Retinal Input to the Circadian System

描述（申请人摘要）：行为和生理的许多方面， 例如睡眠和清醒、血压和体温， 被称为昼夜节律的每日波动。这些昼夜节律的紊乱 节奏是造成时差反应，轮班工作， 以及老年痴呆症患者常见的睡眠障碍 疾病昼夜节律是由一种内在的生物钟驱动的， 从植物到人类。在哺乳动物中，这种生物钟 位于一个称为视交叉上核（SCN）的小细胞群中， 埋藏在大脑深处这些内在的昼夜节律是 与昼夜的日常环境周期同步， 利用光信息来重置生物 时钟在哺乳动物中，光夹带的神经元信号来自于一个小的 视网膜神经节细胞（RGC）的一个子集，将直接投射发送到 SCN。令人惊讶的是，用于编码昼夜信息的视网膜通路 似乎与那些用来编码视觉信息的不同。在 在视觉通路的经典观点中，光只能被视杆细胞检测到， 视锥光感受器然而，这些细胞不需要 光夹带解决这一明显矛盾的办法可能在于最近的 发现了一种新的视觉色素，黑视素，它在一个子集中表达 的RGC。这些发现引出了一个有趣的假设， 投射到SCN表达黑视蛋白，并且对 光到目前为止，对RGC的生理学一无所知， 视网膜对昼夜节律系统的输入。然而，最近，我们开发了 这些技术使我们能够常规地识别和研究这些神经元， 隔离拟议研究的主要目标是研究 使用以下组合投射到SCN的哺乳动物RGC的性质： 分子遗传学和电生理学技术。具体来说，我们将 利用膜片钳技术来检查细胞膜的内在特性， 这些神经元。此外，我们还将测试它们的感光度， RT-PCR和原位杂交，以确定它们是否表达黑视素。的 结果将代表神经元的第一个功能特征 将光夹带信号从视网膜传递到SCN。的 这项研究中收集的知识将为改善照明奠定基础。 昼夜节律紊乱的治疗和/或药物治疗 与阿尔茨海默氏病有关， 时差和轮班工作的影响。

DESCRIPTION (applicant's abstract): 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 commonly 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 in a small cluster of cells called the suprachiasmatic nucleus (SCN), buried deep within the brain. 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 pathways used to encode circadian information seem to be different from those used to encode visual information. In the classical view of the visual pathway, light is detected only by the rod and cone photoreceptors. However, these cells are not required for photoentrainment. The solution to this apparent paradox may lie in the recent discovery of a novel visual pigment, melanopsin, which is expressed in a subset of RGCs. These findings lead to the intriguing hypothesis that the RGCs projecting to the SCN express melanopsin and are intrinsically sensitive to light. To date, nothing is known about the physiology of the RGCs that provide retinal input to the circadian system. Recently, however, we have developed techniques that allow us to routinely identify and study these neurons in isolation. The primary objective of the proposed research is to study the properties of mammalian RGCs that project to the SCN using a combination of molecular genetic and electrophysiological techniques. Specifically, we will utilize patch-clamp techniques to examine the intrinsic membrane properties of these neurons. In addition, we will test their light-sensitivity, and use both RT-PCR and in situ hybridization to determine if they express melanopsin. The results will represent the first functional characterization of the neurons that convey the photoentrainment signal from the retina to the SCN. The knowledge gathered in this study will lay the foundation for improved light therapy and/or pharmacological treatment of circadian disorders that are often associated with Alzheimer's disease and are responsible for the debilitating effects of jet lag and shift work.