Task Representations in Ventral Tegmental Area Dopamine Neurons across Shifts in Behavioral Strategy and Reward Expectation

摘要 最佳决策需要在稳定性和灵活性之间取得微妙的平衡。一方面，稳定是 需要利用环境特征、工具行动和目标之间的已学或有事件。在……上面 另一方面，当突发事件发生变化时，需要灵活地获取新的行为策略。 腹侧被盖区(VTA)的多巴胺(DA)神经元被认为是 这种平衡。与DA功能障碍相关的疾病--最明显的是精神分裂症、帕金森氏症和 亨廷顿氏病--严重扰乱需要行为灵活性的任务的执行，例如 威斯康星州卡片分类测试，通常通过增加跟踪先前学到的 不再相关的功能。许多动物研究也直接表明DA具有 转变策略，在重要投影中使用药物干预、DA耗竭和微透析 VTADA神经元的靶点。此外，VTADA刺激既可以促进维持，也可以促进重组 行为策略取决于它是在时间上模仿主音模式还是阶段模式。然而， 关于内源性神经活动模式是获得一种新策略的基础，人们知之甚少 部分是因为它在大脑深处的解剖位置使VTA无法被大规模接触到 在行为过程中录制。我们已经为老鼠开发了一个需要策略的决策范例 移动，可以在双光子显微镜下进行，允许使用最先进的深部大脑 以细胞分辨率同时监测VTADA活动的成像技术。在这项任务中，受试者 在虚拟现实环境中导航T形迷宫。奖励地点由以下两条规则之一确定： 由视觉空间线索引导的感觉规则，或由先前选择引导的交替规则。在首字母之后 在一个规则的训练中，受试者被要求进行规则转换，以强制获得一种新的策略。 最近在VTADA群体中发现了不同类型的任务-特征表示-这一发现 与VTADA广播全球奖励预测误差信号的标准观点相矛盾-这启发了我们 使用此范例来测试一个有趣的假设：RPE以多个特定于功能的形式表示 组件-而不是作为全局信号-并且VTADA种群的子集跟踪特定的特征 根据它们与当前任务战略的相关性。因此，本提案中概述的研究计划将 允许在行为策略转变期间首次表征内源性VTADA活性，这可能会有所帮助 阐明DA与强化学习理论之间的联系。预计结果将产生广泛的影响 与决策的相关性，并可能揭示将多巴胺功能障碍与缺陷联系起来的特定机制 在灵活性方面。

ABSTRACT Optimal decision-making requires a delicate balance of stability and flexibility. On the one hand, stability is required to exploit learned contingencies between environmental features, instrumental actions, and goals. On the other, flexibility is required for the acquisition of a new behavioral strategy when the contingencies change. Dopamine (DA) neurons of the ventral tegmental area (VTA) have been implicated as important regulators of this balance. Conditions associated with DA dysfunction–most notably schizophrenia, Parkinson’s, and Huntington’s disease–profoundly disrupt performance on tasks requiring behavioral flexibility, such as the Wisconsin Card Sorting Test, typically by increasing “perseverative” responses that track a previously learned feature that is no longer relevant. Numerous animal studies have also directly implicated DA in the capacity to shift strategies, using pharmacological interventions, DA depletion, and microdialysis in important projection targets of VTADA neurons. Moreover, VTADA stimulation can promote either the maintenance or reorganization of behavioral strategy depending on whether it is timed to mimic tonic or phasic modes of firing. However, little is known about the endogenous neural activity patterns that underlie the acquisition of a new strategy–in part, because its anatomical location deep within the brain has kept the VTA inaccessible to large-scale recording during behavior. We have developed a decision making paradigm for mice that requires a strategy shift and can be performed under a two-photon microscope, allowing the use of state-of-the-art deep-brain imaging techniques to simultaneously monitor VTADA activity at cellular resolution. In this task, subjects navigate a T-maze within a virtual reality environment. The reward location is determined by one of two rules: a sensory rule guided by visuospatial cues, or an alternation rule guided by the previous choice. After initial training on one rule, subjects are challenged with a rule shift that enforces the acquisition of a new strategy. The recent discovery of heterogeneous task-feature representations within the VTADA population–a finding that contradicts the standard view that VTADA broadcasts a global reward prediction error signal–has inspired us to use this paradigm to test an intriguing hypothesis: that the RPE is represented in multiple feature-specific components–rather than as a global signal–and that subsets of the VTADA population track specific features based on their relevance to the current task strategy. Thus, the research plan outlined in this proposal will allow the first characterization of endogenous VTADA activity during a shift in behavioral strategy, and may help to clarify the link between DA and theories of reinforcement learning. The results are expected to have broad relevance to decision-making, and may uncover specific mechanisms that link dopamine dysfunction to deficits in flexibility.