Mechanisms of neural compensation in the retina and dysfunction in congenital stationary night blindness

先天性静止性夜盲症视网膜神经代偿机制及功能障碍

• 批准号: 10678730
• 负责人: Jacob Omar Khoussine
• 金额: $ 4.11万
• 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: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678730
• 关键词: 3-Dimensional; Action Potentials; Address; Adopted; Affect; Anatomy; Applications Grants; Architecture; Axon; Behavior; Behavioral; Biological Assay; Biophysics; Brain; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collaborations; Communication; Compensation; Complement; Confocal Microscopy; Coupled; Data; Disease; Electrophysiology (science); Elements; Equilibrium; Eye; Fostering; Functional disorder; Gene Deletion; Generations; Genes; Genotype; Glutamate Receptor; Heterozygote; Human; Immunohistochemistry; Inherited; Ion Channel; Knock-out; Knockout Mice; Knowledge; Light; Maps; Measures; Membrane; Metabotropic Glutamate Receptors; Modeling; Mus; Mutation; Neurons; Neurotransmitter Receptor; Night Blindness; Output; Pathway interactions; Patients; Pattern; Perception; Persons; Photoreceptors; Physiology; Process; Property; Research; Research Training; Retina; Retinal Diseases; Retinal Ganglion Cells; Role; Signal Pathway; Signal Transduction; Sodium Channel; Structure; Synapses; Therapeutic; Training; Travel; Visual; Visual Perception; Visuospatial; Work; behavioral study; blind; experimental study; extracellular; ganglion cell; high resolution imaging; improved; insight; interest; luminance; microscopic imaging; mutant; neural; neural circuit; neuromechanism; neuronal excitability; neurophysiology; null mutation; patch clamp; receptor expression; response; retinal neuron; skills; transmission process; visual information; voltage; voltage clamp

PROJECT SUMMARY/ABSTRACT The retina is comprised of neural circuit ensembles that communicate through connections called synapses to generate visual perception and behavior. Retinal diseases cause signaling deficits that derail this communication and block information flow traveling from the retina to the brain. Severe congenital stationary night blindness is of particular interest because despite complete suppression of signal transmission through the on retinal pathway that signals light increments, the on neural circuitry is anatomically intact. Alpha ganglion cells, the primary output neurons of retinal pathways that code for specific visual features, receive excitatory and inhibitory synaptic inputs, integrate these inputs across their dendritic compartments, and generate and transmit trains of action potentials to the brain. We know that neural circuits can adopt diverse strategies to conduct precise synaptic computations and generate response properties, however, the cellular and synaptic factors prone to alteration during retinal diseases are not well understood. This proposal seeks to address important unanswered questions about the mechanisms of neural compensation that occur in response to specific signaling deficits in well-defined alpha retinal output circuits. Using a set of neurophysiological and anatomical approaches, these experiments will define how intrinsic properties and synaptic computations of alpha retinal ganglion cells are altered when the synaptic inputs and balance of excitation/inhibition that a neuron receives is perturbed. Two CRISPR-edited knockout models of the principal glutamate receptor of the on retinal pathway, mGluR6, will be used to study neural compensation in the inner retina across homozygous (100% block) and heterozygous (50% block) conditions. We will correlate single cell electrophysiology with high resolution imaging and visual behavior assays to complement observations across the cellular, synaptic, and behavioral levels. Together, the proposed experiments stand to significantly deepen our mechanistic understanding of the substrates of neural compensation in the inner retina and define the cellular and synaptic deficits of severe congenital stationary night blindness.

项目概要/摘要 视网膜由神经回路群组成，这些神经回路群通过称为突触的连接进行通信 产生视觉感知和行为。视网膜疾病会导致信号缺陷，从而破坏这种沟通 并阻止从视网膜到大脑的信息流。严重的先天性静止性夜盲症是 特别令人感兴趣，因为尽管完全抑制了通过视网膜通路的信号传输 发出光增量信号的神经回路在解剖学上是完整的。 α神经节细胞，主要输出 视网膜通路的神经元编码特定的视觉特征，接收兴奋性和抑制性突触 输入，将这些输入整合到其树突区室中，并生成和传输一系列行动 大脑的潜力。我们知道神经回路可以采取多种策略来进行精确的突触 计算并生成响应特性，但是细胞和突触因素容易发生改变 视网膜疾病期间的情况尚不十分清楚。 该提案旨在解决有关神经补偿机制的重要未解答问题 这是由于明确的阿尔法视网膜输出电路中的特定信号缺陷而发生的。使用一组 神经生理学和解剖学方法，这些实验将定义内在特性和 当突触输入和平衡时，α视网膜神经节细胞的突触计算会改变 神经元接收到的兴奋/抑制受到干扰。两个 CRISPR 编辑的校长基因敲除模型 视网膜通路上的谷氨酸受体 mGluR6 将用于研究内部神经代偿 视网膜跨越纯合（100％块）和杂合（50％块）条件。我们将关联单细胞 具有高分辨率成像和视觉行为测定的电生理学，以补充跨领域的观察结果 细胞、突触和行为水平。总之，拟议的实验将显着深化 我们对视网膜内神经补偿基质的机械理解并定义了细胞 以及严重先天性静止性夜盲症的突触缺陷。