Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood.
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.
Hampp
Gabriele
G
Department of Medicine, Division of Biochemistry, University of Fribourg, Fribourg, Switzerland.
Ripperger
Jürgen A
JA
Houben
Thijs
T
Schmutz
Isabelle
I
Blex
Christian
C
Perreau-Lenz
Stéphanie
S
Brunk
Irene
I
Spanagel
Rainer
R
Ahnert-Hilger
Gudrun
G
Meijer
Johanna H
JH
Albrecht
Urs
U
D000339:Affect / Q000502:physiology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects; D001683:Biological Clocks / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000502:physiology*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins; D011401:Promoter Regions, Genetic; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D056925:Circadian Rhythm Signaling Peptides and Proteins; D008996:Monoamine Oxidase Inhibitors; C557510:Npas2 protein, rat; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D008995:Monoamine Oxidase; D004298:Dopamine