School of Pharmacy
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.
Digital Commons Citation
Zhong, Peng; Vickstrom, Casey R.; Liu, Xiaojie; Hu, Ying; Yu, Laikang; Yu, Han-Gang; and Liu, Qing-song, "HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress" (2018). Faculty & Staff Scholarship. 1890.
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. https://doi.org/10.7554/elife.32420