Multi-Oscillator Interactions of Hamster Circadian Rhythms

在所有哺乳动物中，行为和生理功能的显著日变化是由位于下丘脑视交叉上核(SCN)的内源性钟状机制产生的。尽管这种昼夜节律的生成器已经被有益地概念化并作为一个单一的、集成的时钟机制进行研究，但相当多的研究表明，它实际上是由多个振荡器组成的，这些振荡器相互作用或耦合，以产生连贯的每日节律。到目前为止，时钟的多重振荡基础被证明是很难研究的，因为在正常的紧耦合状态下，独立的振荡单元不能在时间上分解。此外，促进振子在时间上重组为另一种可以在时间上分辨的耦合状态的条件，与最重要的昼夜节律技术不相容。具体地说，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响应，光脉冲通常使时钟机制与环境日同步。本提议利用了一种新的制备方法，其中仓鼠的昼夜节律被分成两个不同的分量，这两个分量可以通过操纵明/暗环境来单独控制。拟议的实验将首次允许描述SCN内分量振荡器的最具信息量的输出。此外，振荡器之间相互作用的性质，在数学基础上假设，可以通过操纵分量振荡器之间的相对相位关系来进行经验检验。这些研究将与正常、未分裂状态下振子关系的处理并列进行。这些研究可能会为快速操纵人类昼夜节律提供新的途径。

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.