Center for Neuroscience and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University School of Medicine, Hangzhou 310058, China.
CAS Center for Excellence in Brain Science, Chinese Academy of Sciences, Wuhan Institute of Physics and Mathematics, Wuhan 430071, China.
Neuron. 2019 Feb 20;101(4):748-761.e5. doi: 10.1016/j.neuron.2018.12.012. Epub 2019 Jan 10.
Both the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) are involved in affective control and reward-related behaviors. Moreover, the neuronal activities of the VTA and DRN are modulated by opioids. However, the precise circuits from the VTA to DRN and how opioids modulate these circuits remain unknown. Here, we found that neurons projecting from the VTA to DRN are primarily GABAergic. Rostral VTA (rVTA) GABAergic neurons preferentially innervate DRN GABAergic neurons, thus disinhibiting DRN serotonergic neurons. Optogenetic activation of this circuit induces aversion. In contrast, caudal VTA (cVTA) GABAergic neurons mainly target DRN serotonergic neurons, and activation of this circuit promotes reward. Importantly, μ-opioid receptors (MOPs) are selectively expressed at rVTA→DRN GABAergic synapses, and morphine depresses the synaptic transmission. Chronically elevating the activity of the rVTA→DRN pathway specifically interrupts morphine-induced conditioned place preference. This opioid-modulated inhibitory circuit may yield insights into morphine reward and dependence pathogenesis.
腹侧被盖区 (VTA) 和中缝背核 (DRN) 均参与情感控制和与奖励相关的行为。此外，VTA 和 DRN 的神经元活动受阿片类物质调节。然而，VTA 到 DRN 的精确回路以及阿片类物质如何调节这些回路仍不清楚。在这里，我们发现，投射到 DRN 的 VTA 神经元主要是 GABA 能神经元。腹侧被盖区（rVTA）GABA 能神经元优先支配 DRN GABA 能神经元，从而抑制 DRN 5-羟色胺能神经元。该回路的光遗传学激活会引起厌恶。相比之下，尾侧 VTA（cVTA）GABA 能神经元主要靶向 DRN 5-羟色胺能神经元，激活该回路可促进奖励。重要的是，μ-阿片受体（MOPs）选择性地表达在 rVTA→DRN GABA 能突触上，而吗啡抑制突触传递。慢性增加 rVTA→DRN 通路的活性可特异性阻断吗啡诱导的条件性位置偏好。这种阿片类物质调制的抑制性回路可能为吗啡奖赏和依赖的发病机制提供线索。
