The Mesolimbic Dopamine Activity Signatures of Relapse to Alcohol-Seeking
The Mesolimbic Dopamine Activity Signatures of Relapse to Alcohol-Seeking
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DOI：
10.1523/jneurosci.0724-20.2020
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发表时间：
2020-08-12
影响因子：
5.3
通讯作者：
McNally, Gavan P.
中科院分区：
文献类型：
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作者：
Liu, Yu;Jean-Richard-dit-Bressel, Philip;McNally, Gavan P.
中脑边缘多巴胺系统由不同的隔室组成，支持不同的学习和运动功能。不太清楚的是，复杂的上瘾相关行为是如何从这些部分的活动模式中出现的。在这里，我们展示了雄性大鼠不同形式的酒精依赖复发是如何通过VTA和伏隔核的活动组装起来的。首先，我们使用化学遗传学方法显示了VTA TH神经元在两种形式的酒精依赖复发中的因果作用：更新(上下文诱导的恢复)和重新获得。然后，利用VTA TH神经元的GCaMP纤维光度法，我们确定了VTA TH神经元在自我给药、更新和再获得过程中的内侧和外侧的活动谱。接下来，我们使用VTA TH神经元的光遗传抑制来显示VTA亚区在不同形式的复发中的不同因果作用。然后，我们用dLight光纤分光光度法测量了多巴胺在腹侧纹状体(内侧伏隔壳、伏隔核、外侧伏隔壳)的结合，显示了自我给药和复发过程中复杂而不同种类的多巴胺结合曲线。最后，我们使用代表性相似性分析来识别自我管理、灭绝和复发的中脑边缘多巴胺信号。我们的结果表明，可以从中脑边缘多巴胺系统的不同活动谱中识别出复发的特征，并且这些特征对于不同形式的复发是独特的。
The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motiva-tion. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compart-ments. Here we show how different forms of relapse to alcohol-seeking in male rats are assembled from activity across the VTA and the nucleus accumbens. First, we used chemogenetic approaches to show a causal role for VTA TH neurons in two forms of relapse to alcohol-seeking: renewal (context-induced reinstatement) and reacquisition. Then, using gCaMP fiber pho-tometry of VTA TH neurons, we identified medial and lateral VTA TH neuron activity profiles during self-administration, renewal, and reacquisition. Next, we used optogenetic inhibition of VTA TH neurons to show distinct causal roles for VTA subregions in distinct forms of relapse. We then used dLight fiber photometry to measure dopamine binding across the ven-tral striatum (medial accumbens shell, accumbens core, lateral accumbens shell) and showed complex and heterogeneous pro-files of dopamine binding during self-administration and relapse. Finally, we used representational similarity analysis to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. Our results show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signa-tures are unique for different forms of relapse.