Generation of Retinal Signals for Circadian Entrainment

产生昼夜节律的视网膜信号

• 批准号: 6772612
• 负责人: RONALD Lane BROWN
• 金额: $ 29.36万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-09 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772612
• 关键词: biological clocks; biological signal transduction; circadian rhythms; electrophysiology; immunocytochemistry; laboratory rat; membrane channels; neuropharmacology; optical polarization; photoactivation; photostimulus; retina; retinal ganglion; sensory signal detection; suprachiasmatic nucleus; transducin; visual photosensitivity; visual phototransduction; visual pigments; voltage /patch clamp

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.

描述（由申请人提供）：行为和生理的许多方面，如睡眠和觉醒，血压和体温表现出称为昼夜节律的每日振荡。这些昼夜节律的紊乱是造成时差反应、轮班工作和阿尔茨海默病患者睡眠障碍的原因。昼夜节律是由从植物到人类的生物体内的内在生物钟驱动的。在哺乳动物中，这种生物钟位于大脑深处的两个小细胞群中，称为视交叉上核（SCN）。这些内在的昼夜节律通过光诱导过程与昼夜的日常环境周期同步，光诱导过程使用光信息重置生物钟。 在哺乳动物中，光夹带的神经元信号来自视网膜神经节细胞（RGC）的一小部分，这些细胞将直接投射到SCN。令人惊讶的是，引起视觉的视网膜信号可能与那些负责昼夜节律的信号完全不同。虽然视网膜输入需要光夹带，但不需要传统的光感受器。这个明显悖论的解决方案可能在于最近发现，投射到SCN的RGCs表达一种新型感光色素黑视素，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光反应。 迄今为止，很少有人知道的生理学的RGCs产生视网膜输出的昼夜节律系统。在这项资助中，我们建议使用多学科的方法来研究这些细胞如何产生产生光夹带的视网膜信号。具体来说，我们将确定1）黑视素的信号传导特性，昼夜节律系统的色素; 2）什么样的细胞内信号传导途径产生对光的内在反应; 3）介导内在光反应的离子通道。 这项研究将为改善昼夜节律紊乱的治疗提供基础，昼夜节律紊乱通常与神经系统疾病有关，并导致时差和轮班工作的衰弱效应。