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; 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.

项目摘要/摘要 在视网膜内建立功能性神经元回路依赖于产后成熟时期。我们的 对这一发育时期的了解仅限于非灵长类模型系统的信息。这个项目 旨在确定产后成熟在两个不同的主要输出途径中的进展 灵长类动物视网膜 - 阳台性视网膜神经节细胞（RGC） - 通过将RGC的功能活性相关联 通过单细胞电生理学获得突触标记和超微结构的表达曲线 神经元功能的基础突触连通性图。我们的研究将比较三个的观察结果 视觉功能和电路成熟之前的产后时间点达到成人曲线。在目标1中，我们将 确定诱发的发光后和关闭parasol RGC的功能响应的产后发展 包括跨亮度水平和内在电气性能的峰值输出。在AIM 2中，我们将确定 兴奋后和抑制性突触输入的开发和关闭parasol RGC的调节 它们的反应，包括成分前和突触后蛋白的表达谱以及3D 突触输入的超微结构组织。我们的发现将为早期阶段的初次见解 灵长类动物视网膜中的关键平行途径（ON和OFF PARASOL RGC）的产后功能成熟， 从而解决有关产后回路和突触成熟过程的当前知识差距 在主要剩余发展期间。我们的观察结果还将揭示是否功能分歧的视网膜通路 以相似或不同的速率成熟，并确定引起发育视觉缺陷的底物。而且， 我们的发现将提供有关主要常规神经元功能成熟的重要基线信息 对于模仿灵长类动物视网膜功能性能的发展实验室生长的人类干细胞衍生视网膜的至关重要 建模和治疗多种永久性退行性疾病。