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Phase responses to light pulses in mice lacking functional per or cry genes
Kamiel Spoelstra1, Urs Albrecht, Gijsbertus T J van der Horst
1Zoological Laboratory, University of Groningen, The Netherlands. K.Spoelstra@biol.rug.nl
Abstract:
The phase-resetting properties of the circadian system in mice with a functional deletion in mCry1, mCry2, mPer1, or mPer2 were studied in 2 experiments. In experiment 1, mCry1(-/-) and mCry2(-/-) mice as well as mPer1(Brdm1) and mPer2(Brdm1) mutant mice were exposed to 15-min light pulses during the 1st cycle following entrainment, either early (external time [ExT] 20) or late (ExT 4) in the subjective night. In experiment 2, a full PRC was measured for all these strains by exposure to light pulses of the same duration and intensity in free-running conditions in constant darkness. Directly after entrainment (experiment 1), mPer1(Brdm1) animals did not show significant phase advances by a light pulse in the late subjective night (ExT 4), as in the study by Albrecht et al. In the same experiment, mPer2(Brdm1) mice became arrhythmic too frequently to reliably measure their phase responses. Mice with a targeted gene disruption in mCry1 or mCry2 showed increased phase delays compared to wild type after exposure to a light pulse in the early subjective night (ExT 20). Otherwise, phase shifts were not significantly affected. In free run (experiment 2), all genotypes did show phase advances and phase delays. The mPer2(Brdm1) mutant PRC was above the mPer1(Brdm1) mutant and wild-type PRC (i.e., less delayed and more advanced) at most circadian phases. The mPer1(Brdm1) mutant PRC was not distinguishable from the wildtype PRC. The mCry2(-/-) mice showed much smaller phase delays than did mCry1(-/-) mice in the subjective evening (delay phase). In general, mPer2(Brdm1) mutant mice were more accelerated by light compared to mPer1(Brdm1) and wildtype control mice, whereas mCry1(-/-) mice were more delayed by light than were mCry2(-/-) mice.
Insights
Circadian rhythm gene deletions in mice reveal distinct light response patterns. Mutant mice show altered phase shifts, with mPer2 mutants exhibiting accelerated rhythms and mCry1 mutants showing greater delays, impacting overall circadian timing.
Area of Science:
- Chronobiology
- Molecular Biology
- Genetics
Background:
- The circadian system regulates daily biological rhythms, crucial for organismal health.
- Core clock genes, including Period (Per) and Cryptochrome (Cry), are essential for circadian rhythmicity.
- Understanding the specific roles of these genes in light-induced phase resetting is vital.
Purpose of the Study:
- To investigate the phase-resetting properties of the mouse circadian system.
- To determine the impact of targeted gene deletions in mCry1, mCry2, mPer1, and mPer2 on light-induced phase shifts.
- To characterize the phase response curves (PRCs) of these mutant mouse strains.
Main Methods:
- Two experiments were conducted using genetically modified mice (mCry1-/-, mCry2-/-, mPer1(Brdm1), mPer2(Brdm1)) and wild-type controls.
- Mice were exposed to 15-min light pulses at specific times during entrainment and under free-running conditions in constant darkness.
- Phase shifts were measured, and full phase response curves (PRCs) were generated for each genotype.
Main Results:
- mPer1(Brdm1) mice showed no significant phase advances to late-night light pulses. mPer2(Brdm1) mice frequently became arrhythmic.
- mCry1(-/-) and mCry2(-/-) mice exhibited increased phase delays to early-night light pulses compared to wild types.
- In free-running conditions, mPer2(Brdm1) PRCs indicated greater light acceleration, while mPer1(Brdm1) PRCs were similar to wild types. mCry1(-/-) mice showed larger delays than mCry2(-/-) mice.
Conclusions:
- Distinct roles for mPer2 and mCry1/mCry2 in mediating light-induced circadian phase shifts were identified.
- mPer2 plays a significant role in light-induced acceleration, while mCry1 and mCry2 influence light-induced delays.
- These findings highlight the differential contributions of core clock genes to the plasticity of the mammalian circadian system.
