Dopamine Timing-Dependent Plasticity in Reward Learning

奖励学习中多巴胺时间依赖性可塑性

• 批准号: 9904760
• 负责人: HITOSHI MORIKAWA
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904760
• 关键词: ADORA2A gene; Action Potentials; Address; Agonist; Area; Behavior; Brain; Corpus striatum structure; Coupled; Cues; Cytosol; DRD2 gene; Data; Dependence; Distal; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Etiology; Evoked Potentials; Fiber; Fluorescence; GTP-Binding Proteins; Generations; Glutamates; Goals; Inositol; Label; Learning; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Mental Depression; Metabotropic Glutamate Receptors; Mus; Neurons; Nucleus Accumbens; Pharmacology; Phase; Play; Preventive; Protocols documentation; Receptor Activation; Regulation; Reporting; Research; Rewards; Role; Schizophrenia; Signal Transduction; Site; Specificity; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Training; Transgenic Mice; Ventral Tegmental Area; Wild Type Mouse; addiction; base; blind; conditioning; design; detector; dopaminergic neuron; experimental study; insight; mesolimbic system; neurobiological mechanism; neuropsychiatry; novel; optogenetics; postsynaptic; pressure; presynaptic; prevent; public health relevance; receptor; relating to nervous system; response; selective expression; transmission process; tripolyphosphate

Project Summary/Abstract The mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) plays a critical role in reward-based learning. DA neurons in the VTA display phasic burst firing in response to unexpected primary rewards. The timing of this bursting activity shifts to the onset of reward-predicting cues during repeated cue- reward pairing, where cue presentation needs to precede reward delivery for effective conditioning. DA neuron bursting gives rise to phasic DA transients lasting several seconds in the nucleus accumbens (NAc), a key site for the formation of cue-reward memory. In general, reward-evoked DA transients are thought to promote Hebbian plasticity induced by coordinated pairing of presynaptic and postsynaptic activities (pre-post pairing) during conditioning. However, this assumption leads to the following conundrum (known as the distal reward problem): how can DA, which communicates via slow intracellular signaling cascades, influence the consequence of preceding neural activities to regulate synaptic plasticity? In addressing this question, it is of note that DA neuron bursting to the cue develops during the early phase of cue-reward conditioning. This raises the possibility that DA transients elicited by the cue, not by the reward, may act to drive the learning of specific cue-reward associations as conditioning progresses. Thus, this project will explore the cellular mechanisms supporting the idea that DA transients need to precede the pre-post pairing to regulate Hebbian plasticity in the NAc. Cytosolic Ca2+ signaling dependent on the intracellular messenger inositol 1,4,5- triphosphate (IP3) can act as a coincidence detector to mediate synaptic plasticity. Medium spiny projection neurons (MSNs) in the NAc comprise two subpopulations, i.e., D1 receptor-positive and D2 receptor-positive MSNs, that play opposing roles in reward-driven behavior. Our recent study has reported differential regulation of IP3-Ca2+ signaling by preceding DA transients in these two MSN subpopulations. We hypothesize that DA will enhance long-term potentiation (LTP) of glutamatergic transmission in D1-positive MSNs while preventing LTP, or promoting long-term depression (LTD), in D2-positive MSNs through opposing regulation of IP3-Ca2+ signaling. Temporal rules governing DA action on plasticity will be examined by varying the timing of DA transients, produced by local pressure ejection of DA or optogenetic stimulation of DA fibers, relative to the pre-post pairing. The goal of this R21 project is to open a new line of research addressing the role and timing of phasic DA signals in regulating synaptic plasticity underlying reward learning.

项目概要/摘要 起源于腹侧被盖区（VTA）的中脑边缘多巴胺（DA）系统在 基于奖励的学习。 VTA 中的 DA 神经元表现出阶段性爆发放电，以响应意外的初级反应 奖励。这种突发活动的时间转移到重复提示期间奖励预测提示的出现。 奖励配对，提示呈现需要先于奖励传递，以实现有效调节。多巴胺神经元 爆发会在伏隔核 (NAc)（一个关键部位）中产生持续数秒的相位 DA 瞬变 促进提示奖励记忆的形成。一般来说，奖赏诱发的 DA 瞬变被认为可以促进 突触前和突触后活动协调配对（前后配对）诱导的赫布可塑性 调理期间。然而，这种假设会导致以下难题（称为远端奖励） 问题）：通过缓慢的细胞内信号级联进行通信的 DA 如何影响 先前神经活动调节突触可塑性的结果？在回答这个问题时，它是 请注意，DA 神经元对提示的爆发是在提示奖励调节的早期阶段发展的。这 提出了一种可能性，即由提示而不是奖励引起的 DA 瞬变可能会推动学习 随着条件反射的进展，特定的提示-奖励关联。因此，该项目将探索蜂窝 支持以下观点的机制：DA 瞬变需要先于前后配对来调节 Hebbian NAc 中的可塑性。胞浆 Ca2+ 信号传导依赖于细胞内信使肌醇 1,4,5- 三磷酸盐（IP3）可以充当重合检测器来介导突触可塑性。中等刺状突起 NAc 中的神经元 (MSN) 包含两个亚群，即 D1 受体阳性和 D2 受体阳性 MSN 在奖励驱动行为中扮演着相反的角色。我们最近的研究报告了差异调节 这两个 MSN 亚群中先前的 DA 瞬变对 IP3-Ca2+ 信号传导的影响。我们假设 DA 将增强 D1 阳性 MSN 中谷氨酸能传递的长时程增强 (LTP)，同时防止 通过 IP3-Ca2+ 的反向调节，在 D2 阳性 MSN 中促进 LTP 或促进长期抑郁 (LTD) 发信号。将通过改变 DA 的时间安排来审查管理 DA 对可塑性行动的时间规则 瞬变，由 DA 的局部压力喷射或 DA 纤维的光遗传学刺激产生，相对于 前后配对。 R21 项目的目标是开辟一条新的研究路线，解决角色和时间安排问题 阶段性 DA 信号在调节奖励学习的突触可塑性中的作用。