Intrinsically photosensitive retinal ganglion cells and their central projections

 描述（由申请人提供）：我们感知光的各种功能，包括调节生物钟，瞳孔直径，激素水平和警觉性。这些非图像视觉功能与视觉感知的区别在于它们对场景中的细节不敏感，而是由绝对照明水平驱动。我们的目标是 了解这些功能的基础上，在一个昼夜物种的视觉系统有很强的同源性与人类。我们专注于内在光敏视网膜神经节细胞（ipRGC），它使用称为黑视素的受体分子直接对光做出反应，同时还接收来自视杆细胞和视锥细胞驱动通路的输入。IpRGC将它们的轴突从眼睛投射到大脑中的许多靶点，其中它们的两个主要靶点是视交叉上核（SCN）（其是主昼夜节律钟）和顶盖前橄榄核（PON）（其是瞳孔光反射的控制中心）。生物钟和瞳孔在对光的反应上有显著的数量差异。时钟在许多分钟内整合光，以产生对整体辐照度的准确测量，这提供了一天中时间的代理;相比之下，瞳孔在秒的时间尺度上感知光，以动态调节到达视网膜的光量。我们的广泛假设是ipRGC系统内的信号传导机制适合于昼夜哺乳动物中的非图像视觉的综合特征，并调谐到特定的下游功能。为了验证这一假设，我们将确定支配SCN或PON的ipRGC的光转导机制和时空动力学;此外，我们将这些功能与SCN和PON神经元的时空动力学联系起来。我们的实验依赖于体外和体内神经生理学技术的协同作用。我们已经建立了一个后勤和技术平台，允许ipRGC系统在生物组织的多个层次上以逐步的方式定义，从黑视蛋白的光子吸收到下游神经元的色敏感性和行为输出。我们的实验将构成对昼夜哺乳动物ipRGC系统的第一次广泛和系统的研究，并将为精确理解该系统内失调与人类疾病（包括癌症，心血管疾病，代谢紊乱，精神疾病和时差）之间的联系奠定基础。我们的模式生物和人类之间的强烈共性使我们的研究的翻译相关性特别直接。

 DESCRIPTION (provided by applicant): We sense light for a diverse array of functions that include regulation of the circadian clock, pupil diameter, hormone levels, and alertness. These non-image visual functions are distinguished from visual perception in that they are insensitive to details in the scene, being driven instead by the absolute level of illumination. Our goal is to understand the basis of these functions in a diurnal species whose visual system has strong homologies with that of humans. We focus on the intrinsically photosensitive retinal ganglion cells (ipRGCs), which respond directly to light using a receptor molecule called melanopsin, while also receiving inputs from rod- and cone-driven pathways. IpRGCs project their axons from the eye to numerous targets in the brain, with their two principal targets being the suprachiasmatic nucleus (SCN), which is the master circadian clock, and the pretectal olivary nucleus (PON), which is a control center for the pupillary light reflex. The clock and pupil exhibi marked, quantitative differences in their light responses. The clock integrates light over many minutes to produce an accurate measurement of overall irradiance, which provides a proxy for time of day; by contrast, the pupil senses light on a time scale of seconds to dynamically regulate the amount of light reaching the retina. Our broad hypothesis is that signaling mechanisms within the ipRGC system are suited to the integrative character of non-image vision in a diurnal mammal, and tuned to specific downstream functions. To test this hypothesis, we will determine the phototransduction mechanisms and spatiotemporal dynamics of ipRGCs that innervate the SCN or PON; furthermore, we will connect these features to the spatiotemporal dynamics of SCN and PON neurons. Our experiments rely on a synergy of in vitro and in vivo neurophysiological techniques. We have established a logistical and technological platform that allows the ipRGC system to be defined in stepwise fashion across multiple levels of biological organization, from photon absorption by melanopsin to the chromatic sensitivities of downstream neurons and behavioral outputs. Our experiments will constitute the first extensive and systematic investigation of the ipRGC system in a diurnal mammal, and will lay the foundation for a precise understanding of links that have been made between dysregulation within this system and human diseases that include cancer, cardiovascular disease, metabolic disorders, psychiatric disorders, and jet lag. The strong commonalities between our model organism and humans make the translational relevance of our research especially direct.