The clock genes period 1 and period 2 mediate diurnal rhythms in dioxin-induced Cyp1A1 expression in the mouse mammary gland and liver.

Transcription factors expressing Per-Arnt-Sim (PAS) domains are key components of the mammalian circadian clockworks found in most cells and tissues. Because these transcription factors interact with other PAS genes mediating xenobiotic metabolism and because toxin responses are often marked by daily variation, we determined whether the toxin-mediated activation of the signaling pathway involving several PAS genes, the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT), fluctuates rhythmically and whether this diurnal oscillation is affected by targeted disruption of key PAS genes in the circadian clockworks, Period 1 (Per1) and Per2. Treatment with the prototypical Ahr ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), had inductive effects on a key target of AhR signaling, Cyp1A1, in both the mammary gland and liver of all animals. In wild type mice, the amplitude of this TCDD-induced Cyp1A1 expression in the mammary gland and liver was significantly greater (23-43-fold) during the night than during the daytime. However, the diurnal variation in the TCDD induction of mammary gland and liver Cyp1A1 expression was abolished in Per1(ldc), Per2(ldc) and Per1(ldc)/Per2(ldc) mutant mice, suggesting that Per1, Per2 and their timekeeping function in the circadian clockworks mediate the diurnal modulation of AhR-regulated responses to TCDD in the mammary gland and liver.

Duration of melatonin regulates seasonal changes in song control nuclei of the house sparrow, Passer domesticus: independence from gonads and circadian entrainment.

Avian behavior and physiology are temporally regulated by a complex circadian clock on both a daily and an annual basis. The circadian secretion of the hormone melatonin is a critical component of the regulation of circadian/daily processes in passerine birds, but there is little evidence that the gland regulates annual changes in primary reproductive function. Here it is shown that locomotor rhythms of house sparrows, Passer domesticus, which are made arrhythmic by either pinealectomy or maintenance in constant light, can be synchronized by daily administration of melatonin of different durations to simulate the melatonin profiles indicative of long and short photoperiods. Pinealectomized male sparrows maintained in constant darkness were entrained by both melatonin regimens. In both cases, testes were regressed and the song control nuclei were small. Intact male house sparrows maintained in constant light were also entrained to both melatonin regimens. However, sparrows that received a long duration melatonin cycle exhibited small song control nuclei, while sparrows that received short duration melatonin or no melatonin at all exhibited large song control nuclei. The data indicate that seasonal changes in melatonin duration contribute to the regulation of song control nuclei.

Modulation of intercellular calcium signaling by melatonin in avian and mammalian astrocytes is brain region-specific.

Calcium waves among glial cells impact many central nervous system functions, including neural integration and brain metabolism. Here, we characterized the modulatory effects of melatonin, a pineal neurohormone that mediates circadian and seasonal processes, on glial calcium waves derived from different brain regions and species. Diencephalic and telencephalic astrocytes, from both chick and mouse brains, expressed melatonin receptor proteins. Further, using the calcium-sensitive dye Fluo-4, we conducted real-time imaging analyses of calcium waves propagated among mammalian and avian astrocytes. Mouse diencephalic astrocytic calcium waves spread to an area 2-5-fold larger than waves among avian astrocytes and application of 10 nM melatonin caused a 32% increase in the spread of these mammalian calcium waves, similar to the 23% increase observed in chick diencephalic astrocytes. In contrast, melatonin had no effect on calcium waves in either avian or mammalian telencephalic astrocytes. Mouse telencephalic calcium waves radially spread from their initiation site among untreated astrocytes. However, waves meandered among mouse diencephalic astrocytes, taking heterogeneous paths at variable rates of propagation. Brain regional differences in wave propagation were abolished by melatonin, as diencephalic astrocytes acquired more telencephalon-like wave characteristics. Astrocytes cultured from different brain regions, therefore, possess fundamentally disparate mechanisms of calcium wave propagation and responses to melatonin. These results suggest multiple roles for melatonin receptors in the regulation of astroglial function, impacting specific brain regions differentially.