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.

• C57BL/6J mice
• circadian clock
• dorsal raphe nucleus
• melatonin
• seasonal affective disorder
• serotonin
• suprachiasmatic nucleus

Declaration of interest

Authors declare no conflicts of interest. This work was, in part, supported by Grants-in-Aid for Young Scientists (B) (No.24780286) to S. Y., Challenging Exploratory Research (No.24650490) and Scientific Research (A) (No. 23248046) to M. F. from the Japanese Society for the Promotion of Science. Contribution of A. D. N. to this work was supported by the Matsumae International Foundation, and the Hungarian Scientific Research Fund (OTKA-PD100927).

AUTHOR CONTRIBUTIONS

A.D.N. and S.Y. jointly designed the experiments. A.D.N. implemented the experiments, performed data acquisition, analysis and interpretation, and wrote the manuscript. S.Y. developed the concept and gave feedback on the manuscript. Technical assistance was provided by A.I. (in situ hybridization), M.K., R.G. (animal management), H.M., T.O. (HPLC, behavioural studies) and M.N. (equipment maintenance, data analysis). M.F. gave technical support and conceptual advice, including discussions and comments on the manuscript. All authors discussed and drafted the work, and approved the manuscript.