Molecular and circuit mechanisms of learning supported by heterogeneous dopaminergic neurons

异质多巴胺能神经元支持的学习分子和电路机制

• 批准号: 10210788
• 负责人: TOSHIHIDE HIGE
• 金额: $ 32.49万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210788
• 关键词: Address; Anatomy; Animals; Architecture; Behavior; Behavioral; Behavioral Assay; Brain; Calcium; Characteristics; Conflict (Psychology); Data; Disease; Dopamine; Drosophila genus; Electrophysiology (science); Engineering; Feedback; Heterogeneity; Image; Individual; Invertebrates; Learning; Logic; Mammals; Measures; Memory; Midbrain structure; Modeling; Molecular; Mushroom Bodies; Neurons; Neuropeptides; Nitric Oxide; Output; Parkinson Disease; Physiological; Play; Population; Property; Public Health; Research; Role; Schizophrenia; Series; Signal Transduction; Stimulus; Study models; Synapses; Synaptic plasticity; System; Testing; Time; Translating; Vertebrates; base; cell type; classical conditioning; connectome data; dopamine system; dopaminergic neuron; fly; in vivo; insight; learning ability; novel; tool; transcriptome

Project Summary/Abstract Dopaminergic neurons (DANs) are a molecularly, anatomically and functionally heterogeneous neuron group that is essential for learning across animal phyla. In the midbrain, distinct populations of DANs are responsible for memories with different valence or stability. Thus, the dopamine system comprises parallel subsystems, each of which operates as a qualitatively distinct learning system. This raises two important questions: 1. How does the heterogeneity of DANs impact synaptic plasticity to form distinct types of memories in each subsystem? 2. How are the signals from parallel subsystems integrated to ultimately trigger a unified behavior? Answers to these questions are required to understand the logic that governs the parallel memory systems. The mushroom body (MB), the major associative learning center in the Drosophila brain, is an excellent model to tackle these questions because it comprises dopamine subsystems, each of which is clearly defined by a unique set of DANs and MB output neurons (MBONs). These individual MB compartments support distinct types of memories that vary in valence and stability, properties shared with mammalian dopamine subsystems. However, in both invertebrate and vertebrate brains, it remains an open question whether the diversity of memory properties is derived from intrinsic characteristics of DANs or from an extrinsic circuit architecture. Aim 1 will test the hypothesis that combinations of DAN cotransmitters define compartment-specific rules of synaptic plasticity and thereby determine the memory properties. By identifying novel DAN cotransmitters and their physiological and behavioral roles, the causal relationship between plasticity rules and memory properties will be tested. In Aim 2, integration mechanisms of different types of memories will be determined by identifying neurons that pool input from multiple MBONs. Synaptic integration, behavioral roles and activity changes after learning will be determined in these integrator neurons. In this project, cell-type-specific transcriptome and the comprehensive connectome data available in the field will guide our molecular and circuit interrogation by in vivo electrophysiology, calcium imaging and behavioral assays. Collectively, this project will address fundamental questions regarding the heterogeneous organization of the dopamine systems and pioneer the circuit motif that is currently inaccessible in vertebrates.

项目概要/摘要 多巴胺能神经元 (DAN) 是分子、解剖学和功能上异质的神经元群 这对于跨动物门的学习至关重要。在中脑中，不同的 DAN 群体负责 对于具有不同价或稳定性的记忆。因此，多巴胺系统包括并行子系统， 每一个都作为一个性质不同的学习系统运行。这就提出了两个重要问题： 1. 如何 DAN 的异质性是否会影响突触可塑性，从而在每个 DAN 中形成不同类型的记忆？ 子系统？ 2. 来自并行子系统的信号如何集成以最终触发统一的行为？ 需要回答这些问题才能理解控制并行存储系统的逻辑。 蘑菇体（MB）是果蝇大脑中主要的联想学习中心，是一个很好的模型 解决这些问题，因为它包含多巴胺子系统，每个子系统都由一个明确定义 独特的 DAN 和 MB 输出神经元 (MBON) 集。这些单独的 MB 隔间支持不同的 不同价态和稳定性的记忆类型，与哺乳动物多巴胺子系统共有的特性。 然而，在无脊椎动物和脊椎动物的大脑中，大脑的多样性是否存在仍然是一个悬而未决的问题。 存储器属性源自 DAN 的内在特性或外在电路架构。目的 1 将检验以下假设：DAN 协同递质的组合定义了隔室特定的规则 突触可塑性，从而决定记忆特性。通过识别新型 DAN 协同递质和 它们的生理和行为作用、可塑性规则和记忆特性之间的因果关系 将受到测试。在目标 2 中，不同类型记忆的整合机制将通过识别来确定 汇集来自多个 MBON 的输入的神经元。突触整合、行为角色和活动变化后 学习将由这些整合神经元决定。在这个项目中，细胞类型特异性转录组和 现场可用的全面连接组数据将指导我们的分子和电路询问 体内电生理学、钙成像和行为测定。总的来说，该项目将解决 有关多巴胺系统异质组织的基本问题，并开创了 目前在脊椎动物中无法访问的电路基序。