Dopaminergic mechanisms for motivation and reinforcement learning

动机和强化学习的多巴胺能机制

基本信息

批准号：
9896798
负责人：
JOSHUA D BERKE
金额：
$ 39.78万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/9896798
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

项目摘要

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.

项目概要/摘要多巴胺是动机行为的关键调节剂。多巴胺也是强化的关键调节剂驱动学习。然而这些关键功能之间的关系尚不清楚。基于开创性的录音头部固定动物的多巴胺细胞，主导理论是多巴胺信号奖励预测错误 - 即学习信号。然而，一再发现多巴胺的实际释放量随着自由移动的动物接近奖励的方式比奖励更符合奖励预测预测错误。此外，多巴胺的光遗传学刺激会立即激发行为，就好像提高奖励预测。该项目旨在解决这种明显的差异，并获得对多巴胺的新认识信号和监管。先前对脑切片的研究已经证实，多巴胺的释放强烈受局部机制的影响，尤其是多巴胺末端的烟碱乙酰胆碱受体。目标1将直接测试多巴胺放电和多巴胺释放之间是否存在分离。腹侧被盖区多巴胺细胞将使用单个神经元的光遗传学识别和纤维光度测定法来评估身体活动，以及将使用快速扫描循环测量伏隔核和壳中的多巴胺末端活性伏安法和纤维光度法。当老鼠执行多种行为任务时将采取这些措施，包括试错强化学习任务和更被动的巴甫洛夫任务，以便更好地进行比较到之前的研究。目标 2 将在同一时间监测和操纵伏隔胆碱能中间神经元行为任务，同时检查多巴胺末端活动。假设这些中间神经元可以两者都塑造了多巴胺释放所传达的激励信息，并迅速将此信息转换为强化学习信号。最后，目标 3 将使用可变时间的局部光遗传学操作多巴胺和伏隔棘神经元亚群（直接与间接）以研究确切的时间多巴胺作为强化学习信号的要求。该研究计划的长期目标是了解自适应决策的电路机制以及尼古丁等药物如何扰乱这些机制以产生成瘾行为。通过使用通过最先进的技术和精心设计的行为任务来测试新颖的假设，该项目可能改变我们对动机行为的神经生物学的理解。