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 该研究计划旨在描述和理解纹状体多巴胺（DA）信号，尤其是在 伏隔核（NAC）。 NAC DA是动机和与奖励有关的学习的关键调节者，并且 虐待药物具有增强NAC DA的共同特性。但是我们缺乏清楚的说明 信号出现，如何通过本地NAC电路塑造它们，以及它们如何调节NAC输出影响 行为。我们的下一个资金期的目标介绍了DA信号的三个特定方面 在主动辩论下： 首先，为什么NA​​C DA信号与纹状体其他部分的信号不同？我们发现NAC DA 与背区域相比，发展速度较慢，并显示出对奖励预测的独特响应概况 提示。我们假设涉及NAC的神经回路会产生奖励预测和动力 更长的时间范围。使用逆行光遗传标记，我们将比较单个DA的发射模式 投射到NAC子区域和其他纹状体区域的细胞，测试它们是否定义时间地形 奖励期望和反馈。 其次，NAC DA释放是否传达超出传入DA细胞发射的信号？ 我们表明，改变行为任务的可用奖励会影响大鼠工作意愿，并且 改变了NAC DA的释放，没有任何DA细胞发射的明显变化。我们将调查动机 - 相反，DA的相关变化是由局部胆碱能中间神经元雕刻的。为此，我们将结合实地 时间DA和ACH测量值，选择性药理剂以及胆碱能的光遗传学标记 细胞。 第三，DA释放的增加如何迅速提高动力？通常认为这涉及 相对于表达D2的NAC输出神经元的增强的NAC输出神经元的发射 受体。但是，最近的一些结果表明，两个人群都会增加活动，而计算 模型对DA是否可以足够快地调节细胞以解释观察到的行为有疑问 效果。为了解决此问题，我们将记录已鉴定的NAC D1+和D2+输出神经元的峰值，同时也 在关键的行为时刻测量和操纵DA。 在每种情况下，我们都会利用光学化学传感器的最新技术进步和 我们记录在自由移动大鼠中鉴定出鉴定神经元的发射的能力。我们将使用多个 精心控制的行为任务，包括一项创新的新迷宫任务，其中大鼠表现出权衡 在预期的奖励和所需的努力之间。这些研究将为我们的研究提供至关重要的新结果 了解NAC DA功能，以及针对研究界的丰富，公共可用的数据集。