Dopaminergic mechanisms for motivation and reinforcement learning

动机和强化学习的多巴胺能机制

• 批准号: 10456214
• 负责人: JOSHUA D BERKE
• 金额: $ 39.84万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456214
• 关键词: Acetylcholine; Action Potentials; Adaptive Behaviors; Addictive Behavior; Affect; Animals; Attention; Axon; Behavior; Behavioral; Brain; Cells; Confusion; Corpus striatum structure; Data; Decision Making; Dissociation; Dopamine; Drug Addiction; Electrophysiology (science); Eligibility Determination; Fiber; Goals; Head; Interneurons; Joints; Knock-in; Learning; Measures; Methods; Midbrain structure; Monitor; Motivation; Neurobiology; Neuromodulator; Neurons; Neurotransmitters; Nicotine; Nicotinic Receptors; Pathway interactions; Pattern; Performance; Periodicity; Pharmaceutical Preparations; Photometry; Physiologic pulse; Prosencephalon; Psychological reinforcement; Ramp; Rattus; Regulation; Reporting; Research; Rewards; Role; Scanning; Seminal; Shapes; Signal Transduction; Slice; Synapses; Task Performances; Techniques; Testing; Transgenic Organisms; Work; base; cholinergic; cholinergic neuron; classical conditioning; design; dopaminergic neuron; drug of abuse; motivated behavior; novel; optogenetics; presynaptic; programs; receptor; theories; transmission process

PROJECT SUMMARY/ABSTRACT Dopamine is a key modulator of motivated behavior. Dopamine is also a key modulator of reinforcement- driven learning. Yet the relationship between these critical functions is unclear. Based on seminal recordings of dopamine cells in head-fixed animals, the dominant theory is that dopamine signals reward prediction errors - i.e. a learning signal. However, the actual release of dopamine has been repeatedly found to escalate as freely-moving animals approach rewards, in a manner more consistent with reward prediction than reward prediction errors. Furthermore, optogenetic stimulation of dopamine immediately invigorates behavior, as if boosting reward predictions. This project seeks to resolve this apparent discrepancy, and gain a new understanding of dopamine signaling and regulation. Prior studies in brain slices have established that dopamine release is strongly influenced by local mechanisms, especially nicotinic acetylcholine receptors on dopamine terminals. Aim 1 will directly test whether there is a dissociation between dopamine firing and dopamine release. VTA dopamine cell body activity will be assessed using both optogenetic identification of single neurons, and fiber photometry, and dopamine terminal activity in accumbens core and shell will be measured using both fast-scan cyclic voltammetry and fiber photometry. These measures will be taken as rats perform multiple behavioral tasks, including a trial-and-error reinforcement learning task and a more passive Pavlovian task for better comparison to prior studies. Aim 2 will monitor and manipulate accumbens cholinergic interneurons during the same behavioral tasks, while examining dopamine terminal activity. The hypothesis is that these interneurons can both shape the motivational message conveyed by dopamine release, and rapidly switch this message to a reinforcement learning signal. Finally, Aim 3 will use variably-timed local optogenetic manipulations of dopamine and accumbens spiny neuron subpopulations (direct vs indirect) to investigate the exact timing requirements for dopamine to serve as a reinforcement learning signal. The long-term goal of this research program is to understand circuit mechanisms of adaptive decision- making, and how drugs such as nicotine perturb these mechanisms to produce addictive behavior. By using state-of-the-art techniques and carefully-designed behavioral tasks to test novel hypotheses, this project may transform our understanding of the neurobiology of motivated behavior.

项目摘要/摘要 多巴胺是动机行为的关键调节剂。多巴胺也是加固的关键调节剂 - 驱动的学习。然而，这些关键功能之间的关系尚不清楚。基于开创性记录 头固定动物中的多巴胺细胞，主要理论是多巴胺信号奖励预测误差 - 即学习信号。但是，多巴胺的实际释放已被反复发现升级为 自由移动动物的奖励，以一种与奖励预测更一致的方式而不是奖励 预测错误。此外，多巴胺的光遗传学刺激立即使行为振奋，好像 提高奖励预测。 该项目旨在解决这种明显的差异，并获得对多巴胺的新理解 信号传导和调节。先前在大脑切片中的研究已经确定多巴胺释放强烈 受局部机制，尤其是多巴胺末端上的烟碱乙酰胆碱受体的影响。目标1意志 直接测试多巴胺发射和多巴胺释放之间是否存在解离。 VTA多巴胺细胞 将使用单个神经元和纤维光度法的光遗传学鉴定以及身体活性进行评估 将使用两个快速扫描循环测量伏隔核和外壳中的多巴胺末端活性 伏安法和纤维光度法。这些措施将在大鼠执行多个行为任务时采取 包括反复试验的强化学习任务和更具被动的帕夫洛维亚任务，以更好地比较 进行先前的研究。 AIM 2将在同一过程中监测和操纵伏伏胆碱能中间神经元 行为任务，同时检查多巴胺终端活动。假设是这些中间神经元可以 两者都塑造了多巴胺释放传达的动机信息，并将此消息迅速切换到 加强学习信号。最后，AIM 3将使用各种定时的局部光遗传操作 多巴胺和伏伏丁香刺神经元亚群（直接与间接）研究确切的时机 多巴胺作为增强学习信号的要求。 该研究计划的长期目标是了解适应性决策的电路机制 - 制作以及尼古丁等药物如何扰动这些机制，以产生上瘾的行为。通过使用 最先进的技术和精心设计的行为任务以检验新假设，该项目可能 改变我们对动机行为神经生物学的理解。