Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood

Abstract

The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.

Sleep disturbances and circadian CLOCK genes in borderline personality disorder

“…Verkes et al (1996) show that BPD, along with suicide ideation and impulsiveness, was associated with diminished circadian rhythmicity in activity as assessed by actigraphy. That the diurnal variation in mood may be more pronounced in BPD patients than in those with depression and healthy controls was suggested by the study of Cowdry et al (1991) and this observation may be in line with recent insight into how the circadian system may impact on affect (Wirz-Justice 2006; Hampp et al 2008;Golder and Macy 2011). Analysis of the diurnal profile of salivary cortisol in female BPD patients reveals an elevated cortisol response to waking as well as a general upregulation of cortisol levels in BPD (Lieb et al 2004).…”

The daily rhythm of mice

“…Furthermore, these animals display a mania like phenotype similar to that observed in patients with bipolar disorder [87]. A molecular link between the circadian clock mechanism and dopamine metabolism has been established [88]. In mice, the clock proteins BMAL1, NPAS2, and PER2 directly regulate expression levels and activity of monoamine oxidase A, an enzyme important in dopamine degradation, in brain regions relevant for reward and mood related behavior.…”

The circadian clock and mood-related behavior

“…Now, we have reported that monoamine oxidase A (MAOA), a mitochondrial enzyme degrading catecholamines including dopamine, is regulated by components of the circadian clock. 4 Interestingly, this regulation is variable depending on cell type, indicating the presence of cell type specific factors modulating BMAL1/NPAS2 or BMAL1/CLOCK dependent transcription. In the mesolimbic dopaminergic reward circuit, including the ventral tegmental area (VTA) and the ventral striatum/nucleus accumbens (NAc) we found a positive influence of PERIOD 2 (PER2) on transcriptional activation of Maoa using mice mutant in the Per2 gene.…”