Intrinsically photosensitive retinal ganglion cells and their central projections

 描述(由申请人提供)：我们可以感知各种功能的光，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不同之处在于，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 了解白天活动的物种的这些功能的基础，这些物种的视觉系统与人类的视觉系统有很强的同源性。我们专注于本质上对光敏感的视网膜神经节细胞(IpRGCs)，它们通过一种名为黑素蛋白的受体分子直接对光做出反应，同时也接受杆状和视锥驱动的通路的输入。IpRGC将轴突从眼睛投射到大脑中的许多目标，它们的两个主要目标是视交叉上核(SCN)和顶盖前橄榄核(PON)，视交叉上核(SCN)和顶盖前橄榄核(PON)是瞳孔光反射的控制中心。时钟和瞳孔在他们的光反应中表现出明显的数量差异。时钟将光集中在许多分钟内，以产生总辐照度的准确测量，这提供了一天中的时间；相比之下，瞳孔感知光的时间尺度为秒，以动态调节到达视网膜的光量。我们的广泛假设是，ipRGC系统中的信号机制适合于昼夜哺乳动物非成像视觉的综合特征，并调节到特定的下游功能。为了验证这一假说，我们将确定支配SCN或PON的ipRGCs的光传导机制和时空动力学；此外，我们将把这些特征与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。我们已经建立了一个后勤和技术平台，允许以循序渐进的方式在多个生物组织水平上定义ipRGC系统，从黑素的光子吸收到下游神经元和行为输出的颜色敏感性。我们的实验将构成对白天活动哺乳动物的ipRGC系统的第一次广泛而系统的研究，并将为准确了解该系统内部的调节失调与人类疾病之间的联系奠定基础，这些疾病包括癌症、心血管疾病、代谢障碍、精神障碍和时差。我们的模型生物和人类之间的强烈共性使得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.