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

Abstract

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 (ClockD19) 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 ClockD19 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 ClockD19 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 ClockD19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in ClockD19 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.

Hyper-Reactive Human Ventral Tegmental Area and Aberrant Mesocorticolimbic Connectivity in Overgeneralization of Fear in Generalized Anxiety Disorder

“…Furthermore, variability of the patient-specific VTA hyper-reactivity to the GS least similar to CS was correlated with individual differences in trait anxiety. In animal models, excessive VTA dopaminergic activity is implicated in anxiety-like behaviors (Coque et al, 2011), and elevated VTA dopaminergic activity has been linked to vulnerability to social defeat in mouse models (Krishnan et al, 2007). Thus, our results seem to correspond to previous research in animal models providing a key link between abnormal VTA activity and anxiety.…”

“…In the present study, we did not observe a direct relationship between vmPFC dysfunction and abnormal VTA reactivity or connectivity. However, given the extensive literature on the essential role of the two systems (perhaps mediated by the dorsolateral PFC) in adaptive behavior Takahashi et al, 2009Takahashi et al, , 2011Ballard et al, 2011;D'Ardenne et al, 2012), the coupling between these two structures may be important in the fear generalization and the pathophysiology of anxiety.…”

“…Recent studies suggest that a distinct part of the mesocorticolimbic circuit plays a crucial role in negative motivation or aversion (Matsumoto and Hikosaka, 2009;Bromberg-Martin et al, 2010;Zweifel et al, 2011;Cohen et al, 2012). The VTA receives glutamatergic inputs from the lateral habenula and projects dopaminergic innervation to the medial PFC (mPFC) in rodent models (Lammel et al, 2012;Stamatakis and Stuber, 2012).…”

The Role of Clock in Ethanol-Related Behaviors

“…Knocking down Clock expression in the VTA recapitulates the increased DA cell firing seen in ClockD19 mice (Mukherjee et al, 2010). In addition, overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of ClockD19 mice reduces the firing rate of dopamine neurons in ClockD19 mice and results in a normalization of their locomotor-and anxiety-related behaviors (Coque et al, 2011). Taken together, these studies show that abnormalities in dopamine cell firing and associated morphology underlie alterations in locomotor, anxiety-, and drug-related behavior.…”

“…Importantly, CLOCK is involved in regulating dopaminergic transmission. ClockD19 mice have increased tonic and phasic dopamine transmission, as well as cell volume changes (McClung et al, 2005;Coque et al, 2011). Augmented DA firing is associated with increased locomotor activity and drug reward, which is also seen in ClockD19 mice (Adamantidis et al, 2011;Marinelli and White, 2000;McClung et al, 2005;Ozburn et al, 2012).…”