Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Neuron. 2020 Sep 9;107(5):864-873.e4. doi: 10.1016/j.neuron.2020.06.011. Epub 2020 Jun 30.
Like ventral tegmental area (VTA) dopamine (DA) neurons, VTA glutamate neuron activity can support positive reinforcement. However, a subset of VTA neurons co-release DA and glutamate, and DA release might be responsible for behavioral reinforcement induced by VTA glutamate neuron activity. To test this, we used optogenetics to stimulate VTA glutamate neurons in which tyrosine hydroxylase (TH), and thus DA biosynthesis, was conditionally ablated using either floxed Th mice or viral-based CRISPR/Cas9. Both approaches led to loss of TH expression in VTA glutamate neurons and loss of DA release from their distal terminals in nucleus accumbens (NAc). Despite loss of the DA signal, optogenetic activation of VTA glutamate cell bodies or axon terminals in NAc was sufficient to support reinforcement. These results suggest that glutamate release from VTA is sufficient to promote reinforcement independent of concomitant DA co-release, establishing a non-DA mechanism by which VTA activity can support reward-seeking behaviors.
就像腹侧被盖区 (VTA) 多巴胺 (DA) 神经元一样，VTA 谷氨酸能神经元的活动可以支持正强化。然而，VTA 神经元的一部分会共同释放 DA 和谷氨酸，并且 DA 的释放可能是由 VTA 谷氨酸能神经元活动引起的行为强化所负责的。为了验证这一点，我们使用光遗传学刺激 VTA 谷氨酸神经元，其中酪氨酸羟化酶 (TH)，从而 DA 生物合成，使用 floxed Th 小鼠或基于病毒的 CRISPR/Cas9 进行条件性缺失。这两种方法都导致 VTA 谷氨酸神经元中 TH 表达的丧失，以及它们在伏隔核 (NAc) 中的远端末梢中 DA 的释放丧失。尽管 DA 信号丢失，但 VTA 谷氨酸细胞体或轴突末梢在 NAc 中的光遗传学激活足以支持强化。这些结果表明，VTA 释放的谷氨酸足以促进强化，而不需要同时释放 DA，这确立了一种非 DA 机制，通过该机制，VTA 活动可以支持寻求奖励的行为。
