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.

与腹侧被盖区 (VTA) 多巴胺 (DA) 神经元一样，VTA 谷氨酸神经元活动可以支持正强化。然而，VTA 神经元的一个子集共同释放 DA 和谷氨酸，而 DA 的释放可能是 VTA 谷氨酸神经元活动诱导的行为强化的原因。为了测试这一点，我们使用光遗传学来刺激 VTA 谷氨酸神经元，其中酪氨酸羟化酶 (TH) 和 DA 生物合成被有条件地使用 floxed Th小鼠或基于病毒的 CRISPR/Cas9。这两种方法都导致 VTA 谷氨酸神经元中 TH 表达的丧失和伏隔核 (NAc) 中 DA 从其远端末端释放的丧失。尽管 DA 信号丢失，但 NAc 中 VTA 谷氨酸细胞体或轴突末端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，而与伴随的 DA 共同释放无关，从而建立了一种非 DA 机制，VTA 活动可以通过该机制支持寻奖行为。