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School of Pharmacy


Pharmaceutical Sciences


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-naı ̈ve 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.

Source Citation

Zhong, P., Vickstrom, C. R., Liu, X., Hu, Y., Yu, L., Yu, H.-G., & Liu, Q. (2018). HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. eLife, 7.


Copyright Zhong et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.



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