Dopamine Timing-Dependent Plasticity in Reward Learning

奖励学习中多巴胺时间依赖性可塑性

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要/摘要起源于腹侧对段区域（VTA）的中唇多巴胺（DA）系统在基于奖励的学习。 VTA中的DA神经元显示出响应意外初级的阶段性爆发奖励。这种爆发活动的时机转移到反复提示期间的奖励预测提示的开始奖励配对，提示表现需要先于奖励交付以进行有效调理。达神经元爆发产生持续数秒射核（NAC）的阶段DA瞬变，这是一个关键部位为了形成提示 - 奖励记忆。一般而言，被认为是奖励诱发的DA瞬变会促进 HEBBIAN可塑性是由突触前和突触后活动配对（前配对）引起的在调理期间。但是，此假设导致以下难题（称为远端奖励问题）：DA如何通过缓慢的细胞内信号级联反向交流，影响在调节突触可塑性之前进行神经活动之前的结果？在解决这个问题时，它是请注意，在提示奖励调节的早期阶段，向提示爆发的DA神经元会发展出来。这提高了提示引起的瞬态的可能性，而不是通过奖励来推动学习的可能性随着条件的发展，特定的提示奖励关联正在进行中。因此，该项目将探索细胞支持DA瞬变需要先于前配对以调节Hebbian的机制 NAC中的可塑性。胞质Ca2+信号传导取决于细胞内信使肌醇1,4,5-- 三磷酸（IP3）可以充当介导突触可塑性的巧合探测器。中刺影 NAC中的神经元（MSN）包括两个亚群，即D1受体阳性和D2受体阳性 MSN，在奖励驱动的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 IP3-CA2+信号的传导是通过在这两个MSN亚群中进行DA瞬变的。我们假设DA 将增强D1阳性MSN中谷氨酸能传播的长期增强（LTP） LTP或促进长期抑郁（LTD）在D2阳性MSN中通过相反的IP3-CA2+调节信号。将通过改变DA的时间来检查有关可塑性行动的时间规则瞬态是由DA或DA纤维的局部压力射击产生的前配对。这个R21项目的目的是开设一条新的研究线，以解决角色和时机在调节奖励学习基础的突触可塑性方面的阶段性DA信号。