Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States.
Department of Physiology and Pharmacology, West Virginia University, Morgantown, United States.
Elife. 2018 Jan 2;7:e32420. doi: 10.7554/eLife.32420.
Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.
腹侧被盖区（VTA）中的多巴胺神经元是调节与抑郁相关行为的强大调节因子。在基于慢性应激的抑郁模型中，多巴胺神经元活动发生改变，但潜在机制仍不完全清楚。在这里，我们表明，经历慢性轻度不可预测应激（CMS）的小鼠表现出焦虑和抑郁样行为，这与体内和体外 VTA 多巴胺神经元放电减少有关。多巴胺神经元的放电由电压门控离子通道控制，特别是超极化激活环核苷酸门控（HCN）通道。在 CMS 之后，在投射到伏隔核的 VTA 多巴胺神经元中，HCN 介导的电流减少。此外，VTA 中的 HCN2 shRNA 介导的敲低足以在应激-naive 小鼠中再现 CMS 诱导的抑郁和焦虑样行为，而 VTA HCN2 过表达则在很大程度上防止了 CMS 引起的行为缺陷。总之，这些结果揭示了 HCN2 在调节 VTA 多巴胺神经元活性和与抑郁相关行为中的关键作用。
