title: Melatonin adjusts the expression pattern of clock genes in the suprachiasmatic nucleus and induces antidepressant-like effect in a mouse model of seasonal affective disorder.
abstract: Recently, we have shown that C57BL/6J mice exhibit depression-like behavior under short photoperiod and suggested them as an animal model for investigating seasonal affective disorder (SAD). In this study, we tested if manipulations of the circadian clock with melatonin treatment could effectively modify depression-like and anxiety-like behaviors and brain serotonergic system in C57BL/6J mice. Under short photoperiods (8-h light/16-h dark), daily melatonin treatments 2 h before light offset have significantly altered the 24-h patterns of mRNA expression of circadian clock genes (per1, per2, bmal1 and clock) within the suprachiasmatic nuclei (SCN) mostly by increasing amplitude in their expressional rhythms without inducing robust phase shifts in them. Melatonin treatments altered the expression of genes of serotonergic neurotransmission in the dorsal raphe (tph2, sert, vmat2 and 5ht1a) and serotonin contents in the amygdala. Importantly, melatonin treatment reduced the immobility in forced swim test, a depression-like behavior. As a key mechanism of melatonin-induced antidepressant-like effect, the previously proposed phase-advance hypothesis of the circadian clock could not be confirmed under conditions of our experiment. However, our findings of modest adjustments in both the amplitude and phase of the transcriptional oscillators in the SCN as a result of melatonin treatments may be sufficient to associate with the effects seen in the brain serotonergic system and with the improvement in depression-like behavior. Our study confirmed a predictive validity of C57BL/6J mice as a useful model for the molecular analysis of links between the clock and brain serotonergic system, which could greatly accelerate our understanding of the pathogenesis of SAD, as well as the search for new treatments.
authors.affiliation: Faculty of Agriculture, Laboratory of Regulation in Metabolism and Behavior, Kyushu University , Higashi-ku, Fukuoka , Japan and.
authors.forename: Andras David
authors.initials: AD
authors.lastname: Nagy
authors.forename: Ayaka
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Misato
authors.initials: M
authors.lastname: Kawai
authors.forename: Ryosei
authors.initials: R
authors.lastname: Goda
authors.forename: Haruka
authors.initials: H
authors.lastname: Matsuo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Otsuka
authors.forename: Mao
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Furuse
authors.forename: Shinobu
authors.initials: S
authors.lastname: Yasuo
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D057906:Circadian Clocks / Q000187:drug effects* / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D008027:Light; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D056950:Period Circadian Proteins / Q000235:genetics*; D016574:Seasonal Affective Disorder / Q000235:genetics* / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D056950:Period Circadian Proteins; D008550:Melatonin
keywords: C57BL/6J mice; circadian clock; dorsal raphe nucleus; melatonin; seasonal affective disorder; serotonin; suprachiasmatic nucleus