Department of Psychology, University of Colorado, Denver, CO, USA.
Neuropsychopharmacology. 2018 Feb;43(3):665-672. doi: 10.1038/npp.2017.235. Epub 2017 Oct 4.
Manipulations that increase dopamine (DA) signaling can enhance fear extinction, but the circuits involved remain unknown. DA neurons originating in the substantia nigra (SN) projecting to the dorsal striatum (DS) are traditionally viewed in the context of motor behavior, but growing data implicate this nigrostriatal circuit in emotion. Here we investigated the role of nigrostriatal DA in fear extinction. Activation of SN DA neurons with designer G-coupled receptors exclusively activated by designer drugs (G-DREADD) during fear extinction had no effect on fear extinction acquisition, but enhanced fear extinction memory and blocked the renewal of fear in a novel context; a pattern of data paralleled by cFos expression in the central amygdala. D1 receptors in the DS are a likely target mediating the effects of SN DA activation. D1-expressing neurons in the medial DS (DMS) were recruited during fear extinction, and G-DREADD-induced DA potentiated activity of D1-expressing neurons in both the DMS and the lateral DS (DLS). Pharmacological activation of D1 receptors in the DS did not impact fear extinction acquisition or memory, but blocked fear renewal in a novel context. These data suggest that activation of SN DA neurons and DS D1 receptors during fear extinction render fear extinction memory resistant to the disrupting effects of changes in contextual contingencies, perhaps by recruiting habitual learning strategies involving the DLS. Nigrostriatal DA thus represents a novel target to enhance long-term efficacy of extinction-based therapies for anxiety and trauma-related disorders.
操纵多巴胺（DA）信号可以增强恐惧消退，但涉及的回路仍不清楚。起源于黑质（SN）并投射到背侧纹状体（DS）的 DA 神经元在传统上被视为运动行为的背景，但越来越多的数据表明该黑质纹状体回路与情绪有关。在这里，我们研究了黑质纹状体 DA 在恐惧消退中的作用。在恐惧消退期间，用专门由设计药物激活的设计型 G 偶联受体（G-DREADD）激活 SN DA 神经元对恐惧消退的获得没有影响，但增强了恐惧消退记忆并阻止了在新环境中恐惧的重现；这一数据模式与中央杏仁核中的 cFos 表达相平行。DS 中的 D1 受体可能是介导 SN DA 激活作用的靶标。在恐惧消退期间，DS 中的内侧 DS（DMS）中的 D1 表达神经元被招募，并且 G-DREADD 诱导的 DA 增强了 DMS 和外侧 DS（DLS）中的 D1 表达神经元的活性。DS 中的 D1 受体的药理学激活对恐惧消退的获得或记忆没有影响，但在新环境中阻止了恐惧的重现。这些数据表明，在恐惧消退期间激活 SN DA 神经元和 DS D1 受体使恐惧消退记忆能够抵抗上下文条件变化的破坏作用，这可能是通过招募涉及 DLS 的习惯学习策略。因此，黑质纹状体 DA 代表了一种增强基于消退的焦虑和创伤相关障碍治疗长期疗效的新靶点。
