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

项目摘要 多巴胺在动机和强化学习中起着核心作用，使动物能够利用 他们目前的情况，以优化目前和未来的行为。然而，协调不同的角色， 多巴胺仍然是一个挑战，部分原因是很难理解一个单一的神经调质 可以在不同的行为环境中向其细胞目标传递不同的信号。一个突出的模式是， 不同的多巴胺释放模式在下游回路中参与不同的分子途径， 多巴胺的紧张性波动调节动机，而多巴胺的阶段性爆发传递奖励预测 学习的错误。然而，最近的研究表明，阶段性放电模式既可以指导学习， 传达促进运动的激励信号，挑战这种简单的二分法。在这里，我们建议使用 果蝇蘑菇体作为一个强有力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，同样的蘑菇体多巴胺能神经元（DAN）反应， 指导学习的奖励也反映了动物的有目的的行为，强调了双重奖励是如何影响动物的行为的。 奖赏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结构和无与伦比的遗传工具包，我们将 在这些观察的基础上，揭示奖励和运动信号是如何直接转化为不同的 多巴胺的释放模式，并参与不同的多巴胺受体信号级联，以形成回路 加工和行为。在目标1中，我们将在动物在虚拟环境中导航时进行脑功能成像。 嗅觉环境，并揭示如何紧张和阶段性模式的DAN活动传播到他们的后- 突触靶点在目标2中，我们将使用一套光学传感器来测量多巴胺的释放和多巴胺 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反应， 不同的行为背景。在目标3中，我们将测试动物如何使用强直性DAN活性来调节其持续的 行为多巴胺能信号传导功能障碍是一系列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， 成瘾通过应用多学科的方法来询问相对简单的多巴胺能回路， 我们希望能对多巴胺的不同作用提供一个综合的理解， 了解健康和疾病状态下的神经调节。

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.