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

NSF-BSF：联想学习下胆碱能和多巴胺能调节的相互作用

• 批准号: 2034783
• 负责人: Toshihide Hige
• 金额: $ 80万
• 依托单位: University of North Carolina at Chapel Hill
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2034783&HistoricalAwards=false
• 关键词: NSF; BSF; Interaction; Cholinergic; Dopaminergic

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.

学习和记忆由突触可塑性支持，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发挥作用。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节剂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，并提供两个主要神经调节途径如何相互作用以诱导突触可塑性的机制见解。这项研究的结果将使人们对普遍适用于多个物种的学习和记忆的关键机制有一个基本的了解。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，并通过各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平台来研究多种神经调节剂之间的相互作用。重点关注的大脑区域是蘑菇体（MB），这是昆虫的学习中心。尽管已知多巴胺在调节 MB 嗅觉信号中发挥核心作用，但最近的综合超微结构研究表明 MB 神经元之间存在丰富的胆碱能互连。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 蛋白偶联毒蕈碱受体在学习和记忆中所起的作用知之甚少。这项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。将采用先进的遗传工具、体内电生理学、双光子功能成像和行为测定来确定毒蕈碱受体如何调节 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。由于代谢型谷氨酸受体（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，因此拟议的研究不仅有望促进果蝇学习和记忆领域的根本进展，而且还可以为跨多个大脑区域和物种的神经元可塑性提供一般性见解。该奖项反映 通过使用基金会的智力价值和更广泛的影响审查标准进行评估，NSF 的法定使命被认为值得支持。

项目成果

Dopamine-Dependent Plasticity Is Heterogeneously Expressed by Presynaptic Calcium Activity across Individual Boutons of the Drosophila Mushroom Body

• DOI: 10.1523/eneuro.0275-23.2023
• 发表时间: 2023-10-01
• 期刊: ENEURO
• 影响因子: 3.4
• 作者: Davidson，Andrew M.;Kaushik，Shivam;Hige，Toshihide
• 通讯作者: Hige，Toshihide

Lateral axonal modulation is required for stimulus-specific olfactory conditioning in Drosophila.

• DOI: 10.1016/j.cub.2022.09.007
• 发表时间: 2022-10-24
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Manoim, Julia E.;Davidson, Andrew M.;Weiss, Shirley;Hige, Toshihide;Parnas, Moshe
• 通讯作者: Parnas, Moshe