Multi-Oscillator Interactions of Hamster Circadian Rhythms

在所有哺乳动物物种中，行为和生理功能的显著日常变化都是由位于下丘脑视交叉上核（SCN）的内源性时钟机制产生的。尽管这种昼夜节律的产生器已被有效地概念化和研究为一个单一的、集成的时钟机制，但大量研究表明，它实际上由多个相互作用或耦合的振荡器组成，以产生连贯的日常节律。迄今为止，时钟的多振荡基础已被证明是难以研究的，因为在正常的紧密耦合状态下，单独的振荡单元无法暂时解决。此外，促进振荡器的时间重组进入可临时解决的替代耦合状态的条件与最重要的昼夜节律技术不相容。具体来说，以前的研究无法a)操纵振荡器相对于彼此的时间来评估它们的相互作用，或者b)探测它们对光脉冲的反应，这些光脉冲通常使时钟机制与环境同步。本研究采用了一种新的制备方法，将仓鼠的昼夜节律分为两个不同的部分，可以通过光/暗环境的操纵分别控制。提出的实验将首次允许描述SCN内组件振荡器的最具信息量的输出。此外，在数学基础上假设的振子之间相互作用的性质，可以通过操纵分量振子之间的相对相位关系进行经验检验。这些研究将与正常、未分裂状态下振荡器关系的操作并列。这些研究可能为快速操纵人类昼夜节律提供了新的途径。

Lay Abstract Gorman: IBN 9985676In all mammalian species, marked daily variations in behavioral and physiological function are generated by an endogenous clock-like mechanism located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Although this generator of circadian rhythms has been profitably conceptualized and studied as a single, integrated clock mechanism, considerable research suggests that it is, in fact, comprised of multiple oscillators which interact, or couple, to generate coherent daily rhythms. To date, the multi-oscillatory basis of the clock has proven difficult to study because separate oscillatory units cannot be temporally resolved in the normal, tightly coupled state. Conditions which facilitate temporal reorganization of oscillators into an alternative coupled state in which they can be temporally resolved, moreover, are incompatible with the most important circadian techniques. Specifically, previous studies have been unable to a) manipulate the timing of oscillators relative to one another to assess their interactions or b) probe their responses to light pulses which normally synchronize the clock mechanism with environmental day. The present proposal utilizes a novel preparation in which circadian rhythms of hamsters are split into two distinct components which may be separately controlled with manipulations of the light/dark environment. The proposed experiments will allow for the first time a description of the most informative outputs of component oscillators within the SCN. Additionally, the nature of interactions between oscillators, postulated on mathematical grounds, can be tested empirically by manipulations of the relative phase relationships between component oscillators. These studies will be juxtaposed with manipulations of oscillator relations in the normal, unsplit state. These studies may suggest new avenues for rapid manipulation of human circadian rhythms.