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.

项目摘要/摘要 视网膜内功能性神经元回路的建立依赖于出生后的成熟期。我们 对这一发育期的了解仅限于来自非灵长类模型系统的信息。这个项目 目的是确定在两个不同的主要输出途径的出生后成熟的进展， 灵长类视网膜- ON和OFF阳伞视网膜神经节细胞（RGC）-通过RGC的相关功能活性 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 神经元功能突触连接图。我们的研究将比较三个国家的观察结果， 在视觉功能和回路成熟达到成人轮廓之前的出生后时间点。在目标1中， 确定ON和OFF遮阳伞RGCs的光诱发功能反应的出生后发育 包括亮度级上的尖峰输出和固有电特性。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 parasol RGC上， 它们的反应，包括组成突触前和突触后蛋白的表达谱和3D 突触输入的超微结构组织。我们的研究结果将提供对早期阶段的第一个见解 灵长类动物视网膜中关键平行通路（ON和OFF parasolRGC）的出生后功能成熟， 从而填补了目前关于出生后神经回路和突触成熟过程的知识空白 在灵长类视网膜发育过程中。我们的观察还将揭示功能性分歧的视网膜通路 以相似或不同的速率成熟，并确定导致发育性视觉缺陷的底物。此外，委员会认为， 我们的发现将为灵长类视网膜神经元的功能成熟提供重要的基础信息 对于开发模拟灵长类视网膜功能特性的实验室生长的人类干细胞衍生视网膜至关重要 来模拟和治疗各种视网膜变性疾病。