Intrinsically photosensitive retinal ganglion cells and their central projections

本质光敏视网膜神经节细胞及其中央投影

• 批准号: 9548070
• 负责人: Michael Tri Hoang Do
• 金额: $ 4.67万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9548070
• 关键词: Alpha Cell; Anatomy; Animal Model; Axon; Behavioral; Biological; Biophysical Process; Brain; Brain region; Caliber; Cardiovascular Diseases; Cell Nucleus; Cells; Characteristics; Circadian Rhythms; Dendrites; Dextrans; Diagnosis; Disease; Distant; Electrodes; Electrophysiology (science); Exhibits; Eye; Foundations; Goals; Health; Hormones; Human; In Vitro; Injectable; Investigation; Jet Lag Syndrome; Kinetics; Knowledge; Label; Light; Lighting; Link; Logistics; Macaca; Magnetic Resonance Imaging; Malignant Neoplasms; Mammals; Measurement; Measures; Mediating; Mediator of activation protein; Medulla oblongata olive; Mental disorders; Metabolic Diseases; Methods; Morphology; Neurons; Organism; Output; Pathway interactions; Pattern; Pharmacology; Photons; Photophobia; Photoreceptors; Photosensitivity; Phototransduction; Physiological; Physiological Processes; Physiology; Pigments; Population; Primates; Property; Proxy; Publishing; Pupil; Pupil light reflex; Regulation; Research; Retina; Retinal; Retinal Ganglion Cells; Rodent; Roentgen Rays; Signal Transduction; Stimulus; Support System; Synapses; System; Techniques; Testing; Therapeutic Effect; Time; Variant; Vertebrate Photoreceptors; Vision; Visual Perception; Visual system structure; Work; absorption; alertness; circadian pacemaker; experimental study; human disease; in vivo; insight; melanopsin; nerve supply; neurophysiology; public health relevance; receptive field; receptor; response; spatiotemporal; species difference; suprachiasmatic nucleus; synergism; system architecture; visual stimulus

 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.

 描述（由申请人提供）：我们感知光具有多种功能，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 了解昼夜物种的这些功能的基础，该物种的视觉系统与人类的视觉系统具有很强的同源性。我们关注本质上光敏的视网膜神经节细胞（ipRGC），它使用一种称为黑视蛋白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 将轴突从眼睛投射到大脑中的众多目标，其两个主要目标是视交叉上核 (SCN)（主要生物钟）和顶盖前橄榄核 (PON)（瞳孔光反射控制中心）。时钟和瞳孔在光响应方面表现出明显的定量差异。该时钟对许多分钟内的光进行积分，以准确测量整体辐照度，从而提供一天中时间的代理；相比之下，瞳孔以秒为单位感知光线，以动态调节到达视网膜的光线量。我们的广泛假设是 ipRGC 系统内的信号机制适合昼间哺乳动物非图像视觉的整合特征，并调整到特定的下游功能。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，我们会将这些特征与 SCN 和 PON 神经元的时空动态联系起来。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。我们建立了一个后勤和技术平台，允许在生物组织的多个层面上逐步定义 ipRGC 系统，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。我们的实验将首次对昼间哺乳动物的 ipRGC 系统进行广泛和系统的研究，并将为准确理解该系统内的失调与人类疾病（包括癌症、心血管疾病、代谢紊乱、精神疾病和时差反应）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得我们研究的转化相关性特别直接。