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.

Persistent Effects of Developmental Exposure to 17α-Ethinylestradiol on the Zebrafish (Danio rerio) Brain Transcriptome and Behavior

“…Estrogens administered to ovariectomized rats have an effect on the period length and onset of locomotor activity (Krizo and Mintz, 2014). Photoperiod and melatonin, the major hormone in the circadian rhythm, is implied in the modulation of anxiety in rodents (Golombek et al, 1996; Nava and Carta, 2001; Trainor et al, 2007; Bilu and Kronfeld-Schor, 2013; Adamah-Biassi et al, 2014; Kumar et al, 2014; Nagy et al, 2014), possibly mediated by interaction with the GABAergic system (Golombek et al, 1996). Taken together, the observed effects on genes related to the circadian rhythm in female brain might represent a plausible connection to the stress sensitive behavior phenotype.…”

Dietary Sources and Bioactivities of Melatonin

“…Additionally, melatonin was found to adjust the expression pattern of clock genes (per1, per2, bmal1 and clock) in the SCN mainly by increasing amplitude in their expressional rhythms without inducing robust phase shifts in them. In addition, melatonin could alter the expression of genes of serotonergic neurotransmission (tph2, sert, vmat2 and 5ht1a) in the dorsal raphe and serotonin contents in the amygdala, and improve the depression-like behavior in C57BL/6J mice with seasonal affective disorder [218]. …”

Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status

“…Thus, multiple signaling pathways are mediated by melatonin receptor activation. Focusing on the SCN, both melatonin receptors are involved in regulating the expression of the core clock genes ( Per1 , Per2 , Bmal1 , and Clock ) [26, 36, 37]. Although the circadian machinery is present in every cell, the effect of melatonin on rhythmic clock gene expression is not yet clear.…”