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.

总结/摘要 这项研究计划旨在描述和理解纹状体多巴胺（DA）信号，特别是在 延髓核（NAc）。NAc DA是动机和奖励相关学习的关键调节器， 药物滥用具有增强NAc DA的共同特性，但我们缺乏关于DA如何增强的明确说明。 信号产生，它们如何被本地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是解决目前DA信号的三个具体方面， 在激烈的辩论中： 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 与背侧区域相比，背侧区域的发展更慢，并且对奖励预测显示出独特的反应特征。 线索我们假设涉及NAc的神经回路产生奖励预测和动机， 更长的时间范围。使用逆行光遗传标记，我们将比较个体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时间地形 奖励期望和反馈。 第二，NAc DA释放传递的信号是否超出了传入DA细胞放电中编码的信号？ 我们发现，改变行为任务的可用奖励会影响大鼠的工作意愿， 改变NAc DA释放，而DA细胞放电没有任何明显变化。我们会调查动机- DA的相关变化反而由局部胆碱能中间神经元塑造。为此，我们将联合收割机结合真实的- 时间DA和ACh测量、选择性药理学试剂和胆碱能神经元的光遗传学标记 细胞 第三，DA释放的增加如何迅速提高动机？这通常被认为涉及到 表达D1 DA受体的NAc输出神经元相对于表达D2 DA受体的NAc输出神经元的放电增强 受体的然而，最近的一些结果表明，这两个群体增加活动，而计算 模型对DA是否能足够快地调节细胞以解释观察到的行为产生了怀疑。 方面的影响.为了解决这个问题，我们将记录识别的NAc D1+和D2+输出神经元的尖峰，同时还 在关键的行为时刻测量和操纵DA。 在每种情况下，我们将利用光学化学传感器的最新技术进步， 我们记录自由移动的老鼠的单个识别神经元放电的能力。我们将使用多个 仔细控制的行为任务，包括一个创新的新迷宫任务，其中大鼠显示权衡 期望的回报和所需的努力之间的关系。这些研究将为我们提供重要的新结果。 了解NAc DA功能，沿着丰富的、可供研究界公开使用的数据集。