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Neurobiology of Circadian Dysrhythmias

昼夜节律失常的神经生物学

基本信息

批准号：
7219377
负责人：
William J Schwartz
金额：
$ 27.89万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Daily rhythms are governed by endogenous circadian clocks, and, in mammals, by the suprachiasmatic nucleus (SCN). The circadian system is complex, with an SCN tissue pacemaker containing multiple, coupled single-cell oscillators and a system composed of interlocking and nested auto-regulatory feedback loops. Advances have been made in delineating the main elements of this network, and we can now begin to analyze its stimulus-response properties at the molecular, cellular, tissue, and behavioral levels. What we are finding is that the system's output after a given input may not be linear, with striking consequences for animal behavior. Notable examples of this are some of the effects of constant light (LL) - "splitting" in golden hamsters and circadian rhythmicity in genetically-deficient mice - that dramatically reorganize the circadian system. We propose to study these phenomena experimentally, but from a perspective that is not traditionally applied in research on hamsters and mice. It is known that complex systems often exhibit two or more stable states - like split & unsplit, or rhythm & no rhythm - that are accessible by small, properly timed perturbations. The preferred state of such systems may switch under certain conditions, e.g., if the outside environment or a system component is altered. Using hamsters and mice, we present preliminary evidence for the potential bi-stability of the rodent circadian system and outline an experimental program for investigating its neurobiology. In Aim 1, we test our hypothesis that bi-stability in the hamster circadian system is revealed in split hamsters that are transferred from LL to darkness, a condition in which the normally favored unsplit state becomes less robust and more vulnerable to being switched to the split state. In Aim 2, we test our hypothesis that LL fosters splitting by introducing an element of noise into an inherently bi-stable circadian system, ultimately propelling the switch from an unsplit to split state. We also test our hypothesis that the running wheel itself is a necessary part of the splitting process. In Aim 3, we test our hypothesis that genetically-deficient murine circadian systems, being less robust than wild type in the circadian domain, are vulnerable to being switched to alternative rhythmic or quiescent states, [especially] by the tonic or noisy inputs in LL. We predict that our studies will provide new insights on the organization of complex circadian systems, on their vulnerability to imperfections in system components and environmental changes, and perhaps even on our views of circadian dysrhythmias and how they might be repaired.

描述（由申请人提供）：日常节律由内源性生物钟控制，在哺乳动物中，由视交叉上核（SCN）控制。昼夜节律系统是复杂的，SCN组织起搏器包含多个耦合的单细胞振荡器和由互锁和嵌套的自动调节反馈回路组成的系统。在描绘这个网络的主要元素方面已经取得了进展，我们现在可以开始在分子、细胞、组织和行为水平上分析它的刺激-反应特性。我们发现，在给定输入之后，系统的输出可能不是线性的，这对动物行为产生了惊人的影响。这方面值得注意的例子是恒定光（LL）的一些影响-金色仓鼠的“分裂”和遗传缺陷小鼠的昼夜节律-这极大地重组了昼夜节律系统。我们建议通过实验研究这些现象，但从传统上不适用于仓鼠和小鼠研究的角度来看。众所周知，复杂系统通常会表现出两个或两个以上的稳定状态，如分裂和不分裂，或节奏和无节奏，这些状态可以通过小的，适当的时间扰动来实现。这种系统的优选状态可以在某些条件下切换，如果外部环境或系统组件发生改变。利用仓鼠和小鼠，我们提出了啮齿动物昼夜节律系统的潜在双稳定性的初步证据，并概述了研究其神经生物学的实验方案。在目标1中，我们测试了我们的假设，即仓鼠昼夜节律系统中的双稳定性在从LL转移到黑暗的分裂仓鼠中被揭示，在这种情况下，通常有利的未分裂状态变得不那么稳健，更容易被切换到分裂状态。在目标2中，我们测试了我们的假设，即LL通过将噪声元素引入固有的双稳态昼夜节律系统来促进分裂，最终推动从未分裂到分裂状态的切换。我们还测试我们的假设，即运行轮本身是一个必要的一部分，分裂过程。在目标3中，我们测试了我们的假设，即遗传缺陷的小鼠昼夜节律系统在昼夜节律域中不如野生型稳健，容易被切换到交替的节律或静止状态，[特别是]通过LL中的紧张或嘈杂输入。我们预测，我们的研究将为复杂的昼夜节律系统的组织提供新的见解，关于它们对系统组件和环境变化的不完善的脆弱性，甚至可能是我们对昼夜节律紊乱的看法以及如何修复它们。