The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms
Graphical abstract
Introduction
As a result of regularly recurring daily cycles of sun exposure caused by earth's rotation, most living organisms have evolved circadian (ca. 24 h) clocks to anticipate daily environmental changes and orchestrate daily temporal programs of physiology and behavior. Within cells, autoregulatory clock proteins generate ca. 24 h rhythms by transcriptional-translational negative feedback loops. Core clock genes include Bmal1, Clock, Period (Per1/2) and Cryptochrome (Cry1/2). BMAL1 and CLOCK proteins heterodimerize and induce Per and Cry gene expression. Later in the day, PER and CRY proteins inhibit BMAL1/CLOCK and thereby their own transcription, thus completing the circadian cycle (Koike et al., 2012). In mammals, the master circadian pacemaker is located in the suprachiasmatic nucleus (SCN), in the hypothalamus, but most other tissues also harbor circadian clocks (Albrecht, 2012) which regulate the timing of key processes involved in metabolism, physiology, behavior, and mood regulation. These processes may in turn feedback to impact clock function as well. For example, disruption of circadian rhythms is a hallmark of most neuropsychiatric disorders, including bipolar disorder (BD) (Landgraf et al., 2014a, McCarthy and Welsh, 2012, Wulff et al., 2010), a disabling condition characterized by episodes of depression and mania. The mechanisms by which circadian and mood-regulating processes influence each other are unclear (Landgraf et al., 2014b). In the case of BD, however, manic behavior is associated with elevated levels of dopamine (DA) (van Enkhuizen et al., 2015), a neurotransmitter that also impacts circadian rhythms. For example, timed treatment with a D1 DA receptor agonist shifts circadian phase of fetal hamsters (Viswanathan and Davis, 1997, Viswanathan et al., 1994), possibly due to activation of D1 receptors in the mammalian SCN (Rivkees and Lachowicz, 1997, Weiner et al., 1991). DA also regulates core clock components in retina and striatum (Hood et al., 2010, Imbesi et al., 2009, Yujnovsky et al., 2006). Thus, DA may be crucially involved in both manic behavior and disrupted circadian rhythms in BD.
One possible reason for increased DA levels in BD patients is lower expression of the dopamine transporter (DAT) that removes DA from synaptic clefts. Variants of the DAT gene (SLC6A3) have been associated with BD and reduced DAT expression (Greenwood et al., 2001, Greenwood et al., 2006, Kelsoe et al., 1996). These associations are consistent with lower DAT levels observed in BD patients and thus elevated synaptic DA (Amsterdam and Newberg, 2007). Furthermore, in mice, knockout of DAT (DAT−/−) increases DA levels and activity in new environments (Giros et al., 1996), and causes deficits in prepulse inhibition (Ralph et al., 2001). However, behavioral analysis of DAT−/− mice is complicated by poor physical state (Bosse et al., 1997). Mice with constitutive genetic knockdown of DAT (DAT-KD) express 10% of wild-type (WT) DAT levels and also show high DA levels. They display mania-like behaviors such as hyperactivity in a novel environment (Zhuang et al., 2001), replicating hyper-exploration and increased risk-taking behavior of manic BD patients (Perry et al., 2009, van Enkhuizen et al., 2014, Young et al., 2011b) without concomitant developmental defect. For these reasons, DAT-KD mice have been used as a model for mania. In BD patients, valproic acid (VPA) is used as a mood stabilizer, and particularly as an anti-manic agent. Interestingly, observations that VPA also attenuates the hyper-exploration of DAT-KD mice without affecting their WT littermates (van Enkhuizen et al., 2013) provided predictive validity for this model of BD mania (Young et al., 2011a).
Since DA regulates circadian clocks, we hypothesized that elevated DA levels contribute to circadian disturbances in manic BD patients. We tested this hypothesis in DAT-KD mice and cultured SCN explants treated with a D1 receptor agonist and found that increased DA signaling lengthens the period of circadian rhythms. Furthermore, we showed that VPA shortens circadian period, both in vitro and in vivo, and that the effects of VPA on behavior are less pronounced in the absence of a circadian clock in DAT-deficient Drosophila melanogaster. These data suggest that the mood-stabilizing properties of VPA in manic BD patients might be partly based on reversing the effects of elevated DA on circadian period.
Section snippets
Animals
Mouse: All mice used for experiments were on a C57BL/6J genetic background. All mice used for behavioral assays were 19–21 week old male WT, DAT-KD+/−, and DAT-KD−/− littermates (Zhuang et al., 2001). For organotypic SCN cultures we used 8–12 week old male mPer2Luciferase (PER2::LUC) mice. In PER2::LUC knockin mice, the circadian clock gene Period2 (Per2) is replaced by homologous recombination with a construct incorporating the firefly luciferase (Luc) gene in tandem with WT Per2, such that a
DAT-KD mice exhibited chronically increased locomotor activity in running wheels
DAT-KD mice were previously reported to exhibit increased spontaneous locomotor activity when exposed to a new environment (Giros et al., 1996, van Enkhuizen et al., 2013). Here we measured running-wheel behavior over the course of seven months and showed that DAT-KD mice display chronic hyperlocomotion in a familiar environment. Comparing WT, DAT-KD+/−, and DAT-KD−/− littermate mice, we found that genotype was associated with the total activity of the mice under 12:12 LD and DD conditions (
Discussion
We hypothesized that elevated DA levels change the period of circadian rhythms. To test this hypothesis, we measured circadian rhythms in locomotor activity of DAT-KD mice, an animal model of mania with chronically high extracellular DA levels. We found that DAT-KD−/− mice exhibited lengthened free-running circadian periods. Period lengthening was not present in SCN slice cultures, which lack DA afferent inputs. However, in the presence of a D1/D5 receptor agonist (SKF 38393) the period of SCN
Conclusions
In summary, elevated DA levels contribute to mania-like behavior in mice and also lengthen periods of circadian rhythms (Fig. 6A). Circadian effects may be particularly pronounced in brain areas that receive high DA input, leading to circadian misalignment in the brain. In contrast, VPA attenuates mania-like behavior and shortens periods of circadian oscillations (Fig. 6B). Since VPA effects are less pronounced in animals lacking circadian rhythms, it is possible that normalization of
Funding
Study funding was provided to DKW by a Veterans Affairs Merit Award (1I01BX001146). WJJ receives support from an NIH grant (R01-NS072431). MJM is supported by a Veterans Affairs Career Development Award (1IK2BX001275). JWY receives funding from NIH (R01-MH104344). NC is supported by a Canadian Institutes of Health Research grant (MOP-119322). The funders had no role in the analysis, decision to publish, or preparation of the manuscript. None of the authors has competing financial interests
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