Liu Di, Tang Qian-Qian, Wang Di, Song Su-Pei, Yang Xiao-Na, Hu Su-Wan, Wang Zhi-Yong, Xu Zheng, Liu He, Yang Jun-Xia, Montgomery Sarah E, Zhang Hongxing, Han Ming-Hu, Ding Hai-Lei, Cao Jun-Li
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
Neuropsychopharmacology. 2020 Aug;45(9):1557-1566. doi: 10.1038/s41386-020-0713-0. Epub 2020 May 19.
Lithium has been used to treat major depressive disorder, yet the neural circuit mechanisms underlying this therapeutic effect remain unknown. Here, we demonstrated that the ventral tegmental area (VTA) dopamine (DA) neurons that project to the medial prefrontal cortex (mPFC), but not to nucleus accumbens (NAc), contributed to the antidepressive-like effects of lithium. Projection-specific electrophysiological recordings revealed that high concentrations of lithium increased firing rates in mPFC-, but not NAc-, projecting VTA DA neurons in mice treated with chronic unpredictable mild stress (CMS). In parallel, chronic administration of high-dose lithium in CMS mice restored the firing properties of mPFC-projecting DA neurons, and also rescued CMS-induced depressive-like behaviors. Nevertheless, chronic lithium treatment was insufficient to change the basal firing rates in NAc-projecting VTA DA neurons. Furthermore, chemogenetic activation of mPFC-, but not NAc-, projecting VTA DA neurons mimicked the antidepressive-like effects of lithium in CMS mice. Chemogenetic downregulation of VTA-mPFC DA neurons' firing activity abolished the antidepressive-like effects of lithium in CMS mice. Finally, we found that the antidepressant-like effects induced by high-dose lithium were mediated by BNDF signaling in the mesocortical DA circuit. Together, these results demonstrated the role of mesocortical DA projection in antidepressive-like effects of lithium and established a circuit foundation for lithium-based antidepressive treatment.
锂已被用于治疗重度抑郁症，但其治疗效果背后的神经回路机制仍不清楚。在此，我们证明，投射到内侧前额叶皮质（mPFC）而非伏隔核（NAc）的腹侧被盖区（VTA）多巴胺（DA）神经元，对锂的抗抑郁样作用有贡献。投射特异性电生理记录显示，在慢性不可预测轻度应激（CMS）处理的小鼠中，高浓度锂增加了投射到mPFC而非NAc的VTA DA神经元的放电频率。同时，在CMS小鼠中长期给予高剂量锂可恢复投射到mPFC的DA神经元的放电特性，并挽救CMS诱导的抑郁样行为。然而，慢性锂治疗不足以改变投射到NAc的VTA DA神经元的基础放电频率。此外，化学遗传学激活投射到mPFC而非NAc的VTA DA神经元可模拟锂在CMS小鼠中的抗抑郁样作用。化学遗传学下调VTA-mPFC DA神经元的放电活动消除了锂在CMS小鼠中的抗抑郁样作用。最后，我们发现高剂量锂诱导的抗抑郁样作用是由中皮质DA回路中的脑源性神经营养因子（BNDF）信号介导的。总之，这些结果证明了中皮质DA投射在锂的抗抑郁样作用中的作用，并为基于锂的抗抑郁治疗建立了回路基础。
