Forced Desynchronization of the Rat Circadian System

描述(申请人提供)：昼夜节律是由内源性生物计时机制，即生物钟产生的周期约为24小时的行为和生理的振荡。哺乳动物的主生物钟位于下丘脑的视交叉上核(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，设定各种节奏的时间，如激素释放周期、睡眠和清醒以及体温节奏。我们最近发现，暴露于人工短日照(22h)的大鼠的SCN可分离为两个亚区，即SCN的核心和外壳，它们独立地振荡，并与两个运动节律有关，一个周期为22h，另一个与大鼠内源性周期24.9小时。具体目的A.1建议进行实验，以确定该动物模型是否表现出人类强迫去同步化的特征，从而可能代表一种良好的人类内部去同步化动物模型。在特定目标A.2的实验中，利用大鼠强迫去同步化模型来确定SCN调节内分泌节律的输出路径，这些内分泌节律可能不同地依赖于SCN核心或SCN外壳的昼夜活动。针对A.3，我们建议建立一个强迫去同步化的大鼠SCN的体外模型，以研究SCN核壳之间的偶联机制。本申请中提出的实验将揭示特定的输出路径，哺乳动物的主要昼夜节律振荡器通过这些路径乘以特定的节奏输出。此外，这些实验将为利用强迫去同步化的大鼠模型来研究人在SCN内的内部同步性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.