Neural Basis of Mammalian Circadian Organization

描述（由申请人提供）：哺乳动物下丘脑的视交叉上核（SCN）是调节生理和行为的主要生物钟。现在普遍认为，生理节律是通过涉及时钟基因转录和基因产物反馈的分子反馈回路网络在SCN中的单个神经元内产生的。膜现象，包括膜电位，电脉冲和电压控制的离子通量，通常不被认为是核心时钟机制的一部分，而是参与了时间信息从环境到达时钟的途径，以及核心分子计时回路将节律信号传输到SCN组织内和组织外的其他振荡器的途径。最近，在果蝇和哺乳动物中的研究已经提出了膜电导，特别是钙的更重要的作用的可能性。在目前的建议中，我们概述了一系列的实验，这将使我们能够表征膜电位和钙离子内流在SCN节律的调节和产生中所起的确切作用。将讨论四个具体目标。首先，将测试一个假设，即SCN和外周振荡器中持续的节律性需要每日跨膜钙通量，以及钙对起搏器功能的作用是否存在相位依赖性。第二，探讨钙调节生物钟基因节律幅度的功能意义。第三，钙在哺乳动物的昼夜节律夹带的作用将得到解决。最后，将研究钙电导对生物钟影响的潜在机制。总之，这四项实验工作应该为昼夜节律系统同步和节律生成的关键方面提供新的见解。研究哺乳动物昼夜节律的机制与健康有着重要的关系。在疾病状态和人类衰老期间的睡眠质量可以对人类健康产生深远的影响。复杂的轮班工作时间表和跨子午线光线会造成生理中断，需要了解这些情况才能有效解决。人类生理学具有深刻的节律性，需要了解控制这种节律性的机制。

DESCRIPTION (provided by applicant): The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus is a major circadian clock that regulates both physiology and behavior. It is now commonly accepted that circadian rhythms are generated within individual neurons in the SCN through a network of molecular feedback loops involving the transcription of clock genes and feedback by gene products. Membrane phenomena, including membrane potential, electrical impulses and voltage-controlled ionic fluxes, have generally not been considered to be part of the core clock mechanism but rather involved in the pathway by which temporal information reaches the clock from the environment and the pathway by which the core molecular timing loop transmits rhythmic signals to other oscillators within the SCN tissue and beyond. Recently, studies in Drosophila and in mammals have raised the possibility of a more central role for membrane conductances, specifically calcium. In the current proposal we outline a series of experiments that will allow us to characterize the precise role played by membrane potential and calcium influx in the regulation and generation of SCN rhythmicity. Four specific aims will be addressed. First, an hypothesis will be tested that a daily transmembrane calcium flux is required for sustained rhythmicity in the SCN and peripheral oscillators and, also, whether there is a phase dependency for the action of calcium on pacemaker function. Second, the functional significance of calcium regulation of the amplitude of clock gene rhythms will be explored. Third, the role of calcium in mammalian circadian entrainment will be addressed. Finally, the underlying mechanisms governing the effects of calcium conductance on the circadian clock will be studied. Together, the four experimental efforts should provide new insights into critical aspects of circadian system synchronization and rhythm generation. There is significant health relevancy to the study of mechanisms underlying mammalian circadian rhythms. Sleep quality during disease states and in human aging can have a profound effect on human health. Complex shift work schedules and trans-meridian light create physiological disruption that needs to be understood in order to be effectively addressed. Human physiology is profoundly rhythmic and the mechanisms governing this rhythmicity need to be understood.