Suprachiasmatic Control of Peripheral Circadian Rhythms

描述（由申请人提供）：下丘脑视交叉上核（SCN）包含一个主起搏器，控制各种生理和行为的昼夜节律。最近的工作为这些振荡产生的分子机制提供了透彻的理解。周期、Bmal1和隐色素基因的节律性和光调控表达对起搏器功能至关重要。令人惊讶的是，这些基因在各种外周器官中也有节律地表达，但它们在体内的持续振荡似乎取决于SCN的完整性。目前的实验将集中于负责外围振荡持续的scn依赖信号的性质。这些信号可能是神经的、体液的或行为的，各种器官可能依赖于不同的信号或信号的组合。前两个具体目标将集中于神经控制外周振荡的程度。具体目标1将进一步测试神经支配与体液信号在调节外周昼夜节律中的重要性，通过使用叙利亚仓鼠，这些仓鼠的昼夜节律因长期暴露于恒定光线而被诱导分裂。我们将确定这些动物的SCN中haPer1-2和haBmal1的不对称表达是否与双侧配对和未配对的外周器官中身体左右两侧相同基因的不同步表达相关。这些外周器官中重要生理基因的不对称表达也将被评估。特异性目标2将扩展我们的发现，即SCN病变消除仓鼠的外周昼夜节律，并确定睾丸、脾脏或肌肉的去神经支配是否复制SCN病变对haPer1-3和haBmal1节律性表达的影响。具体目标3将通过利用异种小鼠模型的优势来检查非神经信号对外周振荡的调节，在该模型中，SCN病变的影响通过与完整动物的血液供应联系而逆转。我们将在scn受损的异种小鼠中扩展我们的外周昼夜节律振荡特征，并确定社会因素或温度线索是否有助于这种影响。由于起搏器和外周振荡器之间的异常相位关系似乎有助于时差反应，并可能涉及其他病理，包括睡眠障碍，季节性抑郁症和不孕症，我们的研究结果将对人类健康和福利具有应用价值。

DESCRIPTION (provided by applicant): 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.