Dopaminergic mechanisms for motivation and reinforcement learning

动机和强化学习的多巴胺能机制

• 批准号: 10660140
• 负责人: JOSHUA D BERKE
• 金额: $ 53.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660140
• 关键词: Address; Adenosine; Affect; Anesthesia procedures; Animals; Area; Axon; Behavior; Behavioral; Brain; Cell physiology; Cells; Chemicals; Cholinergic Receptors; Communities; Computer Models; Corpus striatum structure; Cues; Data; Data Set; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Electrophysiology (science); Feedback; Funding; Future; Goals; Heterogeneity; Individual; Influentials; Interneurons; Label; Lateral; Learning; Measurement; Measures; Medial; Mediating; Methods; Midbrain structure; Monitor; Motivation; Neurons; Nicotinic Receptors; Nucleus Accumbens; Optics; Output; Pathologic; Pattern; Population; Property; Psychological reinforcement; Ramp; Rattus; Research; Rewards; Role; Shapes; Signal Transduction; Slice; Structure; Substance abuse problem; Synaptic plasticity; Testing; Time; Travel; Uncertainty; Update; Ventral Tegmental Area; Work; behavior influence; cholinergic; discount; dopaminergic neuron; drug of abuse; expectation; experimental study; innovation; motivated behavior; neural circuit; novel; optogenetics; pharmacologic; programs; receptor; response; reward anticipation; sensor; theories; willingness

Summary / Abstract This research program seeks to describe and understand striatal dopamine (DA) signals, particularly in the nucleus accumbens (NAc). NAc DA is a key regulator of both motivation and reward-related learning, and drugs of abuse share the common property of enhancing NAc DA. Yet we lack a clear account of how DA signals arise, how they are shaped by local NAc circuits, and how they modulate NAc output to influence behavior. Our Aims for the next funding period address three specific aspects of DA signals that are currently under active debate: First, why are NAc DA signals different to those in other parts of striatum? We found that NAc DA evolves more slowly compared to dorsal areas, and shows a distinct response profile to reward-predictive cues. We hypothesize that neural circuits involving NAc generate reward predictions and motivation over longer time horizons. Using retrograde optogenetic tagging, we will compare the firing patterns of individual DA cells that project to NAc subregions and other striatal areas, testing whether they define a temporal topography of reward expectation and feedback. Second, does NAc DA release convey signals beyond those encoded in the firing of afferent DA cells? We showed that changing the available reward for a behavioral task influences rats' willingness to work, and alters NAc DA release, without any apparent change in DA cell firing. We will investigate whether motivation- related changes in DA are instead sculpted by local cholinergic interneurons. To do this we will combine real- time DA and ACh measurements, selective pharmacological agents, and optogenetic tagging of cholinergic cells. Third, how do increases in DA release rapidly boost motivation? This is generally thought to involve enhanced firing of NAc output neurons that express the D1 DA receptor, relative to those expressing the D2 receptor. However, some recent results suggest that both populations increase activity, while computational models have cast doubt on whether DA can modulate cells quickly enough to explain observed behavioral effects. To resolve this we will record the spiking of identified NAc D1+ and D2+ output neurons, while also measuring and manipulating DA, at key behavioral moments. In each case we will take advantage of recent technical advances in optical chemical sensors, and of our ability to record the firing of individual identified neurons in freely-moving rats. We will use multiple carefully-controlled behavioral tasks, including an innovative new maze task in which rats display a trade-off between expected reward and required effort. Together these studies will provide vital new results for our understanding of NAc DA functions, along with rich, publicly-available data sets for the research community.

摘要/摘要 该研究项目旨在描述和理解纹状体多巴胺 (DA) 信号，特别是 伏隔核 (NAc)。 NAc DA 是动机和奖励相关学习的关键调节器，并且 滥用药物具有增强 NAc DA 的共同特性。然而我们对 DA 如何 信号出现、它们如何由本地 NAc 电路整形，以及它们如何调制 NAc 输出以影响 行为。我们下一个资助期的目标涉及目前发展议程信号的三个具体方面 正在激烈辩论中： 首先，为什么 NAc DA 信号与纹状体其他部分的信号不同？我们发现NAc DA 与背部区域相比，进化速度更慢，并且对奖励预测表现出独特的反应特征 提示。我们假设涉及 NAc 的神经回路会产生奖励预测和动机 更长的时间范围。使用逆行光遗传学标记，我们将比较各个 DA 的放电模式 投射到 NAc 亚区和其他纹状体区域的细胞，测试它们是否定义了颞部地形 奖励期望和反馈。 其次，NAc DA 释放是否传递超出传入 DA 细胞放电中编码的信号？ 我们表明，改变行为任务的可用奖励会影响老鼠的工作意愿，并且 改变 NAc DA 释放，但 DA 细胞放电没有任何明显变化。我们将调查动机是否- DA 的相关变化是由局部胆碱能中间神经元塑造的。为此，我们将结合实际 时间 DA 和 ACh 测量、选择性药物制剂和胆碱能的光遗传学标记 细胞。 第三，DA释放的增加如何快速提升动力？这通常被认为涉及 相对于表达 D2 的神经元，表达 D1 DA 受体的 NAc 输出神经元的放电增强 受体。然而，最近的一些结果表明，这两个群体的活动都增加了，而计算 模型对 DA 是否能够足够快地调节细胞以解释观察到的行为产生了怀疑 影响。为了解决这个问题，我们将记录已识别的 NAc D1+ 和 D2+ 输出神经元的尖峰，同时也 在关键行为时刻测量和操纵 DA。 在每种情况下，我们都将利用光学化学传感器的最新技术进步，以及 我们有能力记录自由活动的老鼠中单个已识别神经元的放电情况。我们将使用多个 精心控制的行为任务，包括一项创新的迷宫任务，其中老鼠表现出权衡 预期回报和所需努力之间。这些研究将为我们提供重要的新结果 了解 NAc DA 功能，以及为研究界提供的丰富的、公开的数据集。