Molecular and circuit mechanisms of learning supported by heterogeneous dopaminergic neurons

项目总结/摘要 多巴胺能神经元（DAN）是一组在分子水平、解剖结构和功能上均具有异质性的神经元 这是跨动物门学习的关键。在中脑，不同的DAN群体负责 不同效价或稳定性的记忆。因此，多巴胺系统包括并行子系统， 其中每一个都作为性质上不同的学习系统来操作。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，从而在每一个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是如何集成的，以最终触发统一的行为？ 需要回答这些问题才能理解管理并行内存系统的逻辑。 果蝇脑中主要的联想学习中心蘑菇体（MB）是一个很好的模型 解决这些问题，因为它包括多巴胺子系统，每个子系统都由一个 一组独特的DAN和MB输出神经元（MBON）。这些单独的MB隔间支持不同的 不同类型的记忆在效价和稳定性，属性与哺乳动物多巴胺子系统共享。 然而，在无脊椎动物和脊椎动物的大脑中， 存储器特性从DAN的固有特性或从外部电路结构导出。目的 1将检验DAN共传递子的组合定义DAN共传递子的区室特异性规则的假设。 突触可塑性，从而决定记忆特性。通过识别新的DAN共递质和 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 会得到考验在目标2中，不同类型记忆的整合机制将通过识别 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 学习将在这些积分器神经元中确定。在这个项目中，细胞类型特异性转录组和 该领域全面的连接体数据将指导我们的分子和电路研究， 体内电生理学、钙成像和行为测定。总的来说，这个项目将解决 关于多巴胺系统的异质组织的基本问题，并开创了 目前在脊椎动物中无法获得的电路基序。

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.