Suprachiasmatic Control of Peripheral Circadian Rhythms

描述（由申请人提供）：下丘脑的视交叉上核（SCN）包含一个主起搏器，控制各种生理和行为的昼夜节律。最近的工作提供了一个透彻的了解，这些振荡产生的分子机制。周期，Bmal 1和隐花色素基因的节律性和光调节表达是必不可少的起搏器功能。令人惊讶的是，这些基因也在各种外周器官中有节奏地表达，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SCN依赖的信号负责的持久性周边振荡的性质。这些信号可以是神经的、体液的或行为的，并且各种器官可以依赖于不同的信号或信号的组合。前两个具体的目标将集中在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支配与体液信号在外周昼夜节律调节中的重要性，所述叙利亚仓鼠的昼夜节律已通过长期暴露于恒定光而被诱导分裂。我们将确定这种动物SCN中的不对称haPer 1 -2和haBmal 1表达是否与双侧配对和未配对外周器官中身体左侧和右侧相同基因表达的不对称性相关。还将评估这些外周器官中生理学重要基因的不对称表达。具体目标2将扩展我们的发现，SCN病变消除周边昼夜节律仓鼠，并建立是否去神经支配睾丸，脾脏或肌肉复制SCN病变后的影响，节奏haPer 1 -3和haBmal 1的表达。具体目标3将通过利用联体小鼠模型来检查非神经信号对外周振荡的调节，在联体小鼠模型中，通过将血液供应与完整动物的血液供应相联系来逆转SCN损伤的影响。我们将扩展我们的表征周围的昼夜节律振荡SCN损伤，联体小鼠，并确定是否社会因素或温度线索可以有助于这种效果。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.