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Am J Physiol Regul Integr Comp Physiol (February 15, 2007). doi:10.1152/ajpregu.00687.2006
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Submitted on September 27, 2006
Accepted on February 9, 2007

Behavioral Characterization and Modulation of Circadian Rhythms By Light and Melatonin in C3H/HeN Mice Homozygous for the ROR{beta} Knockout

Monica I Masana1, Isabel C Sumaya2, Michael Becker-Andre3, and Margarita L Dubocovich1*

1 Molecular Pharmacology and Biological Chemistry (S-215), Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
2 Department of Psychology, California State University, Bakersfield, California, United States
3 Institute for Biometry and Epidemiology, Ludwig Maximilian University Munich, Munich, Germany

* To whom correspondence should be addressed. E-mail: mdubo{at}northwestern.edu.

This study reports for the first time the effects of ROR{beta} receptor gene deletion [ROR{beta}(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{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 wheel running activity in all genotypes showed entrainment to the light/dark (LD) cycle, and free running in constant dark, with ROR{beta} (C3H)-/- mice showing a significant increase in circadian period (t{alpha}u). Melatonin administration (90 µg/mouse, s.c. for 3 days) at CT 10 induced phase advances while exposure to a light pulse (300 lux) at CT14 induced phase delays of circadian 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 re-entrainment after a 6 hour advance in the L/D cycle compared to (+/+) mice. Yet, the rate of re-entrainment was significantly advanced by melatonin administration at the new dark onset in both (+/+) and (-/-) mice. We conclude that the ROR{beta} 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.




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