成和遗忘中都起着至关重要的双重作用。值得注意的是，多巴胺通过两种多巴胺受体不同地调节记忆；通过Dop1R1（R1）形成记忆，并通过Dop1R2（R2）引起遗忘。最近，我开发了一种接近标记蛋白质组学方法来识别参与这些受体的信号系统，并阐明了它们不同的信号网络。此外，最近有研究表明遗忘是通过R2偶联到G蛋白Gaq介导的，但遗忘是否由Gaq下游的典型途径介导，包括内质网细胞器，目前尚不清楚。在接下来的5年里，我和我的受训者将使用多层次的方法和最先进的技术来研究三个短期目标：(I)识别和比较活果蝇原生记忆回路中的R1和R2近端蛋白，（ii）解剖多巴胺受体近端蛋白的记忆相关性，（iii）表征调节R2介导的遗忘的ER Ca2+信号机制。意义：这项研究的核心是阐明信息是如何在大脑中编码、保存和遗忘的。这个问题是理解动物认知的核心，因此也是神经科学研究中一个活跃和关键的领域。这项研究的重点是遗忘的神经生物学，它为一个令人兴奋和新颖的研究领域做出了贡献。使用尖端工具的创新组合，本研究将显著扩展我们对控制多巴胺介导的记忆系统的细胞系统的理解，以及通过重要细胞器内质网的下游信号如何控制记忆存储。从长远来看，这个项目将为未来进一步扩展我们对记忆系统的认识奠定基础的思想和方法。

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.