Masana MI, Sumaya IC, Becker-Andre M, Dubocovich ML. Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the ROR knockout. Am J Physiol Regul Integr Comp Physiol 292: 2357-2367, 2007. First published February 15, 2007 doi:10.1152/ajpregu.00687.2006.-This study reports for the first time the effects of retinoid-related orphan receptors [ROR; receptor gene deletion ROR(C3H) Ϫ/Ϫ ] 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 (ϩ/ϩ), heterozygous (ϩ/Ϫ), and knockout (Ϫ/Ϫ) mice. The ROR(C3H) Ϫ/Ϫ 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 dark, with ROR(C3H)mice showing a significant increase in circadian period (tau). Melatonin administration (90 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 circadian activity rhythms of the same magnitude in all genotypes. In ROR(C3H) Ϫ/Ϫ 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 (ϩ/ϩ) mice. Yet, the rate of reentrainment was significantly advanced by melatonin administration at the new dark onset in both (ϩ/ϩ) and (Ϫ/Ϫ) 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 RETINOID-RELATED ORPHAN RECEPTORS (ROR) belong to a superfamily of nuclear hormone receptors comprising more than 40 transcription factors (7, 24). Members of this superfamily share a common modular structure consisting of a transactivation domain, a DNA-binding domain, and a ligand-binding domain (24). The family of ROR receptors is a subfamily of orphan receptors comprising ROR␣, ROR, and ROR␥ (21). ROR is a nuclear receptor expressed in areas related to processing of sensory information, as well as circadian rhythmicity (27,33). Recently, structural data and structure-function analysis identified all-trans retinoic acid as a bona fide ligand for the ROR nuclear receptor (37).Circadian oscillations of the mammalian biological clock within the suprachiasmatic nucleus (SCN) are driven by a main transcriptional/translational feedback loop of clock gene products. The negative arm of the loop involves the circadian oscillation of three period (Per) genes and two cryptochrome (Cry) genes, potent repressors of CLOCK/BAML1-induced transcription. The positive loop is...