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Mobilization of endocannabinoids by midbrain dopamine neurons is required for the encoding of reward prediction
Nature Communications ( IF 14.7 ) Pub Date : 2023-11-20 , DOI: 10.1038/s41467-023-43131-3
Miguel Á Luján 1 , Dan P Covey 1, 2 , Reana Young-Morrison 1 , LanYuan Zhang 1 , Andrew Kim 1 , Fiorella Morgado 1 , Sachin Patel 3 , Caroline E Bass 4 , Carlos Paladini 5 , Joseph F Cheer 1, 6
Affiliation  

Brain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) from ventral tegmental area (VTA) dopamine cells in adult mice. We find that DGLα deletion from VTA dopamine neurons prevents depolarization-induced suppression of excitation (DSE), a form of 2-AG-mediated synaptic plasticity, in dopamine neurons. DGLα deletion also decreases effortful, cue-driven reward-seeking but has no effect on non-cued or low-effort operant tasks and other behaviors. Moreover, dopamine recording in the NAc reveals that deletion of DGLα impairs the transfer of accumbal dopamine signaling from a reward to its earliest predictors. These results demonstrate that 2-AG mobilization from VTA dopamine neurons is a necessary step for the generation of dopamine-based predictive associations that are required to direct and energize reward-oriented behavior.



中文翻译:


奖励预测的编码需要中脑多巴胺神经元动员内源性大麻素



大脑中内源性大麻素 2-花生四烯酰甘油 (2-AG) 的水平塑造动机行为和伏隔核 (NAc) 多巴胺释放。然而,尚不清楚从中脑多巴胺神经元中特异性调动 2-AG 是否是预测即将到来的奖励对外部刺激的多巴胺能反应所必需的。在这里,我们使用病毒遗传策略来阻止成年小鼠腹侧被盖区 (VTA) 多巴胺细胞表达 2-AG 合成酶二酰甘油脂肪酶 α (DGLα)。我们发现,VTA 多巴胺神经元中的 DGLα 缺失可以防止去极化诱导的兴奋抑制 (DSE),这是多巴胺神经元中 2-AG 介导的突触可塑性的一种形式。 DGLα 缺失也会减少努力的、线索驱动的奖励寻求,但对非线索或低努力的操作任务和其他行为没有影响。此外,NAc 中的多巴胺记录表明,DGLα 的缺失会损害累积多巴胺信号从奖励到其最早预测因子的转移。这些结果表明,VTA 多巴胺神经元的 2-AG 动员是生成基于多巴胺的预测关联的必要步骤,而多巴胺预测关联是指导和激发奖励导向行为所必需的。

更新日期:2023-11-20
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