Dopaminergic mechanisms for motivation and reinforcement learning

项目总结/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。基于对 大脑固定动物的多巴胺细胞，主流理论是多巴胺信号奖励预测错误- 即学习信号。然而，多巴胺的实际释放一再被发现， 自由移动的动物接近奖励的方式更符合奖励预测，而不是奖励 预测误差。此外，多巴胺的光遗传学刺激立即使行为发生变化，好像 提高奖励预测。 这个项目试图解决这个明显的差异，并获得对多巴胺的新认识 信号和调节。先前在脑切片中的研究已经确定，多巴胺的释放强烈地依赖于脑组织中的多巴胺受体。 受局部机制的影响，特别是多巴胺末梢上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鉴定和纤维光度测定来评估身体活动， 将使用快速扫描循环和快速扫描循环来测量多巴胺核和壳中的多巴胺末端活性。 伏安法和纤维光度法。当大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。 之前的研究。Aim 2将在相同的时间内监测和操纵海马胆碱能中间神经元， 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， 多巴胺和多巴胺棘神经元亚群（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需求。 这项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，从而产生成瘾行为。通过使用 国家的最先进的技术和精心设计的行为任务，以测试新的假设，这个项目可能 改变了我们对动机行为的神经生物学的理解。

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.