Suprachiasmatic Control of Peripheral Circadian Rhythms

描述(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。最近的工作提供了对产生这些振荡的分子机制的透彻理解。Period、BMal1和CryptoChrome基因的节律性和光调控表达是起搏器功能所必需的。令人惊讶的是，这些基因在各种外周器官中也有节奏地表达，但它们在体内的持续振荡似乎取决于SCN的完整性。目前的实验将集中在负责外周振荡持续的依赖于SCN的信号的性质。这样的信号可以是神经、体液或行为的，各种器官可能依赖于不同的信号或信号的组合。前两个具体目标将侧重于神经控制外周振荡的程度。具体目标1将通过使用叙利亚仓鼠进一步测试神经与体液信号在调节外围昼夜节律中的重要性，叙利亚仓鼠的昼夜节律已被长期暴露在持续光照下诱导分裂。我们将确定这类动物SCN中不对称的haPer1-2和haBMal1表达是否与两侧配对和未配对的周围器官中相同基因在身体左侧和右侧的表达不同步有关。这些外周器官中重要的生理基因的不对称表达也将被评估。具体目标2将扩展我们的发现，即SCN损伤消除了金黄地鼠的外周昼夜节律，并确定睾丸、脾或肌肉的去神经是否复制了SCN损伤对节律性haPer1-3和haBMal1表达的影响。具体目标3将利用异种生物小鼠模型来研究非神经信号对外周振荡的调节，在该模型中，SCN损伤的影响通过血液供应与完整动物的联系来逆转。我们将扩展我们对SCN损伤、异种生物小鼠外周昼夜节律振荡的描述，并确定社会因素或温度线索是否会对这种影响起到作用。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因素，包括睡眠障碍、季节性抑郁和不孕不育，我们的发现将应用于人类健康和福利。

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.