The suprachiasmatic nucleus of the hypothalamus (SCN) contains a master pacemaker that controls a wide variety of circadian rhythms of physiology and behavior. Recent work has provided a thorough understanding of molecular mechanisms by which these oscillations are generated. The rhythmic and light-regulated expression of Period, Bmal1, and Cryptochrome genes are essential to pacemaker function. Surprisingly, these genes are also expressed rhythmically in a variety of peripheral organs, but their sustained oscillations in vivo appear to depend upon integrity of the SCN. The present experiments will focus on the nature of the SCN-dependent signals responsible for the persistence of peripheral oscillations. Such signals may be neural, humoral, or behavioral, and various organs may rely on different signals or a combination of signals. The first two specific aims will focus on the extent of neural control of peripheral oscillations.
Specific aim 1 will test further the importance of innervation vs. humoral signals in regulation of circadian rhythms in the periphery through use of Syrian hamsters whose circadian rhythms have been induced to split by long-term exposure to constant light. We will determine whether the asymmetrical haPer1-2 and haBmal1 expression in the SCN of such animals is correlated with asynchrony of expression of the same genes on the left and right sides of the body in bilaterally paired and unpaired peripheral organs. Asymmetrical expression of physiologically important genes in these peripheral organs will also be assessed.
Specific aim 2 will extend our findings that SCN lesions eliminate peripheral circadian rhythms in hamsters, and establish whether denervation of testis, spleen or muscle replicates the effects of SCN lesions upon rhythmic haPer1-3 and haBmal1 expression.
Specific aim 3 will examine the regulation of peripheral oscillations by non-neural signals by taking advantage of a parabiotic mouse model in which the effects of SCN lesions are reversed by linkage of the blood supply to that of an intact animal. We will extend our characterization of peripheral circadian oscillations in SCN-lesioned, parabiotic mice and determine whether social factors or temperature cues can contribute to this effect. Inasmuch as abnormal phase relationships between the pacemaker and peripheral oscillators appear to contribute to jet lag and may be involved in other pathologies including sleep disorders, seasonal depression, and infertility, our findings will have applications to human health and welfare.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biological Rhythms and Sleep Study Section (BRS)
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Vicentic, Aleksandra
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University of Massachusetts Amherst
Schools of Arts and Sciences
United States
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Manoogian, Emily N C; Leise, Tanya L; Bittman, Eric L (2015) Phase resetting in duper hamsters: specificity to photic zeitgebers and circadian phase. J Biol Rhythms 30:129-43
Bittman, Eric L (2014) Effects of the duper mutation on responses to light: parametric and nonparametric responses, range of entrainment, and masking. J Biol Rhythms 29:97-109
Mahoney, Carrie E; Brewer, Judy McKinley; Bittman, Eric L (2013) Central control of circadian phase in arousal-promoting neurons. PLoS One 8:e67173
Bittman, Eric L (2012) Does the precision of a biological clock depend upon its period? Effects of the duper and tau mutations in Syrian hamsters. PLoS One 7:e36119
Krug, Stefanie; McKinley Brewer, Judy; Bois, Alexandre S et al. (2011) Effects of the duper mutation on circadian responses to light. J Biol Rhythms 26:293-304
Mahoney, Carrie E; Brewer, Daniel; Costello, Mary K et al. (2010) Lateralization of the central circadian pacemaker output: a test of neural control of peripheral oscillator phase. Am J Physiol Regul Integr Comp Physiol 299:R751-61
Bittman, Eric L (2009) Vasopressin: more than just an output of the circadian pacemaker? Focus on ""Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei"". Am J Physiol Regul Integr Comp Physiol 296:R821-3
Bittman, Eric L; Costello, Mary K; Brewer, Judy McKinley (2007) Circadian organization of tau mutant hamsters: aftereffects and splitting. J Biol Rhythms 22:425-31