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1.  Specific Role of VTA Dopamine Neuronal Firing Rates and Morphology in the Reversal of Anxiety-Related, but not Depression-Related Behavior in the ClockΔ19 Mouse Model of Mania 
Neuropsychopharmacology  2011;36(7):1478-1488.
Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (ClockΔ19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that ClockΔ19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of ClockΔ19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in ClockΔ19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in ClockΔ19 animals results in a normalization of locomotor- and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes.
doi:10.1038/npp.2011.33
PMCID: PMC3096816  PMID: 21430648
circadian rhythms; ventral tegmental area; bipolar disorder; dopaminergic activity; chronobiology/sleep; mood/anxiety/stress disorders; animal models; dopamine; bipolar disorder; lithium
2.  Knock-down of CLOCK in the VTA through RNAi results in a mixed state of mania and depression-like behavior 
Biological psychiatry  2010;68(6):503-511.
Background
Circadian rhythm abnormalities are strongly associated with bipolar disorder, however the role of circadian genes in mood regulation is unclear. Previously, we reported that mice with a mutation in the Clock gene (ClockΔ19) display a behavioral profile that is strikingly similar to bipolar patients in the manic state.
Methods
Here, we utilized RNA interference (RNAi) and viral-mediated gene transfer to knock-down Clock expression specifically in the ventral tegmental area (VTA) of mice. We then performed a variety of behavioral, molecular and physiological measures.
Results
We found that knock-down of Clock specifically in the VTA results in hyperactivity and a reduction in anxiety-related behavior which is similar to the phenotype of the ClockΔ19 mice. However, VTA specific knock-down also results in a substantial increase in depression-like behavior, creating an overall mixed-manic state. Surprisingly, VTA knock-down of Clock also altered circadian period and amplitude, suggesting a role for Clock in the VTA in the regulation of circadian rhythms. Furthermore, VTA dopaminergic neurons expressing the Clock shRNA have increased activity compared to controls, and this knock-down alters the expression of multiple ion channels and dopamine-related genes in the VTA which could be responsible for the physiological and behavioral changes in these mice.
Conclusions
Taken together, these results suggest an important role for CLOCK in the VTA in the regulation of dopaminergic activity, manic and depressive-like behavior, and circadian rhythms.
doi:10.1016/j.biopsych.2010.04.031
PMCID: PMC2929276  PMID: 20591414
VTA; Bipolar disorder; Anxiety; Depression; Dopamine; RNAi
3.  Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action 
We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs. resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10-day) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2-week), but not acute (single dose), treatments with the antidepressant medication, fluoxetine (20 mg/Kg). Chronic social defeat stress increased hyperpolarization-activated cation current (Ih) in VTA dopamine neurons, an effect which was also normalized by chronic treatment with fluoxetine. As well, local infusion of Ih inhibitors ZD7288 (0.1 μg) or DK- AH 269 (0.6 μg) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual’s responses to chronic stress and antidepressant action.
doi:10.1523/JNEUROSCI.3177-10.2010
PMCID: PMC3061337  PMID: 21147984
dopamine neurons; antidepressant; social defeat; in vivo firing pattern; fluoxetine
4.  Extracellular Signal-Regulated Kinase-2 within the Ventral Tegmental Area Regulates Responses to Stress 
Neurotrophic factors and their signaling pathways have been implicated in the neurobiological adaptations in response to stress and the regulation of mood-related behaviors. A candidate signaling molecule implicated in mediating these cellular responses is the extracellular signal-regulated kinase (ERK1/2), although its functional role in mood regulation remains to be fully elucidated. Here we show that acute (1 d) or chronic (4 weeks) exposure to unpredictable stress increases phosphorylation of ERK1/2 and of two downstream targets (ribosomal S6 kinase and mitogen- and stress-activated protein kinase 1) within the ventral tegmental area (VTA), an important substrate for motivated behavior and mood regulation. Using herpes simplex virus-mediated gene transfer to assess the functional significance of this ERK induction, we show that overexpressing ERK2 within the VTA increases susceptibility to stress as measured in the forced swim test, responses to unconditioned nociceptive stimuli, and elevated plus maze in Sprague Dawley male rats, and in the tail suspension test and chronic social defeat stress procedure in C57BL/6 male mice. In contrast, blocking ERK2 activity in the VTA produces stress-resistant behavioral responses in these same assays and also blocks a chronic stress-induced reduction in sucrose preference. The effects induced by ERK2 blockade were accompanied by decreases in the firing frequency of VTA dopamine neurons, an important electrophysiological hallmark of resilient-like behavior. Together, these results strongly implicate a role for ERK2 signaling in the VTA as a key modulator of responsiveness to stress and mood-related behaviors.
doi:10.1523/JNEUROSCI.0951-10.2010
PMCID: PMC2895424  PMID: 20519540
5.  CREB regulation of nucleus accumbens excitability mediates social isolation–induced behavioral deficits 
Nature neuroscience  2009;12(2):200-209.
Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element–binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K+ channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.
doi:10.1038/nn.2257
PMCID: PMC2721778  PMID: 19151710
6.  PI3K Contributed to Modulation of Spinal Nociceptive Information Related to ephrinBs/EphBs 
PLoS ONE  2012;7(8):e40930.
There is accumulating evidence to implicate the importance of EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3K), as the downstream effectors, participates in modulation of spinal nociceptive information related to ephrinBs/EphBs. Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal PI3K-p110γ, phosphorylation of AKT (p-AKT) and c-Fos expression. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of spinal AKT induced by ephrinB1-Fc. Inhibition of spinal PI3K signaling dose-dependently prevented and reversed pain behaviors and spinal c-Fos protein expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal PI3K,p-AKT and c-Fos protein. Furthermore, pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc-induced ERK activation in spinal. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.
doi:10.1371/journal.pone.0040930
PMCID: PMC3411731  PMID: 22879882
7.  Acid Solution Is a Suitable Medium for Introducing QX-314 into Nociceptors through TRPV1 Channels to Produce Sensory-Specific Analgesic Effects 
PLoS ONE  2011;6(12):e29395.
Background
Previous studies have demonstrated that QX-314, an intracellular sodium channel blocker, can enter into nociceptors through capsaicin-activated TRPV1 or permeation of the membrane by chemical enhancers to produce a sensory-selective blockade. However, the obvious side effects of these combinations limit the application of QX-314. A new strategy for targeting delivery of QX-314 into nociceptors needs further investigation. The aim of this study is to test whether acidic QX-314, when dissolves in acidic solution directly, can enter into nociceptors through acid-activated TRPV1 and block sodium channels from the intracellular side to produce a sensory-specific analgesic effect.
Methodology/Principal Findings
Acidic solution or noradrenaline was injected intraplantarly to induce acute pain behavior in mice. A chronic constrictive injury model was performed to induce chronic neuropathic pain. A sciatic nerve blockade model was used to evaluate the sensory-specific analgesic effects of acidic QX-314. Thermal and mechanical hyperalgesia were measured by using radiant heat and electronic von Frey filaments test. Spinal Fos protein expression was determined by immunohistochemistry. The expression of p-ERK was detected by western blot assay. Whole cell clamp recording was performed to measure action potentials and total sodium current in rats DRG neurons. We found that pH 5.0 PBS solution induced behavioral hyperalgesia accompanied with the increased expression of spinal Fos protein and p-ERK. Pretreatment with pH 5.0 QX-314, and not pH 7.4 QX-314, alleviated pain behavior, inhibited the increased spinal Fos protein and p-ERK expression induced by pH 5.0 PBS or norepinephrine, blocked sodium currents and abolished the production of action potentials evoked by current injection. The above effects were prevented by TRPV1 channel inhibitor SB366791, but not by ASIC channel inhibitor amiloride. Furthermore, acidic QX-314 employed adjacent to the sciatic nerve selectively blocked the sensory but not the motor functions in naïve and CCI mice.
Conclusions/Significance
Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce a sensory-specific analgesic effect.
doi:10.1371/journal.pone.0029395
PMCID: PMC3247264  PMID: 22216270

Results 1-7 (7)