Abstract
Clock genes Cryptochrome (Cry1) and Cry2 are essential for expression of circadian rhythms in mice under constant darkness (DD). However, circadian rhythms in clock gene Per1 expression or clock protein PER2 are detected in the cultured suprachiasmatic nucleus (SCN) of neonatal Cry1 and Cry2 double deficient (Cry1 -/-/Cry2 -/-) mice. A lack of circadian rhythms in adult Cry1 -/-/Cry2 -/- mice is most likely due to developmentally disorganized cellular coupling of oscillating neurons in the SCN. On the other hand, neonatal rats exposed to constant light (LL) developed a tenable circadian system under prolonged LL which was known to fragment circadian behavioral rhythms. In the present study, Cry1 -/-/Cry2 -/- mice were raised under LL from postnatal day 1 for 7 weeks and subsequently exposed to DD for 3 weeks. Spontaneous movement was monitored continuously after weaning and PER2::LUC was measured in the cultured SCN obtained from mice under prolonged DD. Surprisingly, Chi square periodogram analysis revealed significant circadian rhythms of spontaneous movement in the LL-raised Cry1 -/-/Cry2 -/- mice, but failed to detect the rhythms in Cry1 -/-/Cry2 -/- mice raised under light-dark cycles (LD). By contrast, prolonged LL in adulthood did not rescue the circadian behavioral rhythms in the LD raised Cry1 -/-/Cry2 -/- mice. Visual inspection disclosed two distinct activity components with different periods in behavioral rhythms of the LL-raised Cry1-/-/Cry2-/- mice under DD: one was shorter and the other was longer than 24 hours. The two components repeatedly merged and separated. The patterns resembled the split behavioral rhythms of wild type mice under prolonged LL. In addition, circadian rhythms in PER2::LUC were detected in some of the LL-raised Cry1-/-/Cry2-/- mice under DD. These results indicate that neonatal exposure to LL compensates the CRY double deficiency for the disruption of circadian behavioral rhythms under DD in adulthood.
Highlights
Circadian rhythms in physiology and behavior in mammals are regulated by coordination of a central clock located in the hypothalamic suprachiasmatic nucleus (SCN) with peripheral clocks in a variety of tissues [1]
We [4] and another group [5] reported that significant circadian rhythms of clock gene Per1 expression and of clock gene product PER2 were detected in the cultured SCN slice of neonatal Cry1-/-/Cry2-/- mice at the cell as well as the tissue levels
The results indicated that the SCN of adult Cry1-/-/Cry2-/- mice still possesses the capability to oscillate in response to a diffusible factor(s) secreted from the neonatal SCN, and that CRY1 and CRY2 are involved in the developmental reorganization of SCN circadian system to sustain cellular couplings of oscillating cells [4]
Summary
Circadian rhythms in physiology and behavior in mammals are regulated by coordination of a central clock located in the hypothalamic suprachiasmatic nucleus (SCN) with peripheral clocks in a variety of tissues [1]. The molecular clockwork in the SCN is believed to be conducted by an auto-regulatory transcription and translation feedback loop [2], in which clock genes Cryptochrome (Cry1) and Cry and their protein products play crucial roles. The latter notion is based on the observation that Cry and Cry double deficient (Cry1-/-/Cry2-/-) mice become aperiodic in behavior immediately after exposure to constant darkness (DD) [3]. We [4] and another group [5] reported that significant circadian rhythms of clock gene Per expression and of clock gene product PER2 were detected in the cultured SCN slice of neonatal Cry1-/-/Cry2-/- mice at the cell as well as the tissue levels. The results indicated that the SCN of adult Cry1-/-/Cry2-/- mice still possesses the capability to oscillate in response to a diffusible factor(s) secreted from the neonatal SCN, and that CRY1 and CRY2 are involved in the developmental reorganization of SCN circadian system to sustain cellular couplings of oscillating cells [4]
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