Dopaminergic mechanisms for motivation and reinforcement learning

项目摘要/摘要 多巴胺是动机行为的关键调节器。多巴胺也是强化的关键调节器-- 驱动型学习。然而，这些关键功能之间的关系尚不清楚。根据开创性记录 头部固定动物体内的多巴胺细胞，主要的理论是多巴胺信号奖励预测错误- 即学习信号。然而，人们一再发现，多巴胺的实际释放会随着 自由活动的动物以一种更符合奖励预测而不是奖励的方式接近奖励 预测错误。此外，对多巴胺的光遗传刺激会立即激活行为，就好像 提高了奖励预测。 这个项目试图解决这个明显的差异，并对多巴胺有一个新的理解。 信号和调节。先前对脑片的研究已经证实，多巴胺的释放强烈 受局部机制的影响，特别是多巴胺末端的烟碱型乙酰胆碱受体。目标1将 直接测试多巴胺激发和多巴胺释放之间是否存在分离。VTA多巴胺细胞 将使用单个神经元的光遗传鉴定和纤维光度法来评估身体活动，以及 伏隔核和壳中的多巴胺末端活性将使用快速扫描循环 伏安法和纤维光度法。这些措施将在老鼠执行多项行为任务时采取， 包括试错式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。目标2将在同一时间监测和操纵伏核胆碱能中间神经元 行为任务，同时检测多巴胺终末活性。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，并迅速将这一信息转换为 强化学习信号。最后，Aim 3将使用可变时间的局部光遗传操作 多巴胺和伏隔核棘神经元亚群(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。 这项研究计划的长期目标是了解自适应判决的电路机制。 制造，以及尼古丁等药物如何扰乱这些产生成瘾行为的机制。通过使用 最先进的技术和精心设计的行为任务来测试新的假设，这个项目可能 改变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.