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，它涉及多种神经调质的作用。不同的神经调质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回路活动和行为的影响的主要障碍是回路的复杂性和神经调质的冗余受体家族的存在。该项目将通过利用简单的遗传模型生物来解决这些问题，并提供两种主要神经调节剂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学习和记忆的关键机制，通常适用于多个物种的基本理解。该项目还将通过推广计划为公众的STEM教育做出贡献，其中首席研究员将主持K-12教师的夏季实习。此外，美国和以色列的实验室还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。该项目将利用果蝇的嗅觉学习作为研究多种神经调质之间相互作用的平台。集中的大脑区域是蘑菇体（MB），这是昆虫的学习中心。虽然多巴胺已被称为发挥核心作用，在调节嗅觉信号的MB，最近全面的超微结构研究表明，存在丰富的胆碱能神经元之间的互连MB。尽管乙酰胆碱是昆虫脑中主要的兴奋性神经递质，但其G蛋白偶联的毒蕈碱受体在学习和记忆中所起的作用却知之甚少。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。先进的遗传工具，在体内电生理学，双光子功能成像和行为测定将被用来确定如何毒蕈碱受体调节嗅觉反应的MB神经元，以及它们如何影响多巴胺诱导的突触可塑性。由于代谢型谷氨酸受体可以被视为昆虫毒蕈碱受体的哺乳动物对应物，广泛存在于大脑中，并且已知与其他神经调节剂相互作用，因此预计拟议的研究不仅有助于果蝇学习和记忆领域的根本性进展，该奖项反映了NSF的法定使命，并被认为是值得的。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来提供支持。

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.