Depression is highly prevalent throughout the world population (Kessler and Merikangas, 2004). Clinically available antidepressants share the same core mechanisms of blocking serotonin and noradrenaline reuptake in the brain. However, 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). Levels of dopamine metabolites in cerebrospinal fluid are reduced in depressive subjects (Bowden et al., 1997). 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). Additionally, in a double-blind clinical study, the dopamine receptor agonist pramipexole produced antidepressant effects in patients that failed to respond to standard antidepressant treatments (Franco-Chaves 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).

Chronic mild unpredictable stress (CMS) (Willner, 2005) and chronic social defeat stress (CSDS) (Berton et al., 2006; Golden et al., 2011; Krishnan et al., 2007; Krishnan and Nestler, 2011) are well-established rodent models of depression. However, CMS and CSDS induce opposing changes in ventral tegmental area (VTA) dopamine neuron activity: CMS reduced action potential (AP) firing in VTA dopamine neurons (Chang and Grace, 2014; Moreines et al., 2017; Tye et al., 2013), whereas susceptibility to CSDS was accompanied by an increase in AP firing (Cao et al., 2010; Chaudhury et al., 2013; Krishnan et al., 2007; Ku and Han, 2017). The behavioral effects of optogenetically activating or inhibiting VTA dopamine neurons also differ between mice subject to CMS or CSDS. In the CSDS model, optogenetic phasic stimulation of VTA neurons that project to the nucleus accumbens (NAc) induced susceptibility to social defeat, whereas optogenetic inhibition of the VTA–NAc projection induced resilience (Chaudhury et al., 2013). In contrast, optogenetic phasic stimulation of VTA dopamine neurons reversed CMS-induced depressive-like behavior, while optogenetic inhibition of VTA dopamine neurons induced behavioral despair and decreased sucrose preference in stress-naïve mice (Tye et al., 2013). Thus, modulating VTA dopamine neuron firing can enhance or prevent the development of depression-like behavior, and potential factors that might explain these divergent results have been contemplated (Hollon et al., 2015; Lammel et al., 2014).

AP firing in VTA dopamine neurons is governed by multiple voltage-dependent ionic conductances, including the hyperpolarization-activated cation current (I_h), which is generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (McDaid et al., 2008; Okamoto et al., 2006). There are four subtypes of HCN (HCN1-4), which mainly form homotetramers with distinct properties (Wahl-Schott and Biel, 2009) and have different brain distributions (Notomi and Shigemoto, 2004). Although Hcn1-4 mRNAs are expressed in the VTA (Monteggia et al., 2000), immunostaining for HCN protein has shown that HCN2 is the predominant HCN subunit expressed in the VTA (Notomi and Shigemoto, 2004). Tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) is an auxiliary subunit of HCN1-4 channels and is required for HCN trafficking and enrichment at dendrites (Han et al., 2011; Lewis et al., 2009; Lewis et al., 2011; Santoro et al., 2009). Global knockout of Hcn1 or Trip8b reduced behavioral despair, but these mice did not display anxiolytic-like behaviors (Lewis et al., 2011), while lentivirus-mediated shRNA knockdown of HCN1 in the dorsal hippocampus promoted both anxiolytic- and antidepressant-like effects (Kim et al., 2017; Kim et al., 2012). The antidepressant-like effects of global Trip8b knockout can be reversed by reinstating TRIP8b expression in the dorsal hippocampus (Han et al., 2017; Lyman et al., 2017). Apathetic (Hcn2^ap/ap) mice with a spontaneous null mutation in Hcn2 show reduced behavioral despair in the tail suspension test, but these mice exhibit deficits in motor coordination and locomotion and cannot perform the forced swim test due to an inability to swim (Lewis et al., 2011). Thus, HCN channels can be powerful regulators of depressive- and anxiety-like behaviors, and different HCN isoforms in different brain regions may play distinct roles in regulating rodent behavior.

The I_h current generates pacemaker activity via permeability to cations (Biel and Michalakis, 2009), and enhancing I_h current increases AP firing in VTA dopamine neurons (Friedman et al., 2014; McDaid et al., 2008; Okamoto et al., 2006). CSDS leads to an increase in I_h current in VTA dopamine neurons in susceptible mice, and an even further increase in I_h current in resilient mice, but normal AP firing is achieved in resilient mice via homeostatic upregulation of voltage-gated K⁺ currents (Cao et al., 2010; Friedman et al., 2014). Overexpression of HCN2 in VTA dopamine neurons or intra-VTA infusion of an I_h potentiator in susceptible animals produced a reversal of social avoidance behavior, likely by a homeostatic upregulation of K⁺ current and the subsequent normalization of AP firing (Friedman et al., 2014). However, given that CMS and CSDS induce distinct neuroadaptations in VTA dopamine neurons (Chaudhury et al., 2013; Hollon et al., 2015; Lammel et al., 2014; Tye et al., 2013), in particular the observation that CMS leads to decreased VTA dopamine neuron firing, it is of interest to investigate whether CMS alters I_h current in VTA dopamine neurons, and if so, whether the alteration of I_h current contributes to the development of depressive-like behaviors.

VTA dopamine neurons are heterogeneous in their projection targets and HCN expression (Gantz et al., 2017; Morales and Margolis, 2017). In mice, neurons that project to the lateral shell of the NAc display large I_h current, whereas those that project to the medial prefrontal cortex (mPFC), medial shell of the NAc, or basolateral amygdala exhibit minimal I_h current (Baimel et al., 2017; Lammel et al., 2008; Lammel et al., 2011). Dopamine neurons projecting to the lateral shell of the NAc are thought to signal primary reward and salience (Bromberg-Martin et al., 2010; Lammel et al., 2011), and optogenetic stimulation of an excitatory input to dopamine neurons projecting to the NAc lateral shell elicits reward (Lammel et al., 2012). Thus, in the present study, we investigated how CMS affects I_h current in VTA dopamine neurons that project to the lateral shell of the NAc. Furthermore, we determined whether virus-mediated knockdown or overexpression of HCN2 in the VTA affects depression- and anxiety-like behaviors. We provide evidence that CMS led to a decrease in I_h current in NAc lateral shell-projecting VTA dopamine neurons, and that manipulating HCN2 expression in the VTA can powerfully regulate depressive- and anxiety-like behavior.

VTA dopamine neuron 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). Here, we have identified a putative mechanism linking CMS to decreased VTA dopamine neuron firing and the resulting behavioral deficits. We show in mice that following CMS, depressive- and anxiety-like behaviors and decreased VTA dopamine neuron firing are associated with reduced I_h current and a hyperpolarizing shift in I_h current in VTA dopamine neurons. Importantly, this decrease in I_h current is behaviorally relevant, as shRNA knockdown of HCN2 in the VTA was sufficient to recapitulate depressive- and anxiety-like behavior, while VTA HCN2 overexpression prevented the CMS-induced development of depressive-like behavior. Thus, the downregulation of HCN2 channels in VTA dopamine neurons may be a primary contributor to the CMS-induced development of depressive- and anxiety-like behaviors.

CMS or other homotypic chronic stressors typically cause decreases in population activity, tonic and burst firing in VTA dopamine neurons (Chang and Grace, 2014; Moore et al., 2001; Moreines et al., 2017; Tye et al., 2013). We showed that the population activity, as well as the frequency of tonic and burst firing in VTA dopamine neurons were decreased in CMS-exposed mice. Importantly, our in vivo recordings targeted the lateral PBP, which is a more lateral subdivision of the VTA where dopamine neurons predominantly project to the lateral shell of the NAc (Lammel et al., 2008; Lammel et al., 2011) and play a primary role in reward and motivated behavior (Lammel et al., 2011; Lammel et al., 2012). Interestingly, CMS leads to decreased population activity in medial and central regions of the VTA but does not significantly alter population activity in the lateral VTA in the rat (Moreines et al., 2017). Further, no change in firing rate or burst firing was found in any VTA region (Moreines et al., 2017), consistent with their previous work (Chang and Grace, 2014; Moore et al., 2001). In contrast, our study and a previous study (Tye et al., 2013) found significant reductions in firing rate and burst firing following CMS, and we found decreased population activity in lateral VTA dopamine neurons. We suspect this discrepancy is due to differences in CMS paradigms and animal species, as the former studies applied 3–4 stressors/week over 4 weeks in rats (Chang and Grace, 2014; Moreines et al., 2017), whereas our study applied 14 stressors/week over 5 weeks in mice, and Tye et al. (2013) applied 14 stressors/week over 8–12 weeks in mice.

Both CMS and CSDS are commonly-used rodent models of depression (Golden et al., 2011; Krishnan et al., 2007; Krishnan and Nestler, 2011; Willner, 2005). Interestingly, CMS and CSDS produce distinct, even opposite effects on VTA dopamine neuron firing (Chaudhury et al., 2013; Hollon et al., 2015; Tye et al., 2013). CSDS, in contrast to CMS, increases tonic and burst firing in mice susceptible to CSDS, but not in resilient mice (Anstrom et al., 2009; Cao et al., 2010; Chaudhury et al., 2013; Friedman et al., 2014; Krishnan et al., 2007). Additionally, optogenetic phasic stimulation of NAc-projecting VTA neurons induced susceptibility to subthreshold social defeat stress, whereas optogenetic inhibition of the VTA–NAc projection induced resilience to CSDS (Chaudhury et al., 2013). However, optogenetic phasic stimulation of VTA dopamine neurons reversed the CMS-induced decrease in sucrose preference and increase in immobility in the tail suspension test (TST) (Tye et al., 2013). Interestingly, in non-stressed mice, optogenetic inhibition of VTA dopamine neurons was sufficient to reduce sucrose preference and increase immobility in the TST (Tye et al., 2013). Thus, these two models do not produce unitary effects on dopamine neuronal activity, and optogenetic manipulations of dopamine neuronal activity produce divergent behavioral changes, depending on the animal model used. Perhaps manipulations that normalize disruptions in AP firing induced by CMS or CSDS can produce antidepressant-like or resilient phenotypes.

In VTA dopamine neurons, I_h current generates pacemaker activity together with other voltage-dependent ion channels. Pharmacological manipulations that increase I_h current in VTA dopamine neurons lead to increased AP firing frequency (Friedman et al., 2014; Wanat et al., 2008), whereas the I_h blocker ZD7288 reduces spontaneous AP firing in VTA dopamine neurons (McDaid et al., 2008; Okamoto et al., 2006). We therefore investigated whether CMS altered I_h current in VTA dopamine neurons, as this may contribute to the CMS-induced reduction in AP firing. VTA dopamine neurons are heterogeneous in their afferent and efferent connectivity (Brischoux et al., 2009; Morales and Margolis, 2017) and electrophysiological properties (Gantz et al., 2017; Lammel et al., 2008; Lammel et al., 2011). Dopamine neurons in the lateral VTA typically fire with low-frequency (<10 Hz), project to the NAc lateral shell, and exhibit a large I_h current, and both rewarding and aversive stimuli modify synapses onto these dopamine neurons (Lammel et al., 2011). CSDS increases I_h current in NAc-projecting VTA neurons but not in mPFC-projecting VTA neurons in susceptible mice (Cao et al., 2010; Friedman et al., 2014). Interestingly, the amplitude of I_h current in NAc-projecting VTA neurons is further increased in resilient mice, but normal AP firing in these mice is made possible via homeostatic upregulation of voltage-gated K⁺ currents (Friedman et al., 2014; Krishnan et al., 2007). However, whether CMS affects I_h current in these neurons had not been previously investigated.

Using Retrobead injections into the NAc lateral shell, we found that I_h amplitude and I_h current density were significantly decreased in NAc-projecting VTA dopamine neurons in CMS-exposed mice compared with that of control mice. CMS also led to a significant hyperpolarizing shift (~−5 mV) of V_1/2, which can reduce I_h activation to hyperpolarizing stimuli. The mechanisms for this hyperpolarizing shift remain to be investigated. Additionally, we found that AP firing in VTA dopamine neurons ex vivo was significantly decreased in CMS-exposed mice. Unlike in vivo, the burst firing activity of VTA dopamine neurons is lacking ex vivo, likely due to the severing of synaptic inputs during slice cutting (McDaid et al., 2008). Nevertheless, we isolated the cell-autonomous effect of I_h current on AP firing by performing cell-attached recordings in the presence of the glutamate receptor and GABA_A receptor antagonists. We found that AP firing was decreased in CMS slices, and that the I_h blocker ZD7288 produced a greater decrease in the firing rate in control slices than in CMS slices. Together, these studies indicate that CMS induced a decrease in I_h current in VTA dopamine neurons, likely leading to the decrease in AP firing in vivo following CMS.

HCN channels contribute to resting membrane potential and conductance in neuronal cell bodies (Banks et al., 1993), dendrites (Tsay et al., 2007), and presynaptic terminals (Huang and Trussell, 2011). Consistent with this, we found that knockdown of HCN2 led to a significant decrease in resting membrane conductance, as derived from the instantaneous inward currents present immediately after hyperpolarizing voltage steps from a holding potential of −60 mV. Additionally, CMS led to a non-significant trend towards reduced resting conductance. These results together suggest that HCN2 channels modestly contribute to overall resting membrane conductance.

HCN1, HCN2 and the auxiliary subunit TRIP8b have previously been shown to regulate behavioral despair. Hcn1 or Trip8b knockout leads to reduced immobility in the tail suspension test and forced swim test, and Hcn2^ap/ap mice show reduced immobility in the tail-suspension test, but these mice exhibit deficits in motor coordination and locomotion and cannot swim (Lewis et al., 2011). However, anxiety-like behavior is not altered in these three knockout mice in the elevated plus maze, dark/light box and marble burying tests (Lewis et al., 2011). Additionally, CMS induces an increase in HCN1 currents in the dorsal hippocampus, and shRNA knockdown of HCN1 in the dorsal hippocampus produced anxiolytic- and antidepressant-like behaviors (Kim et al., 2017, 2012). Hippocampal CA1 pyramidal neurons usually do not fire spontaneous APs at resting membrane potential, and HCN1 channels at CA1 neuron distal dendrites limit neuronal excitability by reducing the integration of synaptic inputs (Magee, 1998, 1999; Tsay et al., 2007), in part through interactions with M-type K⁺ channels (George et al., 2009). Interestingly, depolarizing current injections elicited significantly more action potentials following HCN1 knockdown, knockout, and I_h blockade in hippocampal neurons (Kim et al., 2012; Lewis et al., 2011). In contrast, consistent with previous studies (McDaid et al., 2008; Okamoto et al., 2006), we found that an HCN blocker or knockdown of HCN2 decreases AP firing in VTA dopamine neurons. Thus, it seems that the functional role of HCN channels depends on several factors, including the cellular location of HCN expression (e.g. distal dendrite vs. cell soma), the HCN isoform, the cell type in which HCN channels are expressed, and likely other factors. In VTA dopamine neurons, our results support a ‘pro-excitability’ role for HCN2, likely by generating a pacemaker current to support repetitive AP firing. It is possible that the differing neurophysiological functions of HCN channels in the dorsal hippocampus compared with VTA dopamine neurons may account for the opposing behavioral effects of HCN inhibition or activation in these structures.

Overexpression of HCN2 in VTA dopamine neurons, or intra-VTA infusion of the I_h potentiator lamotrigine, produces the resilient phenotype in mice subjected to CSDS by activating a homeostatic mechanism leading to an upregulation of voltage-gated K⁺ channels and normalization of AP firing (Friedman et al., 2014). Interestingly, intra-VTA infusion of an I_h inhibitor can also promote the resilient phenotype following CSDS (Cao et al., 2010). How might an I_h inhibitor lead to the same behavioral effect as I_h potentiation? Whereas the I_h inhibitor was applied acutely to CSDS-susceptible mice and presumably decreased abnormally elevated dopamine neuron firing (Cao et al., 2010), lamotrigine was administered repeatedly for five days and HCN2 was allowed to overexpress for four days before behavioral assessments were carried out (Friedman et al., 2014). I_h potentiation led to an upregulation of K⁺ currents in each scenario, leading to a reduction in otherwise abnormally elevated dopamine neuron excitability. In our study, CMS- or shRNA-mediated suppression of I_h current leads to abnormally decreased dopamine neuron firing, and results in depressive- and anxiety-like behavior. Altogether, these findings support the notion that abnormal dopamine neuron firing is a unifying contributor to the development of depressive-like behavior.

Although shRNA-mediated HCN2 knockdown recapitulated the behavioral effects of CMS, it did not affect body weight. As body weight was measured 3 weeks after HCN2 knockdown, whereas the CMS-induced decrease in body weight was observed after 5 weeks of CMS, it is possible that body weight perturbations induced by HCN2 knockdown require additional time to manifest. Alternatively, HCN2 knockdown may not recapitulate all effects of CMS. Importantly, although the HCN2 knockdown was not cell type-specific, VTA dopamine neurons should be predominantly affected by the knockdown, as VTA GABA and glutamate neurons in mice exhibit little to no I_h current (Chieng et al., 2011; Hnasko et al., 2012). Further, VTA dopamine neurons projecting to the mPFC, NAc medial shell, or basolateral amygdala exhibit minimal I_h current (Baimel et al., 2017; Lammel et al., 2008; Lammel et al., 2011). Thus, NAc lateral shell-projecting VTA dopamine neurons should be the predominant VTA population affected by the knockdown.

Additionally, overexpression of HCN2 in the VTA prevented the majority of CMS-induced behavioral deficits and produced antidepressant-like effects. In the CSDS model, HCN2 overexpression selectively in NAc-projecting VTA neurons, but not in mPFC-projecting VTA neurons, normalizes social interaction deficits (Friedman et al., 2014). Thus, it is likely that enhancing I_h current promotes the resilient phenotype in CSDS via effects on the VTA-NAc pathway. A limitation of our study is that although HCN2 overexpression is VTA-specific, it is not cell type- or projection-specific. As the VTA is heterogeneous with regard to cell type, connectivity, and behavioral function (Morales and Margolis, 2017), future studies employing more sophisticated viral tools for cell- and projection-specific overexpression of HCN2 will likely be necessary to parse out the contributions of individual VTA circuits to CMS-induced behavioral deficits. Nevertheless, a salient commonality between these studies is that I_h potentiation is capable of producing antidepressant-like phenotypes in both models, despite the fact that CSDS and CMS induced distinct neuroadaptations in VTA dopamine neuron activity and I_h current.

HCN channels have been implicated in a variety of brain disorders, including epilepsy (Benarroch, 2013), Parkinson’s disease (Chan et al., 2011), neuropathic pain (DiFrancesco and DiFrancesco, 2015), tinnitus (Li et al., 2015), and Neurofibromatosis type 1 (Omrani et al., 2015). Additionally, the rewarding effects of ethanol are believed to arise in part from activating HCN channels in VTA dopamine neurons (Okamoto et al., 2006; Tateno and Robinson, 2011). Consistent with this idea, overexpression of HCN2 in the VTA increases ethanol reward and consumption in rats (Rivera-Meza et al., 2014), perhaps through an increased ethanol-induced activation of I_h current and AP firing in dopamine neurons. Further, chronic ethanol exposure can reduce I_h current in VTA dopamine neurons (Okamoto et al., 2006). Given that alcohol use disorder (AUD) and major depressive disorder (MDD) are frequently comorbid in humans (Yoon et al., 2015), and that AUD can prospectively predict future MDD (Boschloo et al., 2012; Brière et al., 2014), a speculative mechanistic explanation is that chronic alcohol use leads to downregulation of HCN2 in VTA dopamine neurons, which may directly contribute to the development of depressive behavior. Given the widespread distribution (Notomi and Shigemoto, 2004) and functional diversity (Santoro and Baram, 2003) of HCN channels in the brain, it is likely that HCN channels play important roles in a wide variety of physiological and pathophysiological processes.

Clinical and animal studies suggest that VTA dopamine neurons and their major projection target, the NAc, play a critical role in the pathophysiology of depression. Depression and anxiety occur in 40–50% of patients with Parkinson's disease and these symptoms sometimes precede the appearance of motor dysfunction (Burn, 2002; Dooneief et al., 1992; Taylor et al., 1986). The dopamine agonist pramipexole produces antidepressant effects in patients who failed to respond to standard antidepressant treatments (Franco-Chaves et al., 2013). Different molecular changes in the VTA to NAc pathway confer vulnerability or resilience to chronic social defeat stress (CSDS) (Berton et al., 2006; Francis and Lobo, 2017; Krishnan et al., 2007), though relatively few studies have been conducted to study CMS-induced neuroadaptations in the mesolimbic dopamine system. The present study reveals that CMS is associated with a decrease in both AP firing and I_h current in VTA dopamine neurons that project to the NAc. Additionally, HCN2 knockdown in the VTA was sufficient to induce depressive- and anxiety-like behavior in non-stressed mice, whereas HCN2 overexpression prevented the CMS-induced development of depressive-like behavior. Thus, HCN2 channels in the VTA play a critical role in regulating depressive- and anxiety-like behavior in both unstressed and chronically stressed mice.

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Author details

1. Peng Zhong

   Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States

   Present address

   Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

2. Casey R Vickstrom

   Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States

   Contribution

   Conceptualization, Data curation, Funding acquisition, Validation, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0536-1211

3. Xiaojie Liu

   Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

4. Ying Hu

   Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

5. Laikang Yu

   Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing—original draft

   Competing interests

   No competing interests declared

6. Han-Gang Yu

   Department of Physiology and Pharmacology, West Virginia University, Morgantown, United States

   Contribution

   Conceptualization, Resources, Validation, Visualization

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6838-8310

7. Qing-song Liu

   Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Project administration, Writing—review and editing

   For correspondence

   qsliu@mcw.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1858-1504

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