Circuit maturation and function in postnatal primate retina

灵长类动物出生后视网膜的电路成熟和功能

• 批准号: 10642337
• 负责人: Mrinalini Hoon
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642337
• 关键词: 3-Dimensional; Address; Adult; Biological Models; Birth; Cells; Communication; Development; Disparate; Electron Microscopy; Electrophysiology (science); Event; Exhibits; Functional disorder; Goals; Knowledge; Light; Maps; Mediating; Modeling; Morphology; Neurodevelopmental Disorder; Neurons; Output; Pathway interactions; Peripheral; Photophobia; Photoreceptors; Physiology; Primates; Process; Property; Proteins; Resolution; Retina; Retinal Degeneration; Retinal Ganglion Cells; Rodent; Rodent Model; Sensory; Shapes; Signal Transduction; Synapses; Testing; Vision; Visual; Visual Pathways; Visual System; Work; biophysical properties; cell type; developmental disease; electrical property; functional mimics; human stem cells; insight; light microscopy; luminance; motion sensitivity; neural; neural circuit; neuronal circuitry; novel; parallel processing; postnatal; postnatal development; postnatal period; postsynaptic; presynaptic; response; retinal neuron; segregation; timeline; visual dysfunction

PROJECT SUMMARY/ABSTRACT Establishment of functional neuronal circuits within the retina relies on a period of postnatal maturation. Our knowledge of this developmental period is restricted to information from non-primate model systems. This project aims to determine the progression of postnatal maturation across two divergent primary output pathways in the primate retina– ON and OFF parasol retinal ganglion cells (RGCs) - by correlating functional activity of RGCs obtained by single cell electrophysiology to expression profiles of synaptic markers and the ultrastructural synaptic connectivity map underlying neuronal function. Our studies will compare observations from three postnatal timepoints before visual function and circuit maturation reaches adult profiles. In Aim 1 we will determine the postnatal development of light evoked functional responses of ON and OFF parasol RGCs including spike output across luminance levels and intrinsic electrical properties. In Aim 2 we will determine the postnatal development of excitatory and inhibitory synaptic inputs onto ON and OFF parasol RGCs that regulate their responses, including expression profiles of constituent pre- and postsynaptic proteins and the 3D ultrastructural organization of synaptic inputs. Our findings will provide the first insights into the early stages of postnatal functional maturation across key parallel pathways (ON and OFF parasol RGCs) in the primate retina, thereby addressing the current knowledge gap about the process of postnatal circuit and synapse maturation during primate retinal development. Our observations will also reveal if functionally divergent retinal pathways mature at similar or disparate rates and identify substrates that cause developmental visual deficits. Moreover, our findings will provide important baseline information about functional maturation of primate retinal neurons critical for developing lab grown human stem cell derived retinas that mimic functional properties of primate retina to model and treat a wide range of retinal degenerative diseases.

项目概要/摘要 视网膜内功能性神经回路的建立依赖于出生后的成熟期。 该发育时期的知识仅限于来自非灵长类动物模型系统的信息。 旨在确定出生后成熟在两个不同的主要输出途径中的进展 灵长类视网膜 - 打开和关闭遮阳伞视网膜神经节细胞 (RGC) - 通过关联 RGC 的功能活动 通过单细胞电生理学获得突触标记物的表达谱和超微结构 我们的研究将比较三个观察结果的突触连接图。 在目标 1 中，我们将在视觉功能和回路成熟之前的产后时间点进行。 确定 ON 和 OFF 遮阳伞 RGC 的光诱发功能反应的出生后发育 在目标 2 中，我们将确定 出生后发育的兴奋性和抑制性突触输入到 ON 和 OFF 遮阳伞 RGC 上，调节调节 他们的反应，包括突触前和突触后蛋白的表达谱以及 3D 我们的研究结果将为突触输入的早期阶段提供第一个见解。 灵长类视网膜中关键平行通路（ON和OFF遮阳伞RGC）的出生后功能成熟， 从而解决目前关于出生后回路和突触成熟过程的知识差距 在灵长类动物视网膜发育过程中，我们的观察还将揭示功能上不同的视网膜通路。 以相似或不同的速度成熟并识别导致发育性视觉缺陷的基质。 我们的研究结果将提供有关灵长类视网膜神经元功能成熟的重要基线信息 对于开发模拟灵长类视网膜功能特性的实验室培养人类干细胞衍生视网膜至关重要 建立模型并治疗多种视网膜退行性疾病。