Department of Medical Psychology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
Biochem Biophys Res Commun. 2021 Nov 19;579:22-28. doi: 10.1016/j.bbrc.2021.09.062. Epub 2021 Sep 24.
Orexin has been implicated in comorbid diseases of depression, making it a promising target for anti-depression treatment. Although orexin neurons exhibit abnormal activity in depression, the neurocircuit mechanism of orexin remains unclear. As one of the important downstream factors of orexin neurons, the ventral tegmental area (VTA) is considered crucial to the mechanism of depression. However, the role of VTA orexinergic afferents in depression remains unclear. In this study, we applied a combination of opto/chemogenetic and neuropharmacology methods to investigate whether the VTA orexinergic afferents participate in the pathogenesis of depression in a chronic unpredictable mild stress (CUMS) mouse model. We found that c-Fos expression in these VTA-projecting orexin neurons specifically decreased in CUMS-treated mice. Optogenetic and chemogenetic activation of orexin terminals in the VTA significantly reversed depressive behavior. Microinjection of orexin-A, but not orexin-B, into the VTA significantly improved depressive-like behavior. Our study provided direct evidence that the VTA orexinergic afferents participate in the mechanism of depression, and the orexin-1 receptor plays a major role.
食欲素与抑郁症的共病有关，使其成为抗抑郁治疗的有希望的靶点。尽管食欲素神经元在抑郁症中表现出异常活动，但食欲素的神经回路机制尚不清楚。作为食欲素神经元的重要下游因子之一，腹侧被盖区（VTA）被认为对抑郁症的机制至关重要。然而，VTA 食欲素能传入纤维在抑郁症中的作用尚不清楚。在这项研究中，我们应用光/化学遗传和神经药理学方法的组合，研究 VTA 食欲素能传入纤维是否参与慢性不可预测轻度应激（CUMS）小鼠模型中抑郁症的发病机制。我们发现，在 CUMS 处理的小鼠中，这些投射到 VTA 的食欲素神经元中的 c-Fos 表达特异性降低。VTA 中食欲素末端的光遗传学和化学遗传学激活显著逆转了抑郁行为。将食欲素-A 而非食欲素-B 微注射到 VTA 中可显著改善抑郁样行为。我们的研究提供了直接证据，表明 VTA 食欲素能传入纤维参与了抑郁症的发病机制，而食欲素-1 受体起主要作用。
