Structure & Function of Ganglion-Cell Photoreceptors Contributing to Form Vision

结构

• 批准号: 8597434
• 负责人: Maureen Estevez Stabio
• 金额: $ 4.1万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597434
• 关键词: Age related macular degeneration; Anatomy; Axon; Axonal Transport; Biological Clocks; Brain; Brain Part; Brain region; Cell physiology; Cells; Clinical Treatment; Color; Confocal Microscopy; Conscious; Data; Dependence; Discrimination; Dorsal; Dyes; Eye; Foundations; Frequencies; Goals; Green Fluorescent Proteins; Hormones; Hybrids; Image; Immunohistochemistry; In Vitro; Individual; Intrinsic drive; Jet Lag Syndrome; Label; Laboratories; Lateral Geniculate Body; Leber' s amaurosis; Light; Link; Mammalian Cell; Moods; Morphology; Motion; Mus; Neurosecretory Systems; Output; Pathway interactions; Patients; Pattern; Pharmacology; Photoreceptors; Physiological; Physiology; Play; Population; Property; Public Health; Publishing; Pupil; Pupil light reflex; Regulation; Reporter; Residual state; Resolution; Retina; Retinal; Retinal Cone; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; Role; Seasonal Affective Disorder; Seasonal Variations; Signal Transduction; Stratification; Structure; Synapses; Techniques; Thalamic structure; Tracer; Training; Unconscious State; Vertebrate Photoreceptors; Vision; Visual; Visual Acuity; Visual Perception; Visual system structure; Work; alertness; base; blind; circadian pacemaker; ganglion cell; improved; interest; melanopsin; neuronal cell body; novel; patch clamp; receptive field; relating to nervous system; response; retinal rods; selective expression; shift work; superior colliculus Corpora quadrigemina; voltage clamp

DESCRIPTION (provided by applicant): Only a decade has elapsed since the discovery of the novel retinal photopigment melanopsin expressed in a small subset of retinal ganglion cells, called intrinsically photosensitive retinal ganglion cells (ipRGCs). Rapid progress in this field has linked these cells to the regulation the circadian clock, the pupillary reflex, neuroendocrine secretions, and seasonal variations of mood. The canonical view has been that the functional contributions of ipRGCs are limited to these purely reflexive, homeostatic, and non-image forming roles. However, new varieties of ipRGCs have recently been discovered that send signals to brain regions involved in conscious visual perception of form, motion and color. The goal of this study is to provide the first systematic description of the form and function of these novel melanopsin-based visual channel(s) projecting to image- forming centers of the brain. Specific Aim 1 will characterize the morphology of ipRGCs projecting to two image-forming visual centers of the brain - the dorsal lateral geniculate nucleus of the thalamus (dLGN) and the superior colliculus (SC). Such structural data will permit the identification of which ipRGC subtypes participate in this channel, but will also form a crucial descriptive foundation for working out the synaptic relationships of these cells. Specific Aim 2 will characterize the physiological properties of the ipRGCs that project to the dLGN and SC. These studies will help define the unique attributes of this enigmatic perceptual channel. To identify the cells of interest, a genetically modified mouse with selective expression of GFP in ipRGCs will be used, and a contrasting retrograde axon tracer will label those that have geniculate or collicular projections. This will be just one of many techniques utilized in the pursuit of these aims, making this project an ideal training venue. Others include patch clamp recording, intracellular dye filling, immunohistochemistry, axon transport tracing, receptive field analysis, synaptic pharmacology, and confocal microscopy. These studies will provide a broader and more complete picture of the functional contribution of melanopsin and irradiance-encoding ipRGCs to normal visual perceptual mechanisms. Given the key role that ipRGCs play in the body's responses to daylight, these studies are relevant to such public health issues as jet lag, seasonal affective disorder, and alertness during shift work. In addition, this work may be shed new light on residual visual capacities in ocularly blind patients with outer retinal diseases, such as retinitis pigmentosa, age-related macular degeneration or Leber's congenital amaurosis, in which the inner retina is largely spared. New understanding of residual ganglion cell photoreception in these individuals might be harnessed to develop clinical treatments and improve lives.

描述（由申请人提供）： 自从发现在视网膜神经节细胞的一个小子集（称为固有光敏视网膜神经节细胞（ipRGC））中表达的新型视网膜色素黑视素以来，仅仅过去了十年。在这一领域的快速进展已经将这些细胞与调节生物钟、瞳孔反射、神经内分泌和情绪的季节性变化联系起来。规范观点认为ipRGC的功能贡献仅限于这些纯粹的自反性、稳态和非图像形成作用。然而，最近发现了新品种的ipRGC，它们将信号发送到涉及形式，运动和颜色的有意识视觉感知的大脑区域。本研究的目的是提供对投射到大脑的图像形成中心的这些新的基于黑视蛋白的视觉通道的形式和功能的第一次系统描述。具体目标1将表征投射到脑的两个图像形成视觉中心-丘脑背外侧膝状体核（dLGN）和上级丘（SC）的ipRGC的形态。这些结构数据将允许识别哪些ipRGC亚型参与该通道，但也将形成用于确定这些细胞的突触关系的关键描述性基础。具体目标2将表征投射到dLGN和SC的ipRGCs的生理特性。这些研究将有助于定义这个神秘的感知通道的独特属性。为了鉴定感兴趣的细胞，将使用在ipRGC中选择性表达GFP的遗传修饰的小鼠，并且对比逆行轴突示踪剂将标记具有膝状体或丘状体投射的那些。这将只是在追求这些目标中使用的许多技术之一，使该项目成为理想的培训场所。其他包括膜片钳记录，细胞内染料填充，免疫组织化学，轴突运输跟踪，感受野分析，突触药理学和共聚焦显微镜。这些研究将提供黑视蛋白和辐照编码ipRGC对正常视觉感知机制的功能贡献的更广泛和更完整的图片。鉴于ipRGC在人体对日光的反应中发挥的关键作用，这些研究与时差反应、季节性情感障碍和轮班工作期间的警觉性等公共卫生问题有关。此外，这项工作可能为患有视网膜色素变性，年龄相关性黄斑变性或Leber先天性黑蒙等外部视网膜疾病的失明患者的剩余视觉能力提供新的线索，其中内部视网膜基本上幸免。对这些个体中残余神经节细胞光感受的新理解可能被利用来开发临床治疗和改善生活。