Neurobiology of Circadian Dysrhythmias

描述(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，一个SCN组织起搏器包含多个耦合的单细胞振荡器和一个由互锁和嵌套的自动调节反馈回路组成的系统。在描述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，系统在给定输入后的输出可能不是线性的，这会对动物行为产生显著的影响。值得注意的例子是恒定光照(LL)的一些影响--金黄仓鼠的“分裂”和遗传缺陷小鼠的昼夜节律--戏剧性地重组了昼夜节律系统。我们建议通过实验来研究这些现象，但从一个传统上不适用于仓鼠和老鼠研究的角度进行研究。众所周知，复杂系统经常表现出两种或两种以上的稳定状态--如分裂和不分裂，或者节奏&没有节奏--这些状态可以通过适当的小的、适当的时间扰动来获得。这种系统的优选状态可以在某些条件下转换，例如，如果外部环境或系统组件被改变。利用仓鼠和小鼠，我们提出了啮齿动物昼夜节律系统潜在的双稳定性的初步证据，并概述了研究其神经生物学的实验计划。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，通常喜欢的未分裂状态变得不那么健壮，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通过在固有的双稳定昼夜节律系统中引入噪声元素来促进分裂，最终推动从未分裂到分裂状态的切换。我们还测试了我们的假设，即转轮本身是拆分过程中必要的一部分。在目标3中，我们测试了我们的假设，即在昼夜节律领域中，遗传缺陷的小鼠昼夜节律系统不如野生型那么健壮，容易被转换到另一种节律或静止状态，[特别是]通过L1中的强音或噪声输入。我们预测，我们的研究将为复杂的昼夜节律系统的组织、它们对系统组成部分的不完善和环境变化的脆弱性提供新的见解，甚至可能提供我们对昼夜节律紊乱的看法以及如何修复它们。

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.