HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

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...

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Published ineLife Vol. 7
Main Authors Zhong, Peng, Vickstrom, Casey R, Liu, Xiaojie, Hu, Ying, Yu, Laikang, Yu, Han-Gang, Liu, Qing-song
Format Journal Article
LanguageEnglish
Published England eLife Sciences Publications Ltd 02.01.2018
eLife Sciences Publications, Ltd
Subjects
action potential
Animal models
Anxiety
Behavior
chronic mild stress (CMS)
depression
Dopamine
dopamine neuron
Hyperpolarization
Ion channels (cyclic nucleotide-gated)
Mental depression
Neurons
Neuroscience
Nucleus accumbens
Rodents
Stress
Sucrose
Ventral tegmentum
United States > US
anxiety
mouse
chronic mild stress (CMS)
neuroscience
dopamine neuron
depression
action potential
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Summary: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.
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Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, United States.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.32420