Optogenetic investigations of motivational circuits in rats and mice

先前的研究表明，多巴胺系统的激活和抑制分别引起奖励和厌恶。这些作用通常归因于腹侧被盖区（VTA）和中脑边缘多巴胺系统的多巴胺神经元。另一方面，黑质致密部（SNc）和黑质纹状体系统中的多巴胺神经元通常与运动和认知控制有关，包括刺激-反应关联的学习。在这里，我们发现SNc中多巴胺神经元的兴奋和抑制会引起奖励和厌恶。TH-Cre转基因小鼠将编码通道视紫红质2 （ChR2）、盐视紫红质（NpHR）或无视蛋白的腺相关病毒载体送入VTA或SNc。携带ChR2的小鼠很快学会了对向VTA或SNc传递光线的杠杆做出反应。而且，当激活和不激活杠杆的分配改变时，他们改变了对杠杆的偏好。他们也表现出对同时接受颅内光的隔室的位置偏好。此外，NpHR小鼠避开了同时接收颅内光进入VTA或SNc的隔室，而对照组小鼠则没有。我们的研究结果证实，SNc多巴胺神经元的兴奋和抑制与VTA多巴胺神经元相似，可以诱导奖励和厌恶。目前的数据挑战了情感过程由VTA的多巴胺神经元介导而不是SNc的二分概念，并表明黑质纹状体投射在动机和情感中的作用。因此，SNc多巴胺神经元可能在药物成瘾（如渴望）和帕金森患者（即抑郁、快感缺乏和冷漠）的动机和情感方面发挥作用。

Previous studies show that activation and suppression of dopamine systems elicit reward and aversion respectively. These effects are usually attributed to dopamine neurons in the ventral tegmental area (VTA) and the mesolimbic dopamine system. On the other hand, dopamine neurons in the substantia nigra pars compacta (SNc) and the nigrostriatal system often linked with motor and cognitive control, including the learning of stimulus-response associations. Here we show that excitation and inhibition of dopamine neurons in the SNc elicit reward and aversion. TH-Cre transgenic mice received adeno-associated viral vectors encoding channelrhodopsin2 (ChR2), halorhodopsin (NpHR), or no opsin into the VTA or SNc. Mice with ChR2 quickly learned to respond on the lever that delivered light into the VTA or SNc. And, when the assignment of active and inactive levers was changed, they shifted their lever preference. They also showed place preference to the compartment in which they concurrently received intracranial light. In addition, mice with NpHR avoided the compartment in which they concurrently received intracranial light into the VTA or SNc, while control mice did not. Our findings confirm that the excitation and inhibition of SNc dopamine neurons induces reward and aversion similar to the VTA dopamine neurons. The present data challenge the dichotomous notion that affective processes are mediated by dopamine neurons in the VTA, but not SNc and suggest the role of nigrostriatal projections in motivation and affect. Therefore, SNc dopamine neurons may play motivational and affective aspects of drug addiction such as craving and those of Parkinsons patients (i.e., depression, anhedonia, and apathy).