Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20726-31. doi: 10.1073/pnas.1211258109. Epub 2012 Nov 26.
Temporal control, or how organisms guide movements in time to achieve behavioral goals, depends on dopamine signaling. The medial prefrontal cortex controls many goal-directed behaviors and receives dopaminergic input primarily from the midbrain ventral tegmental area. However, this system has never been linked with temporal control. Here, we test the hypothesis that dopaminergic projections from the ventral tegmental area to the prefrontal cortex influence temporal control. Rodents were trained to perform a fixed-interval timing task with an interval of 20 s. We report several results: first, that decreasing dopaminergic neurotransmission using virally mediated RNA interference of tyrosine hydroxylase impaired temporal control, and second that pharmacological disruption of prefrontal D1 dopamine receptors, but not D2 dopamine receptors, impaired temporal control. We then used optogenetics to specifically and selectively manipulate prefrontal neurons expressing D1 dopamine receptors during fixed-interval timing performance. Selective inhibition of D1-expressing prefrontal neurons impaired fixed-interval timing, whereas stimulation made animals more efficient during task performance. These data provide evidence that ventral tegmental dopaminergic projections to the prefrontal cortex influence temporal control via D1 receptors. The results identify a critical circuit for temporal control of behavior that could serve as a target for the treatment of dopaminergic diseases.
时间控制，即生物体如何在时间上引导运动以实现行为目标，取决于多巴胺信号。内侧前额叶皮层控制着许多目标导向的行为，主要接收来自中脑腹侧被盖区的多巴胺能输入。然而，这个系统从未与时间控制联系起来。在这里，我们测试了这样一个假设，即来自腹侧被盖区的多巴胺能投射到前额叶皮层会影响时间控制。啮齿动物被训练执行一个间隔为 20 秒的固定间隔计时任务。我们报告了几个结果：第一，使用病毒介导的酪氨酸羟化酶 RNA 干扰来减少多巴胺能神经传递会损害时间控制，第二，药理学破坏前额叶 D1 多巴胺受体，但不是 D2 多巴胺受体，会损害时间控制。然后，我们使用光遗传学在执行固定间隔计时任务期间特异性和选择性地操纵表达 D1 多巴胺受体的前额叶神经元。选择性抑制表达 D1 的前额叶神经元会损害固定间隔计时，而刺激会使动物在任务执行过程中更有效率。这些数据提供了证据，表明腹侧被盖区的多巴胺能投射到前额叶皮层通过 D1 受体影响时间控制。该结果确定了行为时间控制的关键回路，可作为治疗多巴胺能疾病的靶点。
