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.
Most behavioral experiments within circadian research are based on the analysis of locomotor activity. This paper introduces scientists to chronobiology by explaining the basic terminology used within the field. Furthermore, it aims to assist in designing, carrying out, and evaluating wheel-running experiments with rodents, particularly mice. Since light is an easily applicable stimulus that provokes strong effects on clock phase, the paper focuses on the application of different lighting conditions.
Circadian clocks are internal timekeepers present in almost all organisms. Driven by a genetic network of highly conserved structure, they generate selfsustained oscillations that entrain to periodic external signals such as the 24 h light-dark cycle. Vertebrates possess multiple, functionally overlapping homologues of the core clock genes. Furthermore, vertebrate clocks entrain to a range of periods three times as narrow as that of other organisms. We asked whether genetic redundancies play a role in governing entrainment properties and analysed locomotor activity rhythms of genetically modified mice lacking one set of clock homologues. Exposing them to non-24 h light-dark cycles, we found that the mutant mice have a wider entrainment range than the wild types. Spectral analysis furthermore revealed nonlinear phenomena of periodically forced self-sustained oscillators for which the entrainment range relates inversely to oscillator amplitude. Using the forced oscillator model to explain the observed differences in entrainment range between mutant and wild-type mice, we sought to quantify the overall oscillator amplitude of their clocks from the activity rhythms and found that mutant mice have weaker circadian clocks than wild types. Our results suggest that genetic redundancy strengthens the circadian clock leading to a narrow entrainment range in vertebrates.
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