Forced Desynchronization of the Rat Circadian System

描述（由申请人提供）：昼夜节律是由内源性生物计时机制（即生物钟）产生的具有约24小时周期的行为和生理振荡。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，暴露于人工短天（22小时）的大鼠SCN可以被解离成两个子区域，SCN的核心和外壳，独立振荡，并与两个节律的自发活动，一个与一个周期为22小时，另一个与大鼠内源性周期为24.9小时。具体目标A.1提出了实验，以确定该动物模型是否具有人类强制去骨化的特征，因此可能是人类内部去骨化的良好动物模型。特定目标A.2中的实验利用大鼠强迫去极化模型来确定SCN调节内分泌节律的输出途径，这些输出途径可能不同地依赖于SCN核心或SCN外壳的昼夜节律活动。对于特定目标A.3，我们建议开发一种强制去角质化大鼠SCN的体外模型，以研究SCN核与壳之间的偶联机制。本申请中提出的实验将揭示特定的输出途径，通过该途径，哺乳动物的主昼夜节律振荡器对特定的节律输出进行计时。此外，本实验还为进一步研究人SCN内同步化和细胞间耦合的神经基础奠定了基础。

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.