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.
