Circuit Specificity in the Inhibitory Architecture of the VTA Regulates Behavioral Responses to Cocaine

腹侧被盖区（VTA）的传入输入通过调节多巴胺神经元的活动来控制奖赏相关行为。延髓核（NAc）提供了一个最突出的投射到腹侧被盖区，但最近的研究提供了相互矛盾的证据，这些抑制性输入的功能作用。使用光遗传学，细胞特异性消融，全细胞膜片钳，和免疫电子显微镜，我们表明，NAc输入突触直接到多巴胺神经元，优先激活GABAB受体。我们证明，GABA能输入从NAc和本地腹侧被盖区GABA神经元的差异调制和激活多巴胺神经元内的单独的受体群体。成年小鼠多巴胺神经元GABAB受体的基因缺失不影响一般或吗啡诱导的运动活动，但大大增加可卡因诱导的运动。总的来说，我们的研究结果表明VTA的抑制结构具有显著的选择性，并表明多巴胺神经元的长距离GABA能输入从根本上调节对可卡因的行为反应。

Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA, however recent studies have provided conflicting evidence regarding the functional role of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp, and immuno-electron microscopy, we show that NAc inputs synapse directly onto dopamine neurons, preferentially activating GABAB receptors. We demonstrate that GABAergic inputs from the NAc and local VTA GABA neurons are differentially modulated and activate separate receptor populations within dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but profoundly increased cocaine-induced locomotion. Collectively, our findings demonstrate remarkable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.