No abstract

The neurotransmitter serotonin plays an important role in the regulation of the circadian clock. To gain further insight into the mechanisms by which serotonin regulates rhythmicity, the authors investigated photic and nonphotic effects on the circadian clock in Pet-1 knockout mice. In these mice, the serotonergic system suffers a developmental loss of 70% of serotonin neurons, with the remaining neurons being deficient in serotonergic function as well. Pet-1 knockout mice show significantly decreased phase delays of the circadian clock in response to light pulses in the early night; however, this difference was not reflected in a difference in the expression of Fos protein in the suprachiasmatic nucleus. There were no genotypic differences detected in the phase-shifting response to injection of the 5-HT1A/7 (serotonin 1A and 7) agonist 8-OH-DPAT ((±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide); however, there were small but significant differences in the phase-shifting responses to cages between genotypes and sexes. Several different patterns of wheel-running activity were observed in knockout mice that differed from those in wild-type mice, suggesting that normal serotonergic function is necessary for the proper consolidation of nocturnal activity. Overall, these data are consistent with other pharmacological and genetic studies demonstrating a significant role for serotonin in circadian clock function.

Serotonin plays an important role in the central regulation of circadian clock function. Serotonin levels are generally higher in the brain during periods of high activity, and these periods are in turn heavily regulated by the circadian clock located in the suprachiasmatic nucleus. However, the role of serotonin as a regulator of circadian rhythms elsewhere in the brain has not been extensively examined. In this study, we examined circadian rhythms of clock gene expression in the cerebellum in mice lacking the Pet-1 transcription factor, which results in a developed brain that is deficient in serotonin neurons. If serotonin helps to synchronize rhythms in brain regions other than the suprachiasmatic nucleus, we would expect to see differences in clock gene expression in these serotonin deficient mice. We found minor differences in the expression of Per1 and Per2 in the knockout mice as compared to wild type, but these differences were small and of questionable functional importance. We also measured the response of cerebellar clocks to injections of the serotonin agonist 8-OH-DPAT during the early part of the night. No effect on clock genes was observed, though the immediate-early gene Fos showed increased expression in wild type mice but not the knockouts. These results suggest that serotonin is not an important mediator of circadian rhythms in the cerebellum in a way that parallels its regulation of the circadian clock in the suprachiasmatic nucleus.