Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
Pain. 2018 Jan;159(1):175. doi: 10.1097/j.pain.0000000000001083.
Increasing evidence suggests that the mesolimbic reward system plays critical roles in the regulation of depression and nociception; however, its circuitry and cellular mechanisms remain unclear. In this study, we investigated the output-specific regulatory roles of dopaminergic (DA) neurons within the ventral tegmental area (VTA) in depressive-like and nociceptive behaviors in mice subjected to unpredictable chronic mild stress (CMS), using the projection-specific electrophysiological recording, pharmacological manipulation, behavioral test, and molecular biology technologies. We demonstrated that CMS decreased the firing activity in VTA projecting to medial prefrontal cortex (VTA → mPFC), but not in VTA to nucleus accumbens (VTA → NAc), DA neurons. However, both VTA → mPFC and VTA → NAc DA neurons showed increased firing activity in response to morphine perfusion in CMS mice. Behavioral results showed that intra-VTA microinjection of morphine (25.5 ng/0.15 μL) relieved depressive-like behaviors, intriguingly, accompanied by a thermal hyperalgesia. Furthermore, the relief of depressive-like behaviors induced by intra-VTA injection of morphine in CMS mice could be prevented by blocking brain-derived neurotrophic factor (BDNF) signaling and mimicked by the administration of exogenous BDNF in mPFC rather than in NAc shell. Nociceptive responses induced by the activation of VTA DA neurons with morphine in CMS mice could be prevented by blocking BDNF signaling or mimicked by administration of exogenous BDNF in NAc shell, but not in mPFC. These results reveal projection-specific regulatory mechanisms of depression and nociception in the mesolimbic reward circuitry and provide new insights into the neural circuits involved in the processing of depressive and nociceptive information.
越来越多的证据表明，中脑边缘奖赏系统在调节抑郁和痛觉中起着关键作用；然而，其回路和细胞机制仍不清楚。在这项研究中，我们使用投射特异性电生理记录、药理学操作、行为测试和分子生物学技术，研究了腹侧被盖区（VTA）多巴胺能（DA）神经元在经历不可预测的慢性轻度应激（CMS）的小鼠的抑郁样和痛觉行为中的输出特异性调节作用。我们证明，CMS 降低了投射到内侧前额叶皮质（VTA→mPFC）的 VTA 神经元，但不降低投射到伏隔核（VTA→NAc）的 VTA 神经元的放电活动。然而，在 CMS 小鼠中，VTA→mPFC 和 VTA→NAc 的 DA 神经元对吗啡灌注的反应均表现出放电活动增加。行为学结果表明，VTA 内微量注射吗啡（25.5ng/0.15μL）缓解了抑郁样行为，令人惊讶的是，还伴随着热痛觉过敏。此外，VTA 内注射吗啡缓解 CMS 小鼠的抑郁样行为可以被阻断脑源性神经营养因子（BDNF）信号所阻止，而在 mPFC 而非 NAc 壳内给予外源性 BDNF 可以模拟这种作用。在 CMS 小鼠中，用吗啡激活 VTA DA 神经元引起的痛觉反应可以通过阻断 BDNF 信号或在 NAc 壳内给予外源性 BDNF 来模拟，但在 mPFC 内给予外源性 BDNF 则不能模拟。这些结果揭示了中脑边缘奖赏回路中抑郁和痛觉的投射特异性调节机制，并为参与处理抑郁和痛觉信息的神经回路提供了新的见解。
