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Dissecting the dual role of dopamine in context-dependent and learned behaviors

剖析多巴胺在情境依赖性和学习行为中的双重作用

基本信息

批准号：
10376356
负责人：
Vanessa Ruta
金额：
$ 38.99万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376356
关键词：
Acute Address Affinity Animal Testing Animals Architecture Behavior Behavioral Behavioral Paradigm Cells Color Development Disease Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Drosophila genus Drug Addiction Environment Foundations Functional Imaging Functional disorder Future Genetic Individual Knock-out Learning Locomotion Mammals Measures Mental Depression Modeling Molecular Motivation Movement Mushroom Bodies Neuromodulator Neurons Odors Output Parkinsonian Disorders Pathway interactions Patients Pattern Phase Play Population Property Psychological reinforcement Receptor Signaling Rewards Role Schizophrenia Second Messenger Systems Sensory Shapes Signal Pathway Signal Transduction Synapses System Testing Time Translating Work addiction cellular targeting dopaminergic neuron experimental study fly information processing insight interdisciplinary approach knock-down learned behavior motivated behavior motor control motor deficit neuronal circuitry neuropsychiatry neuroregulation novel novel therapeutics optical sensor optogenetics recruit relating to nervous system response sugar virtual

项目摘要

Project Summary Dopamine plays a central role in motivation and reinforcement learning, allowing animals to take advantage of their current circumstances to optimize both present and future behavior. Yet reconciling the diverse roles of dopamine has remained a challenge, in part due to the difficulty of understanding how a single neuromodulator can convey different signals to its cellular targets in distinct behavioral contexts. One prominent model is that different patterns of dopamine release engage distinct molecular pathways in downstream circuits, such that tonic fluctuations in dopamine regulate motivation while phasic bursts of dopamine convey reward prediction errors for learning. However, recent work has suggested that phasic firing patterns can both instruct learning and convey motivational signals that promote movement, challenging this simple dichotomy. Here we propose to use the Drosophila mushroom body as a powerful model to dissect dopamine’s diverse roles in modulating behavior. Recent work from our lab has shown that the same mushroom body dopaminergic neurons (DANs) responsive to rewards that instruct learning also reflect an animal’s purposive actions, underscoring how the dual representation of reward and locomotion is a conserved feature of dopaminergic systems from flies to mammals. Taking advantage of the mushroom body’s simple circuit architecture and unparalleled genetic toolkit, we will build on these observations to reveal how reward and locomotor signals are directly translated to different patterns of dopamine release and engage distinct dopamine receptor signaling cascades to shape circuit processing and behavior. In Aim 1, we will perform multicolor functional imaging as animals navigate in a virtual olfactory environment and reveal how tonic and phasic patterns of DAN activity are propagated to their post- synaptic targets. In Aim 2 we will use a suite of optical sensors to measure dopamine release and dopamine receptor signaling to understand how the same neuromodulator engages different sub-cellular cascades in different behavioral contexts. In Aim 3 we will test how animals use tonic DAN activity to regulate their ongoing behavior. Dysfunction in dopaminergic signaling is at the core of a wide array of neuropsychiatric conditions, from the severe motor deficits of Parkinsonian patients to motivational disorders like depression and drug addiction. By applying a multidisciplinary approach to interrogate the relatively simple dopaminergic circuitry of the fly, we hope to provide an integrative understanding of dopamine’s diverse actions with important implications to understanding neuromodulation in both healthy and diseased states.

项目概要多巴胺在动机和强化学习中发挥着核心作用，使动物能够利用他们当前的情况来优化当前和未来的行为。然而，协调不同的角色多巴胺仍然是一个挑战，部分原因是难以理解单一神经调节剂如何可以在不同的行为环境中向其细胞目标传递不同的信号。一个突出的模型是不同的多巴胺释放模式涉及下游回路中不同的分子途径，例如多巴胺的紧张性波动调节动机，而多巴胺的阶段性爆发则传达奖励预测学习错误。然而，最近的研究表明，阶段性放电模式既可以指导学习，也可以指导学习。传达促进运动的激励信号，挑战这种简单的二分法。这里我们建议使用果蝇蘑菇体作为一个强大的模型来剖析多巴胺在调节行为中的不同作用。我们实验室最近的工作表明，相同的蘑菇体多巴胺能神经元（DAN）响应指导学习的奖励也反映了动物的有目的的行为，强调了双重奖励和运动的表征是从果蝇到哺乳动物的多巴胺能系统的保守特征。利用蘑菇体简单的电路架构和无与伦比的遗传工具包，我们将以这些观察为基础，揭示奖励和运动信号如何直接转化为不同的信号多巴胺释放模式并参与不同的多巴胺受体信号级联来塑造电路处理和行为。在目标 1 中，我们将在动物在虚拟环境中导航时执行多色功能成像嗅觉环境并揭示 DAN 活动的强直和阶段模式如何传播到其后嗅觉突触目标。在目标 2 中，我们将使用一套光学传感器来测量多巴胺释放和多巴胺受体信号传导以了解相同的神经调节剂如何参与不同的亚细胞级联不同的行为背景。在目标 3 中，我们将测试动物如何利用补品 DAN 活性来调节其持续的活动行为。多巴胺能信号传导功能障碍是多种神经精神疾病的核心，从帕金森病患者的严重运动缺陷到抑郁症和药物等动机障碍瘾。通过应用多学科方法来探究相对简单的多巴胺能电路苍蝇，我们希望对多巴胺的多种作用有重要意义的综合理解了解健康和患病状态下的神经调节。