The role of the circadian clock in encoding seasonal variations in day length

描述(申请人提供)：主要的哺乳动物起搏器，位于下丘脑的视交叉上核(SCN)，驱动生理和行为的昼夜节律，与环境同步。在温带气候中，动物利用日长或光周期的年度变化来调整自己的生理状态，以适应季节的变化。时钟编码光周期的方式尚不清楚，但两个耦合振荡器，一个同步于早晨(M)，另一个同步于晚上(E)，其相位关系随白天的长度变化，将允许SCN计算光周期的季节性变化。这些双重振荡器可能嵌入在参与SCN内源性昼夜节律产生的分子转录和翻译反馈环中(4)。时钟基因周期1(Perl)是节律产生的重要组成部分，也参与了时钟与光的同步。目前的建议将研究分离的SCN在光周期Perl报告基因大鼠中编码日长的作用，该报告基因是通过将光周期Fischer 344(F344)品系与在Perl启动子控制下表达荧光素酶的转基因PER1：：LUC大鼠杂交而产生的。通过对暴露在短日长或长日长的光周期大鼠的SCN亚区中实时成像Perl启动子活性，将研究假定的M和E振荡器的解剖位置。单细胞发光成像将用于检测单个SCN神经元内Perl启动子活性的光周期依赖差异。这项建议还将通过比较暴露于繁殖抑制或允许日长的大鼠的Perl启动子活性谱，来研究分子时钟在编码生殖临界光周期允许中的作用。此外，还将确定光周期F344和非光周期Wistar大鼠在SCN中的光周期编码是否不同。光周期的季节变化也可能影响人类的神经过程。公共卫生相关性许多被诊断为季节性情感障碍(SAD)的患者只在秋季和冬季经历抑郁发作，清晨明亮的光线治疗可以纠正他们昼夜节律的延迟。因此，研究SCN在光周期编码中的作用可能会导致SAD患者新的治疗方法的发展。

DESCRIPTION (provided by applicant): The primary mammalian pacemaker, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, drives circadian rhythms in physiology and behavior that are synchronized with the environment. In temperate climates, animals use annual changes in day length, or photoperiod, to adjust their physiological state with changes in season. The way in which the clock encodes photoperiod is unknown, but two coupled oscillators, one synchronized to morning (M) and the other synchronized to evening (E), whose phase relationship varies with day length would allow the SCN to compute seasonal changes in photoperiod. These dual oscillators may be embedded in the molecular transcriptional and translational feedback loops that participate in endogenous circadian rhythm generation in the SCN (4). The clock gene, Period 1 (Perl), is an important component of rhythm generation and also participates in the synchronization of the clock to light. The current proposal will investigate role of the isolated SCN in encoding day length in photoperiodic Perl reporter rats generated by crossing the photoperiodic Fischer 344 (F344) strain with transgenic Per1::luciferase (Per1::luc) rats that express luciferase under the control of the Perl promoter. The anatomical locations of putative M and E oscillators will be investigated by imaging real-time Perl promoter activity in subdivisions of the SCN in photoperiodic rats exposed to either short or long day lengths. Singlecell luminescence imaging will be used to examine photoperiod-dependent differences in Perl promoter activity within an individual SCN neuron. This proposal will also investigate the role of the molecular clock in encoding the critical photoperiod permissive for reproduction by comparing the Perl promoter activity profile of rats exposed to either inhibitory or permissive day lengths for reproduction. Furthermore, it will be determined whether photoperiod encoding in the SCN differs between photoperiodic F344 and nonphotoperiodic Wistar rats. Seasonal variations in photoperiod may also affect neurological processes in humans. PUBLIC HEALTH RELEVANCE Many patients diagnosed with seasonal affective disorder (SAD) experience depressive episodes only during the fall and winter, and treatment with early morning bright light corrects the delay in their circadian rhythms. Therefore, investigating the role of the SCN in encoding photoperiod may lead to the development of novel therapeutic treatments for SAD patients.