The circadian clock and mood-related behavior

Abstract

Over many years evidence accumulated that circadian rhythms are related to psychiatric disorders.1-3 However, a mechanistic relationship between the circadian clock and mood related behaviors remained enigmatic. 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. These animals show less Maoa mRNA expression and MAO activity compared to wild type littermates. This is probably the reason for the observed increase in dopamine levels in the striatum of Per2 mutant mice what leads to alteration in despair-based behavioral tests. These results suggest that clock components can influence dopamine metabolism and mood-related behaviors.

Keywords: circadian rhythm; feeding; light; lithium; motivation.

Figure 1

Diurnal variation of tyrosine hydroxylase (TH) and Protein Phosphatase 2A (PP2A) in wild type and Per2 mutant mice. (A) TH protein levels in the nucleus accumbens. (B) PP2A activity in the striatum. (C) TH activity in the striatum. Data are plotted as means ± SEM (n = 3 or more). Significant differences were determined by two-way ANOVA combined with Bonferroni posttests and two-tailed unpaired t-test. The white and black bars indicate light and dark phase. Animals were entrained to a 12:12 h LD cycle. Asterisks mark significant differences determined by Bonferroni posttest. Values 0/24 are double plotted.

Figure 2

Model of how PER2 affects monoamine oxidase A (Maoa) expression and dopamine levels in the mesolimbic dopaminergic system (for details see text). Light affects the molecular clock mechanism in the suprachiasmatic nuclei (SCN) via the retinohypothalamic tract (RHT), which directly connects the retina of the eye with the SCN. How this signal is transmitted to mesolimbic dopaminergic cells is not known. BMAL1 = brain and muscle arnt-like factor 1; GSK-3β = glycogen synthase kinase-3 β; NPAS2 = neuronal Period-Arndt-Single-minded-domain protein 2; PER2 = period 2.