Postsynaptic mechanisms underlying negative prediction error

负预测误差背后的突触后机制

• 批准号: 10682471
• 负责人: Xiaoxi Zhuang
• 金额: $ 19.76万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682471
• 关键词: Address; Adenylate Cyclase; Analysis of Variance; Association Learning; Corpus striatum structure; Cyclic AMP; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor; Dose; Extinction; Food; Incentives; Knockout Mice; Learning; Light; Motivation; Mus; Neurons; Operant Conditioning; Paper; Pathway interactions; Performance; Phase; Property; Psychological reinforcement; Receptor Activation; Rewards; Role; Signal Pathway; Signal Transduction; Synaptic plasticity; Testing; Work; antagonist; cohort; designer receptors exclusively activated by designer drugs; dopamine system; dopaminergic neuron; experience; inhibitor; learning extinction; motor learning; optogenetics; pharmacologic; postsynaptic; prevent; receptor; reinforcer; response; temporal measurement

ABSTRACT The role of the dopamine system in reward has been well established. Whether dopaminergic mechanisms may underlie reinforcement learning or incentive motivation has been a central issue in the field. Evidence that supports the reinforcement learning hypothesis mostly come from recordings of dopamine neuron firing or dopamine release that are often temporally correlated with prediction error. In contrast, causal evidence that supports the incentive motivation hypothesis mostly come from pharmacological manipulations of dopaminergic signaling that often show altered motivation in reward seeking. One study that stands out is Roy Wise’s 1978 study that used dopamine antagonist and unambiguously demonstrated that decreased dopaminergic signaling is sufficient in causing extinction learning. It is often cited as one of the best causal evidence that supports reinforcement learning but not incentive motivation hypothesis. However, a number of questions remain unanswered. Is it dose dependent? Is it receptor specific? Is it post-synaptic signaling pathway specific? Does such manipulation represent negative prediction error? To address these questions, the present application will employ operant conditioning paradigms similar to what’s used in the Wise paper and test the following hypothesis: lack of dopaminergic signaling--> negative prediction error--> lack of dopamine D2 receptor activation-->lack of inhibition of adenylyl cyclase 5 (AC5) --> elevated cAMP in D2 striatal neurons-->extinction learning. In Aim 1, we will use D2 antagonist and use Gs DREADD expressed in D2 striatal neurons to cause extinction (to test sufficiency). We will also use AC5 knockout mice, AC5 inhibitor and Gi DREADD expressed in D2 striatal neurons to prevent extinction (to test necessity). The objective of Aim 1 is to establish that “D2-AC5-cAMP elevation” is indeed necessary and sufficient in causing extinction learning using natural reward. However, those studies will not demonstrate if this pathway is in fact processing the negative prediction error signal in causing extinction learning. Aim 2 studies will use experimentally generated phasic dip in dopamine release to test this hypothesis. In addition, we will use light induced phasic dopamine neuron firing during no reward condition. We will test if such a manipulation will be able to prevent extinction caused by lack of reward.

抽象的 多巴胺系统在奖赏中的作用已经明确。 强化学习或激励动机可能是该领域的一个核心问题。 支持强化学习假设的主要来自多巴胺神经元放电的记录或 相比之下，多巴胺的释放通常与预测误差存在时间相关性。 支持激励动机假说主要来自于药理操作 罗伊的一项研究表明，多巴胺能信号通常会改变寻求奖励的动机。 Wise 1978 年的研究使用多巴胺拮抗剂并明确证明， 多巴胺能信号足以引起消退学习，它经常被认为是最好的因果信号之一。 然而，有一些证据支持强化学习但不支持激励动机假设。 问题仍然没有答案。它是否具有受体特异性？ 这种操纵是否代表了负面的预测误差？ 为了解决这些问题，本申请将采用类似于 Wise 论文中使用了什么并测试以下假设：缺乏多巴胺能信号传导 - > 阴性 预测错误-->缺乏多巴胺 D2 受体激活-->缺乏腺苷酸环化酶 5 (AC5) 抑制--> D2 纹状体神经元中的 cAMP 升高——>消退学习。 在目标1中，我们将使用D2拮抗剂并使用D2纹状体神经元中表达的Gs DREADD来引起 我们还将使用 AC5 敲除小鼠、AC5 抑制剂和 Gi DREADD 表达。 在 D2 纹状体神经元中防止消退（测试必要性）。 目标 1 的目标是确定“D2-AC5-cAMP 升高”确实是必要且充分的 然而，这些研究不会证明这种途径是否有效。 事实上，目标 2 研究将使用处理负预测误差信号。 通过实验产生多巴胺释放的阶段性下降来检验这一假设。此外，我们将使用光。 在无奖励条件下诱导阶段性多巴胺神经元放电我们将测试这种操作是否有效。 能够防止因缺乏奖励而导致的灭绝。