Regulation of the intrinsic melanopsin-based light response in ipRGCs

ipRGC 中基于内在黑视蛋白的光响应的调节

• 批准号: 10516757
• 负责人: RONALD Lane BROWN
• 金额: $ 62.61万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516757
• 关键词: Address; Affect; Amacrine Cells; Animals; Attenuated; Behavior; Behavioral; Biochemical; Brain; Cell Culture System; Cell Culture Techniques; Cell physiology; Cells; Circadian Rhythms; Collection; Cyclic AMP-Dependent Protein Kinases; Data; Detection; Dopamine; Dopamine Receptor; Electrophysiology (science); Family; Genetic; Glare; Goals; Health; Human; Individual; Ion Channel; Knock-in Mouse; Knowledge; Label; Learning; Light; Mammals; Measures; Mediating; Memory; Modeling; Molecular; Moods; Mus; Mutate; Neuromodulator; Outcome; Pathway interactions; Pattern; Performance; Phosphorylation; Phosphorylation Site; Photosensitivity; Phototransduction; Physiological; Physiology; Play; Population; Population Heterogeneity; Proteins; Publications; Pupil light reflex; Regulation; Reporting; Research; Retina; Retinal Ganglion Cells; Retinal Photoreceptors; Role; Signal Pathway; Signal Transduction; Sleep; Stratification; Synapses; System; Vertebrate Photoreceptors; Virus; Work; base; behavior measurement; behavioral outcome; circadian; circadian regulation; conditional knockout; contrast enhanced; driving behavior; expectation; experimental study; in vivo; insight; interdisciplinary approach; knockout animal; melanopsin; mouse model; novel strategies; prevent; receptor; response; transcriptome

Abstract Light has a profound effect on human physiology and behavior. In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) play a key role in light-dependent behaviors, including circadian photoentrainment, pupillary light reflex, sleep, mood, memory and learning. Originally thought to be a homogeneous population, ipRGCs are now known to be a diverse collection of cells with six subtypes (M1-6) in mouse. These subtypes differ in many ways, including expression levels of the photopigment melanopsin, dendritic stratification, synaptic inputs, firing patterns, and central projection targets in the brain. These ipRGCs respond to light by integrating intrinsic melanopsin-based phototransduction and extrinsic synaptic inputs driven by conventional rod and cone outer retinal photoreceptors. Early studies suggested that melanopsin phototransduction utilizes exclusively a Gq-signaling cascade that leads to the activation of Plc4 and TrpC-family ion channels. This model has been challenged, however, by discovery of alternative signaling pathways in non-M1 ipRGCs, but the precise identity of the signaling components remains controversial. These findings have thereby revealed a large gap in knowledge about the identity of the downstream components of melanopsin’s phototransduction cascade. Furthermore, we have recently shown that melanopsin signaling can be regulated by dopamine, a well-known neuromodulator in the retina, in a cell culture system. Our overall goal for this proposal is to understand how the complexity of the melanopsin-based signaling pathway and its regulation in distinct ipRGC subtypes contributes to the large array of behaviors. In Specific Aim 1, we will determine the physiological and behavioral consequences of dopamine-dependent melanopsin phosphorylation in M1 ipRGCs, using a knock-in mouse model, in which phosphorylation sites in melanopsin are mutated. In Specific Aim 2, we will identify distinct roles of M1 and M4 ipRGCs in light-dependent behaviors by subtype-selective manipulation of phototransduction pathways. These studies will provide a critical understanding of the biochemical and molecular mechanisms by which light influences human health and performance through the regulation of circadian rhythms, sleep, mood, memory and learning.

摘要 光对人类的生理和行为有着深远的影响。在哺乳动物中，天生对光敏感的视网膜 神经节细胞(IpRGC)在光依赖行为中发挥关键作用，包括昼夜节律光携带， 瞳孔光反射、睡眠、情绪、记忆和学习。最初被认为是同质的种群， 目前已知ipRGCs是小鼠体内具有六种亚型(M1-6)的细胞的多样性集合。这些子类型 在许多方面不同，包括光色素黑素的表达水平，树突状细胞层化，突触 输入，放电模式，以及大脑中的中央投射目标。这些ipRGC通过整合 由传统视杆细胞和视锥细胞驱动的基于黑素的内源性光传导和外源性突触输入 视网膜外光感受器。早期的研究表明，黑素的光转导只利用一种 Gq-信号级联导致Plc4和TrpC家族离子通道的激活。这一模式已经被 然而，挑战在于发现了非M1 ipRGC中的替代信号通路，但确切的身份 信令组件的选择仍然存在争议。因此，这些发现揭示了在 了解黑素的光转导级联下游成分的特性。 此外，我们最近发现，黑素信号可以被多巴胺调节，这是一种众所周知的 视网膜中的神经调节剂，在细胞培养系统中。我们对这项建议的总体目标是了解 基于黑素蛋白的信号通路的复杂性及其在不同ipRGC亚型中的调节作用 大量的行为。在具体目标1中，我们将确定生理和行为 利用敲入小鼠研究多巴胺依赖的黑素视黄素在M1 ipRGC中的磷酸化结果 模型，在该模型中，黑素的磷酸化位点发生突变。在具体目标2中，我们将确定不同的角色 光信号转导亚型选择性操作对M1和M4ipRGCs光依赖行为的影响 小路。这些研究将通过以下方式提供对生化和分子机制的关键理解 哪些光线通过调节昼夜节律、睡眠、情绪、 记忆和学习。