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

This study reports for the first time the effects of retinoid-related orphan receptors [RORP; receptor gene deletion ROR beta(C3H)(-/-)] in C3H/ HeN mice on behavioral and circadian phenotypes. Pineal melatonin levels showed a robust diumal rhythm with high levels at night in wild-type (+/+), heterozygous (+/-), and knockout (-/-) mice. The ROR beta(C3H)(-/-) mice displayed motor (duck gait, hind paw clasping reflex) and olfactory deficits, and reduced anxiety and learned helplessness-related behaviors. Circadian rhythms of wheelrunning activity in all genotypes showed entrainment to the light-dark (LD) cycle, and free running in constant (lark, with RORP(C3H)(-/-) mice showing a significant increase in circadian period (tau). Melatonin administration (90 mu g/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 cireadian activity rhythms of the same magnitude in all genotypes. In ROR beta(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 RORP 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.