The Role of a Novel Population of Intrinsically Photosensitive Retinal Ganglion Cells in the Dorsal Retina

背侧视网膜中新型本质光敏视网膜神经节细胞群的作用

• 批准号: 10437028
• 负责人: Michael Hayden Berry
• 金额: $ 5.18万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437028
• 关键词: Activities of Daily Living; Address; Adult; Axon; Behavior; Behavioral; Biochemical; Biological Clocks; Biology; Brain; Brain region; Cell Extracts; Cell Nucleus; Cell physiology; Cells; Characteristics; Chronic; Circadian desynchrony; Code; Collection; Complex; Confocal Microscopy; Dorsal; Electrophysiology (science); Environment; Exercise; Eye; Functional disorder; Future; Goals; Health; Homeostasis; Hormonal; Hour; Human body; Image; Immunosuppression; Industrialization; Interruption; Investigation; Lateral Geniculate Body; Lead; Light; Lighting; Location; Maintenance; Mediating; Metabolic Diseases; Methods; Modernization; Mood Disorders; Mus; Neurons; Neurotransmitters; Output; Patients; Periodicity; Photoreceptors; Photosensitivity; Phototransduction; Physiology; Play; Population; Preparation; Regulation; Reporter; Retina; Retinal Cone; Retinal Ganglion Cells; Role; Sampling; Signal Transduction; Signal Transduction Pathway; Sleep; Sleep Disorders; Societies; Techniques; Technology; Time; Travel; United States; Vertebrate Photoreceptors; Viral; Visual; Visual Fields; Visual Perception; Work; base; cancer risk; cell type; circadian; clinically relevant; confocal imaging; density; gamma-Aminobutyric Acid; glycine transporter; inhibitory neuron; luminance; melanopsin; metabolic rate; multi-electrode arrays; neurotransmission; novel; response; retinal rods; selective expression; shift work; suprachiasmatic nucleus; tool; visual information; visual process

Project Summary Modern technological changes have lead to circadian misalignment in large portions of the population. This has resulted in increased rates of metabolic, sleep, and mood disorders. The dysfunction is due to the vast range of biological clocks that regulate many aspects of physiology. Entrainment of these clocks is achieved through the light and dark of the day- night cycle sensed by a unique class of photoreceptors in the retina referred to as the intrinsically photosensitive retinal ganglion cells (ipRGCs). Distinct from the rod and cone photoreceptors, which underlie the majority of visual perception, ipRGCs form direct connections to non-visual areas of the brain and exercise bio-synchronous control over many hormonal and neuronal aspects of body function. ipRGC-mediated light/dark entrainment is important for health maintenance and interruptions can lead to endogenous clock dysregulation. This significant health burden demonstrates a clear need for methods of circadian realignment and maintenance. IpRGCs are responsible for encoding changes in ambient light across the entire retina but are far more complex than originally anticipated. Though they only make up 2-5% of the RGC population in the eye, ipRGCs are diverse, consisting of at least 6 distinct subpopulations that project to more than 30 discrete brain regions. While each of these classes express melanopsin, they are thought to have distinct downstream signal transduction pathways. Therefore, each subpopulation is extracting, encoding, and projecting different aspects of visual information in order to influence a separate collection of light-driven behaviors. The specific functional roles of the majority of ipRGC subpopulations remain unclear. To address this shortcoming we will investigate a previously undescribed subpopulation of ipRGCs present only in the dorsal hemisphere of the retina. These ventral-coding ipRGCs express Cre under control of the glycine transporter and are immunopositive for melanopsin and GABA. Their distribution and neurotransmitter type are characteristics that are thus far unique among RGCs. Our goal is to understand their functional sensitivity, central connectivity, and signal transduction pathways. I will do this using electrophysiology in isolated preparations of retina, Cre-dependent viral tracing, and novel photochemical tools. We hypothesize that this dorsally located subpopulation of ipRGCs extract, encode, and project information differently from the greater ipRGC population. This will be the first study describing this novel neuronal population and will serve to generate techniques that can be applied to future investigations in the retina and brain. Artificial light contributes to interference of the biological clocks through the function of the ipRGCs. However, the distribution and inhibitory neurotransmission of this novel subpopulation may suggest that location of light within the visual field is important for regulation. The clinical relevance of this information may lead to location-based methods of realignment in patients suffering from circadian derangements.

项目摘要 现代技术变化导致大部分人口的昼夜节律错位。这导致了 代谢，睡眠和情绪障碍的发生率提高。功能障碍是由于广泛的生物钟造成的 调节生理的许多方面。这些时钟的夹带是通过白天的浅色和黑暗实现的 夜间周期是由视网膜中独特的一类光感受器感知的，称为本质上具有光敏性视网膜 神经节细胞（IPRGC）。与大多数视觉感知的基础的杆和锥形感光器不同， IPRGC与大脑的非视觉区域形成直接连接，并对许多人进行生物同步控制 身体功能的激素和神经元方面。 IPRGC介导的轻/黑暗夹带对健康很重要 维护和中断会导致内源性时钟失调。这种重大的健康负担表明 明确需要昼夜节律调整和维护方法。 IPRGC负责编码整个视网膜环境光的变化，但比 最初是预料的。尽管他们只占眼中RGC人群的2-5％，但IPRGC是多样的，包括 至少有6个不同的亚群，这些亚群将超过30个离散的大脑区域投射。这些班级中的每一个都表达 黑色素蛋白，他们被认为具有不同的下游信号转导途径。因此，每个亚群是 提取，编码和投影视觉信息的各个方面，以影响单独的集合 轻度驱动行为。大多数IPRGC亚群的特定功能作用尚不清楚。 为了解决这一缺点，我们将研究仅在 视网膜的背半球。这些在甘氨酸转运蛋白控制下的腹侧编码IPRGC表达CRE，是 黑色素和GABA的免疫阳性。它们的分布和神经递质类型是因此 在RGC中非常独特。我们的目标是了解它们的功能敏感性，中心连接和信号 转导途径。我将使用电生理学在视网膜，Cre依赖性病毒的孤立制剂中进行此操作 跟踪和新颖的光化学工具。我们假设这是IPRGC提取物的背侧亚群， 编码和项目信息与更大的IPRGC人群不同。这将是描述这一点的第一个研究 新型神经元种群，将用于生成可用于视网膜未来研究的技术 和大脑。 人造光通过IPRGC的功能有助于生物钟的干扰。但是， 这种新型亚群的分布和抑制性神经传递可能表明光的位置 视野对于调节很重要。此信息的临床相关性可能导致基于位置的方法 患有昼夜节律的患者的重新对准。