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

腹侧被盖区多巴胺神经元的任务表征跨越行为策略和奖励期望的转变

• 批准号: 10679825
• 负责人: Michael James Siniscalchi
• 金额: $ 6.95万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679825
• 关键词: Anatomy; Animal Model; Animals; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Brain; Brain imaging; Complex; Contralateral; Cues; Decision Making; Dependence; Dimensions; Dopamine; Equilibrium; Event; Functional disorder; Goals; Heterogeneity; Huntington Disease; Image; Imaging Techniques; Individual Differences; Intervention; Learning; Link; Location; Maintenance; Microdialysis; Microscope; Modeling; Monitor; Motor; Mus; Neuromodulator; Neurons; Outcome; Parkinson Disease; Pattern; Performance; Phase; Population; Positioning Attribute; Psychological reinforcement; Research; Resolution; Rewards; Role; Schizophrenia; Sensory; Signal Transduction; Sorting; Testing; Training; Ventral Tegmental Area; Visuospatial; Wisconsin; arm; dopaminergic neuron; expectation; flexibility; human model; kinematics; learning algorithm; neural; neurotransmission; novel; pharmacologic; response; reward expectancy; sensory stimulus; theories; two-photon; virtual; virtual reality; virtual reality environment

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.

抽象的 最佳决策需要稳定性和灵活性之间的微妙平衡，一方面，稳定性是关键。 需要利用环境特征、工具行动和目标之间习得的偶发事件。 另一方面，当突发事件发生变化时，需要灵活性来获取新的行为策略。 腹侧被盖区 (VTA) 的多巴胺 (DA) 神经元被认为是重要的调节因子 这种平衡与 DA 功能障碍相关——最明显的是精神分裂症、帕金森病和 亨廷顿病——严重影响需要行为灵活性的任务的表现，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内容的“持久”反应 许多动物研究也直接暗示了 DA 的能力。 转变策略，在重要预测中使用药物干预、DA 消耗和微透析 此外，VTADA 刺激可以促进维持或重组。 行为策略取决于是否定时模仿紧张或阶段性放电模式。 人们对新策略习得背后的内源性神经活动模式知之甚少—— 部分原因是它的解剖位置位于大脑深处，使得 VTA 无法大规模接触到 我们为小鼠开发了一种需要策略的决策范例。 位移，可以在双光子显微镜下进行，允许使用最先进的深脑 成像技术以细胞分辨率同时监测 VTADA 活动。 在虚拟现实环境中导航 T 型迷宫，奖励位置由以下两个规则之一确定： 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。 在针对一条规则进行培训时，受试者会面临规则转变的挑战，从而强制获得新的策略。 最近在 VTADA 群体中发现了异构任务特征表示——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——启发我们 使用这个范式来测试一个有趣的假设：RPE 以多个特定特征表示 组成部分——而不是作为全局信号——并且 VTADA 群体的子集跟踪特定特征 因此，本提案中概述的研究计划将基于它们与当前任务策略的相关性。 允许在行为策略转变期间首次表征内源性 VTADA 活性，并且可能有助于 阐明 DA 和强化学习理论之间的联系，预计结果将具有广泛的意义。 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具体机制 在灵活性方面。