Developmental disruption of the serotonin system alters circadian rhythms

Abstract

Serotonin (5-HT) plays an important role in circadian rhythms, acting to modulate photic input to the mammalian clock, the suprachiasmatic nucleus (SCN), as well as playing a role in non-photic input. The transcription factor Pet-1 is an early developmental indicator of neurons that are destined for a 5-HTergic fate. Mice lacking the Pet-1 gene show a 70% loss of 5-HT immunopositive cell bodies in adult animals. 5-HT neurotoxic lesion studies using 5,7-dihydroxytryptamine (5,7-DHT) have highlighted species-specific differences in response to 5-HT depletion and studies using knockout mice lacking various 5-HT receptors have helped to elucidate the role of individual 5-HT receptors in mediating 5-HT's effects on circadian rhythms. Here we investigate the effects of a developmental disruption of the 5-HT system on the SCN and circadian wheel-running behavior. Immunohistochemical analysis confirmed depletion of 5-HT fiber innervation to the SCN as well as greatly reduced numbers of cell bodies in the raphe nuclei in Pet-1 knockout mice. These mice also display significantly longer free-running periods than wildtype or heterozygote counterparts. In light–dark cycles, knockouts showed a shift in peak wheel running behavior towards the late night as compared to wildtype and heterozygote animals. When kept in constant darkness for 70days, wildtype animals showed decreases in free-running period over time while the period of knockout animals remained constant. Immunohistochemical analysis for neuropeptides within the SCN indicates that the behavioral changes observed in Pet-1 knockout mice were not due to gross changes in SCN structure. These results suggest that developmental loss of serotonergic input to the clock has long-term consequences for both circadian clock parameters and the temporal organization of activity.