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

学习和记忆是由突触可塑性支持的，突触可塑性涉及多种神经调节剂的作用。不同的神经调节剂通常针对相同的大脑区域和神经元，以协同或拮抗的方式起作用。研究这些相互作用对神经回路活动和行为的影响的主要障碍是神经回路的复杂性和神经调节剂的冗余受体家族的存在。该项目将利用一个简单的遗传模式生物来解决这些问题，并提供两种主要神经调节通路如何相互作用以诱导突触可塑性的机制见解。这项研究的结果将导致对一般适用于多种物种的学习和记忆的关键机制的基本理解。该项目还将通过外展计划为公众的STEM教育做出贡献，其中首席研究员将接待K-12教师进行暑期实习。此外，美国和以色列的实验室将培训本科生和研究生研究人员，并通过两国之间的密切合作促进他们的科学互动。本项目将以果蝇的嗅觉学习为平台，研究多种神经调节剂之间的相互作用。大脑集中的区域是蘑菇体（MB），昆虫的学习中心。虽然已知多巴胺在MB的嗅觉信号调节中起核心作用，但最近全面的超微结构研究表明，MB神经元之间存在丰富的胆碱能相互连接。尽管乙酰胆碱是昆虫大脑中主要的兴奋性神经递质，但人们对其g蛋白偶联的毒蕈碱受体在学习和记忆中的作用知之甚少。本研究的目的是了解多巴胺和乙酰胆碱如何协同作用于同一组神经元以发挥其对学习的影响。复杂的遗传工具、体内电生理学、双光子功能成像和行为分析将被用来确定毒毒碱受体如何调节MB神经元的嗅觉反应，以及它们如何影响多巴胺诱导的突触可塑性。由于代谢性谷氨酸受体可被视为昆虫毒蕈碱受体的哺乳动物对应物，在大脑中广泛存在，并且已知与其他神经调节剂相互作用，因此该研究不仅有望为果蝇学习和记忆领域的基础性进展做出贡献，而且还将为跨大脑区域和物种的神经元可塑性提供一般见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.