Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
Neuron. 2019 Feb 20;101(4):662-672.e5. doi: 10.1016/j.neuron.2018.12.018. Epub 2019 Jan 10.
Cholinergic interneurons (ChIs) in the nucleus accumbens (NAc) have been implicated in drug addiction, reward, and mood disorders. However, the physiological role of ChIs in depression has not been characterized. Here, we show that the tonic firing rate of ChIs in NAc shell is reduced in chronic stress mouse models and in a genetic mouse model of depression. Chemogenetic inhibition of NAc ChIs renders naive mice susceptible to stress, whereas enhancement of ChI activity reverses depressive phenotypes. As a component of the molecular mechanism, we found that the expression and function of the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) are decreased in ChIs of NAc shell in depressed mice. Overexpression of HCN2 channels in ChIs enhances cell activity and is sufficient to rescue depressive phenotypes. These data suggest that enhancement of HCN2 channel activity in NAc ChIs is a feasible approach for the development of a new class of antidepressants.
伏隔核（NAc）中的胆碱能中间神经元（ChIs）与药物成瘾、奖赏和情绪障碍有关。然而，ChIs 在抑郁症中的生理作用尚未得到明确。在这里，我们表明，慢性应激小鼠模型和抑郁症的遗传小鼠模型中 NAc 壳层 ChIs 的紧张性放电率降低。NAc ChIs 的化学遗传抑制使幼稚小鼠易受应激影响，而增强 ChI 活性则逆转了抑郁表型。作为分子机制的一部分，我们发现抑郁小鼠 NAc 壳层 ChIs 中的超极化激活环核苷酸门控通道 2（HCN2）的表达和功能降低。ChIs 中 HCN2 通道的过表达增强了细胞活性，足以挽救抑郁表型。这些数据表明，增强 NAc ChIs 中的 HCN2 通道活性是开发新型抗抑郁药的可行方法。
