Generation of Retinal Signals for Circadian Entrainment

描述(由申请人提供)：行为和生理的许多方面，如睡眠和清醒、血压和体温都表现出每日的振荡，称为昼夜节律。这些昼夜节律的紊乱是时差、倒班工作和阿尔茨海默病患者睡眠障碍造成的衰弱效应的原因。昼夜节律是由一种内在的生物钟驱动的，这种生物钟存在于从植物到人类的各种生物中。在哺乳动物中，这种生物钟位于大脑深处的两个被称为视交叉上核(SCN)的小细胞团中。这些内在的昼夜节律通过光携带过程与昼夜的日常环境周期同步，光携带过程使用光信息来重置生物时钟。 在哺乳动物中，光包裹的神经元信号来自视网膜神经节细胞(RGC)的一小部分，这些细胞向SCN发送直接投射。令人惊讶的是，引起视力的视网膜信号可能与导致昼夜节律缠绕的视网膜信号截然不同。虽然视网膜输入是光携带所必需的，但传统的光感受器不是必需的。这个明显的悖论的解决方案可能在于最近的发现，投射到SCN的RGC表达一种新的光色素--黑素，并且可以在没有光感受器驱动的突触输入的情况下产生内在的光反应。 到目前为止，人们对RGC产生视网膜输出到昼夜节律系统的生理学知之甚少。在这项资助中，我们建议使用多学科方法来研究这些细胞如何产生产生光夹带的视网膜信号。具体地说，我们将确定1)黑素的信号特性，即昼夜节律系统的光色素；2)什么细胞内的信号通路产生对光的内在反应；以及3)介导内在光反应的离子通道。 这项研究将为改进昼夜节律紊乱的治疗提供基础，这些昼夜节律紊乱通常与神经紊乱有关，并对时差和倒班工作造成的虚弱影响负责。

DESCRIPTION (provided by applicant): Many aspects of behavior and physiology, such as sleeping and wakefulness, blood pressure, and body temperature exhibit daily oscillations known as circadian rhythms. Disturbances in these circadian rhythms are responsible for the debilitating effects of jet lag, shift work and the sleep disorders seen in patients suffering from Alzheimer's disease. Circadian rhythms are driven by an intrinsic biological clock found in organisms ranging from plants to humans. In mammals, this biological clock is housed deep within the brain in two small clusters of cells called the suprachiasmatic nuclei (SCN). These intrinsic circadian rhythms are synchronized to the daily environmental cycle of day and night by the process of photoentrainment, which uses light information to reset the biological clock. In mammals, the neuronal signal for photoentrainment arises from a small subset of retinal ganglion cells (RGCs) that send a direct projection to the SCN. Surprisingly, the retinal signals that give rise to vision may be quite different from those responsible for circadian entrainment. Although retinal input is required for photoentrainment, traditional photoreceptors are not required. The solution to this apparent paradox may lie in the recent discovery that RGCs that project to the SCN express a novel photopigment, melanopsin, and can generate an intrinsic light response in the absence of photoreceptor-driven synaptic input. To date, little is known about the physiology of the RGCs that generate the retinal output to the circadian system. In this grant, we propose to use a multidisciplinary approach to study how these cells generate the retinal signals that produce photoentrainment. Specifically, we will determine 1) the signaling properties of melanopsin, the photopigment of the circadian system; 2) what intracellular signaling pathway generates the intrinsic response to light; and 3) the ion channel that mediates the intrinsic light response. This research will provide a foundation for improved treatment of circadian disorders that are often associated with neurological disorders, and are responsible for the debilitating effects of jet lag and shift work.