Postsynaptic mechanisms underlying negative prediction error

摘要 多巴胺系统在奖赏中的作用已经得到了很好的证实。多巴胺能机制是否 强化学习或激励动机可能是该领域的一个中心问题。有证据表明 支持强化学习假说的大部分来自多巴胺神经元放电或 多巴胺的释放通常与预测误差在时间上相关。相比之下，因果证据表明 支持激励动机假说的大部分来自于对 多巴胺能信号，通常在寻求奖赏时表现出改变的动机。一项引人注目的研究是罗伊 Wise在1978年的研究中使用了多巴胺拮抗剂，并明确地表明 多巴胺能信号足以引起消亡学习。它经常被认为是最好的因果关系之一 支持强化学习但不支持激励动机假说的证据。然而，一些人 问题仍然没有得到回答。它是剂量依赖的吗？它是受体特异性的吗？是突触后信号吗 特定的路径？这种操纵是否代表了负预测误差？ 为了解决这些问题，本申请将使用类似于 怀斯的论文中使用了什么，并检验了以下假设：缺乏多巴胺能信号--&gt；阴性 预测错误--&GT；缺乏多巴胺D2受体激活--&GT；缺乏对腺苷环化酶5(AC5)的抑制--&GT； D2纹状体神经元中cAMP升高--&gt；消退学习。 在目标1中，我们将使用D2拮抗剂，并使用D2纹状体神经元表达的Gs DREADD来引起 灭绝(以测试充分性)。我们还将使用AC5基因敲除小鼠、AC5抑制剂和GI DREADD表达 在D2纹状体神经元中防止消亡(以测试必要性)。 目标1的目标是确定“D2-AC5-营地提升”在#年确实是必要和充分的。 使用自然奖赏导致灭绝学习。然而，这些研究不会证明这条途径是否 事实上，在引起消退学习中处理负预测误差信号。AIM 2研究将使用 实验产生的多巴胺释放的阶段性下降来验证这一假说。此外，我们将使用光 在无奖赏条件下诱导时相多巴胺神经元放电。我们将测试这样的操纵是否会 能够防止因缺乏奖励而导致的灭绝。

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.