Circadian rhythms, which measure time on a scale of 24 h, are the overt consequences of biological clocks. When isolated from environmental time cues, a circadian oscillator free-runs with its own period which is usually different from 24 h. However, in the presence of the natural cycle of light and temperature, circadian oscillators are adjusted to exactly 24 h. Because these two major environmental signals are closely associated in nature, it is not surprising that the entraining effect of temperature cycles mimics that of the light-dark cycle in fungi, plants and poikilotherms. Most scientists, however, would predict that homeotherms would not be affected by temperature. Nevertheless, using Per1-luc transgenic rats to measure circadian fluctuations of Per1 from cultured suprachiasmatic nuclei (SCN), we have shown that the isolated SCN can be entrained by temperature cycles with an amplitude as low as 1 ?C, well within the range of the normal brain temperature rhythm of rodents (1 to 1.5 ?C). One of the unique and fundamental phenomena in circadian rhythms is temperature compensation; rhythms exhibit similar cycle durations over a wide range of temperatures. Although this phenomenon was discovered nearly 50 years ago, the biochemical or molecular mechanisms mediating this phenomenon are still not known. It was previously shown that the rhythms in the SCN and retina in mammals are temperature compensated. Our lab recently demonstrated that temperature compensation also exists in peripheral cells. In this proposal, the two major impacts of temperature on the mammalian circadian system: entrainment and compensation will be analyzed. The hypothesis that temperature entrainment is mediated by changing Per1 mRNA levels, whereas temperature compensation is affected by different degradation rates of mRNAs in three Period genes will be studied. ? The overall goal of our proposal is to identify molecular targets in the clock mechanism responsible for the demonstrated temperature effects. Information obtained in this proposal will be essential for the informed use of circadian approaches to the understanding and treatment of circadian-related concerns in humans, such as shift work, jet-lag, and chrono-cancer therapy. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BRS (01))
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Mitler, Merrill
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Vanderbilt University Medical Center
Schools of Arts and Sciences
United States
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Pendergast, Julie S; Yamazaki, Shin (2011) Masking responses to light in period mutant mice. Chronobiol Int 28:657-63
Yeom, Mijung; Pendergast, Julie S; Ohmiya, Yoshihiro et al. (2010) Circadian-independent cell mitosis in immortalized fibroblasts. Proc Natl Acad Sci U S A 107:9665-70
Pendergast, Julie S; Friday, Rio C; Yamazaki, Shin (2010) Photic entrainment of period mutant mice is predicted from their phase response curves. J Neurosci 30:12179-84
Pendergast, Julie S; Friday, Rio C; Yamazaki, Shin (2010) Distinct functions of Period2 and Period3 in the mouse circadian system revealed by in vitro analysis. PLoS One 5:e8552
Shi, Shuqun; Hida, Akiko; McGuinness, Owen P et al. (2010) Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2. Curr Biol 20:316-21
Pendergast, Julie S; Nakamura, Wataru; Friday, Rio C et al. (2009) Robust food anticipatory activity in BMAL1-deficient mice. PLoS One 4:e4860
Pendergast, Julie S; Friday, Rio C; Yamazaki, Shin (2009) Endogenous rhythms in Period1 mutant suprachiasmatic nuclei in vitro do not represent circadian behavior. J Neurosci 29:14681-6
Mistlberger, Ralph E; Yamazaki, Shin; Pendergast, Julie S et al. (2008) Comment on ""Differential rescue of light- and food-entrainable circadian rhythms"". Science 322:675;author reply 675
Akashi, Makoto; Hayasaka, Naoto; Yamazaki, Shin et al. (2008) Mitogen-activated protein kinase is a functional component of the autonomous circadian system in the suprachiasmatic nucleus. J Neurosci 28:4619-23
Reyes, Bryan A; Pendergast, Julie S; Yamazaki, Shin (2008) Mammalian peripheral circadian oscillators are temperature compensated. J Biol Rhythms 23:95-8

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