Retinal Input to the Circadian System

描述(申请人摘要)：行为和生理的许多方面， 如睡眠和清醒、血压和体温，展示了 日振荡称为昼夜节律。在这些昼夜节律中的干扰 节奏是时差、倒班工作、 阿尔茨海默氏症患者中常见的睡眠障碍 疾病。昼夜节律是由一种内在的生物钟驱动的 从植物到人类的各种生物。在哺乳动物中，这种生物钟是 位于一小群称为视交叉上核(SCN)的细胞中， 深深地埋在大脑里。这些内在的昼夜节律是 通过过程与昼夜的日常环境循环同步 它使用光信息来重置生物 钟。在哺乳动物中，光携带的神经元信号来自一个小的 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，用于编码昼夜节律信息的视网膜通路 似乎不同于那些用来编码视觉信息的东西。在 视觉通路的经典观点，光只被杆子和 视锥感光器。但是，这些单元格不是必需的 光夹带作用。这一明显悖论的解决方案可能在于最近的 发现一种新的视觉色素--黑色素，它在一个亚群中表达 RGC的。这些发现导致了一个耐人寻味的假设，即RGC 投射到SCN表达黑素并对其固有地敏感 灯。到目前为止，对RGC的生理学还知之甚少。 视网膜输入到昼夜节律系统。然而，最近，我们开发了 使我们能够常规地识别和研究这些神经元的技术 与世隔绝。拟议研究的主要目标是研究 投射到SCN的哺乳动物视网膜节细胞的特性 分子遗传学和电生理学技术。具体来说，我们将 利用膜片钳技术检测细胞固有膜特性 这些神经元。此外，我们还将测试它们的光敏性，并使用这两种 逆转录-聚合酶链式反应和原位杂交检测其是否表达黑素。这个 这些结果将代表神经元的第一个功能特征 将光携带信号从视网膜传递到SCN。这个 在这项研究中收集的知识将为改进光线奠定基础 昼夜节律紊乱的治疗和/或药物治疗 与阿尔茨海默病有关，并对使人虚弱的 时差和倒班工作的影响。

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.