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SLEEP AND TEMPERATURE REGULATION

Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the ROR knockout

¹Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois; ²Glaxo Institute for Molecular Biology, Geneva, Switzerland; ³Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine and ⁴Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, Illinois

Submitted 27 September 2006 ; accepted in final form 9 February 2007

This study reports for the first time the effects of retinoid-related orphan receptors [ROR; receptor gene deletion ROR(C3H)^–/–] in C3H/HeN mice on behavioral and circadian phenotypes. Pineal melatonin levels showed a robust diurnal rhythm with high levels at night in wild-type (+/+), heterozygous (+/–), and knockout (–/–) mice. The ROR(C3H)^–/– mice displayed motor ("duck gait," hind paw clasping reflex) and olfactory deficits, and reduced anxiety and learned helplessness-related behaviors. Circadian rhythms of wheel-running activity in all genotypes showed entrainment to the light-dark (LD) cycle, and free running in constant dark, with ROR(C3H)^–/– mice showing a significant increase in circadian period (tau). Melatonin administration (90 µg/mouse sc for 3 days) at circadian time (CT) 10 induced phase advances, while exposure to a light pulse (300 lux) at CT 14 induced phase delays of circadian activity rhythms of the same magnitude in all genotypes. In ROR(C3H)^–/– mice a light pulse at CT 22 elicited a larger phase advance in activity rhythms and a slower rate of reentrainment after a 6-h advance in the LD cycle compared with (+/+) mice. Yet, the rate of reentrainment was significantly advanced by melatonin administration at the new dark onset in both (+/+) and (–/–) mice. We conclude that the ROR nuclear receptor is not involved in either the rhythmic production of pineal melatonin or in mediating phase shifts of circadian rhythms by melatonin, but it may regulate clock responses to photic stimuli at certain time domains.

retinoid-related orphan receptors gene; circadian activity rhythms; melatonin receptors; suprachiasmatic nucleus

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