Forced Desynchronization of the Rat Circadian System

描述（由申请人提供）：昼夜节律是行为和生理的振荡，周期约为24小时，由内源性生物计时机制（即生物钟）产生。哺乳动物的主生物钟位于下丘脑视交叉上核（SCN）内。SCN由数千个单细胞昼夜节律振荡器（神经元）组成，它们共同产生有节奏的输出，为激素释放周期、睡眠和觉醒以及体温节律等多种节律设定时间。我们最近表明，暴露于人工短日（22小时）的大鼠的SCN可以分离成两个亚区，SCN核和壳，它们独立振荡，并与两种运动活动节律有关，一种周期为22小时，另一种与大鼠内源性周期为24.9小时。具体目标a .1提出了实验来确定该动物模型是否具有人类强制去同步的特征，因此可能代表了人类内部去同步的良好动物模型。Specific Aim A.2中的实验利用大鼠强制去同步模型来确定SCN调节内分泌节律的输出通路，这些内分泌节律可能依赖于SCN核心或SCN外壳的昼夜节律活动。针对Specific Aim A.3，我们建议建立强制去同步大鼠SCN的体外模型，以研究SCN核与壳之间的耦合机制。本应用程序中提出的实验将揭示哺乳动物的主昼夜节律振荡器乘以特定节律输出的特定输出途径。此外，该实验将为利用强迫去同步大鼠模型研究人类SCN内部同步和细胞间耦合的神经基础奠定基础。

DESCRIPTION (provided by applicant): Circadian rhythms are oscillations of behavior and physiology with a period of approximately 24 hours that are generated by an endogenous biological timing mechanism, that is, a biological clock. In mammals the master circadian clock is located within the suprachiasmatic nucleus of the hypothalamus (SCN). The SCN is composed of thousands of single cell circadian oscillators (neurons) that together produce a rhythmic output that sets the time for a diversity of rhythms like hormonal release cycles, sleep and wakefulness, and body temperature rhythms. We have recently shown that the SCN of rats exposed to artificially short days (22 h) can be dissociated into two subregions, the SCN core and shell, that oscillate independently and that are associated with two rhythms of locomotor activity, one with a period of 22 hours and the other with the rat endogenous period of 24.9 hours. Specific Aim A.1 proposes experiments to determine whether this animal model presents features of human forced desynchronization and may therefore represent a good animal model for human internal desynchronization. Experiments in Specific Aim A.2 exploit the rat forced desynchronization model to identify output pathways by which the SCN regulates endocrine rhythms that are likely to rely differentially on the circadian activity of the SCN core or that of the SCN shell. For Specific Aim A.3 we propose to develop an in vitro model of the forced desynchronized rat SCN to study the coupling mechanisms between the SCN core and shell. The experiments proposed in this application will unmask specific output pathways by which the master circadian oscillator of mammals times specific rhythmic outputs. Furthermore, the experiments will establish the foundations for the potential use of the forced desynchronized rat model to study the neural bases of human internal synchronization and intercellular coupling in the SCN.