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

Peng Zhong,Casey R Vickstrom,Han-Gang Yu,Ying Hu,Laikang Yu,Qing-Song Liu,Xiaojie Liu

doi:10.7554/elife.32420

Peng Zhong, Casey R Vickstrom + Show 5 more

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https://doi.org/10.7554/elife.32420

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Journal: eLife	Publication Date: Jan 2, 2018
Citations: 57	License type: CC BY 4.0

Affiliation: Medical College of Wisconsin, West Virginia University

Abstract

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.

Highlights

Depression is highly prevalent throughout the world population (Kessler and Merikangas, 2004)
ventral tegmental area (VTA) dopamine neuron action potential (AP) firing is altered in chronic stress models of depression (Cao et al, 2010; Chang and Grace, 2014; Moreines et al, 2017; Tye et al, 2013), and modulating this firing can reverse or enhance the development and/or expression of depression-like behavior (Chaudhury et al, 2013; Friedman et al, 2014; Tye et al, 2013)
We show in mice that following chronic mild unpredictable stress (CMS), depressive- and anxiety-like behaviors and decreased VTA dopamine neuron firing are associated with reduced Ih current and a hyperpolarizing shift in Ih current in VTA dopamine neurons

Summary

Introduction

Depression is highly prevalent throughout the world population (Kessler and Merikangas, 2004). Available antidepressants share the same core mechanisms of blocking serotonin and noradrenaline reuptake in the brain. A significant number of patients with depression do not fully respond to serotonin and/or noradrenaline reuptake inhibitors (Al-Harbi, 2012). There is an increasing appreciation for the role of dopamine in the pathophysiology of depression (Nestler and Carlezon, 2006). There is a high incidence (30–50%) of comorbid depression in patients with Parkinson’s disease (Burn, 2002), which is characterized by the degeneration of midbrain dopaminergic neurons (Alberico et al, 2015). In patients with untreated Parkinson’s disease, higher depression scores were associated with lower dopamine synthesis capacity in the striatum (Joutsa et al, 2013). Given the well-established role of dopamine in reward processing and motivation (Brischoux et al, 2009; Morales and Margolis, 2017), and that anhedonia and lack of motivation are core symptoms of depression (Duman, 2007; Nestler and Carlezon, 2006), it is thought that dysfunction of the dopamine reward system might contribute to anhedonia and the loss of motivation common in depression (Nestler and Carlezon, 2006)

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