Neuromuscular Control of Primate Eye Movements

灵长类动物眼球运动的神经肌肉控制

• 批准号: 9919573
• 负责人: Marc A Sommer
• 金额: $ 19.7万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919573
• 关键词: Anatomy; Basic Science; Binocular Vision; Brain Stem; Cell Nucleus; Cephalic; Characteristics; Curiosities; Data; Disease; Electrodes; Electrophysiology (science); Etiology; Eye; Eye Movements; Fiber; Genes; Goals; Histologic; Histology; Immunohistochemistry; Individual; Injections; Intervention; Lazy Eyes; Learning; Length; Light; Link; Location; Macaca; Methods; Microscopy; Motor; Motor Neurons; Movement; Muscle; Muscle Fibers; Neuromuscular Diseases; Neuromuscular Junction; Neurons; Oculomotor nucleus; Operative Surgical Procedures; Opsin; Outcome; Outcome Study; Pattern; Play; Population; Primates; Protocols documentation; Resolution; Role; Saccades; Safety; Sampling; Simplexvirus; Smooth Pursuit; Strabismus; Structure; Structure-Activity Relationship; Symptoms; System; Techniques; Testing; Time; Viral; Viral Vector; Visual; Work; base; clinical application; conventional therapy; craniofacial; design; effective therapy; experimental study; fluorophore; gaze; gene therapy; in vivo; interest; motor control; nerve supply; neuromuscular; neuromuscular system; neurophysiology; neurotoxicity; nonhuman primate; novel; oculomotor; optogenetics; orbit muscle; sample fixation; success; transgene expression; vector; visual motor

Analyzing the visual world requires the meticulous coordination of both eyes, achieved by six muscles that surround each eye. Controlled by motoneurons in the brainstem, these muscles move the eyes rapidly to acquire targets (using saccades) or track them (smooth pursuit). The muscles also make slower adjustments to maintain proper binocular alignment in depth (vergence) and keep the eyes still for target inspection (fixation). Common visuomotor disorders such as strabismus result from abnormalities in this neuromuscular system. Current treatments mitigate symptoms, but do not fix the underlying problems. To progress toward cures for the disorders, we need to learn more about the details of the neuromuscular circuits. A longstanding curiosity about extraocular muscle fibers has been that they come in two major types: multiply-innervated fibers (MIFs) that receive numerous neuromuscular junctions along their entire length, and singly-innervated fibers (SIFs) that receive a single band of neuromuscular junctions in their middle region. It was discovered recently in primates that these two types of muscle fibers are supplied by distinct groups of motoneurons, revealing that the MIF vs. SIF distinction extends to full motor units. Anatomical characteristics of MIFs and their motoneurons suggest they control slow, binocular alignment (vergence and fixation) whereas SIFs and their motoneurons control faster, targeting movements (saccades and smooth pursuit). The overall goal is to test this hypothesis of dual- motor control of the eyes. This will be accomplished using linear array recordings and optogenetics to study MIF and SIF motoneurons in behaving macaques. Pilot work showed that macaque extraocular motoneurons can be virally transduced to express exogenous genes, setting the stage for the optogenetic approach. The first aim is to achieve reliable, robust viral transduction and opsin expression in macaque motoneurons. Three viral vectors will be injected into orbital muscles at varying volumes and titers. Consequent transgene expression in motoneurons, along with any evidence of neurotoxicity, will be analyzed histologically up to 1 year post-injection to determine optimal parameters. The second aim is to distinguish the functional roles of MIF and SIF motoneurons. Exploiting the separate, colinear locations of MIF and SIF motoneurons in the primate oculomotor nucleus, we will angle linear array electrodes to sample both populations simultaneously. Motoneuron activity will be analyzed in relation to vergence, saccade, and smooth pursuit movements made by the macaques. MIF motoneurons will be identified with in vivo optogenetic phototagging and histological analyses. The outcome of the study will be to resolve whether MIF and SIF motor units constitute a dual-motor system for controlling the eyes. If the MIF subsystem is specialized for binocular alignment, as predicted, it would be implicated as a locus of disruption in strabismus, providing a specific target for treatment. More generally, the work will provide new viral and neurophysiological techniques for studying primate motoneurons, establish a novel testbed for primate optogenetics, and inform the safety and efficacy of gene therapy for neuromuscular disorders.

分析视觉世界需要两只眼睛的细致协调，这是由六个肌肉实现的 包围每只眼睛。这些肌肉由脑干中的运动神经元控制，迅速移动眼睛以获取 目标（使用扫视）或跟踪它们（平滑追击）。肌肉还可以使调整较慢以保持 正确的双目对准深度（Gergence），并保持眼睛静止以进行目标检查（固定）。常见的 该神经肌肉系统中异常引起的视觉运动障碍，例如斜视。当前的 治疗缓解症状，但不要解决潜在的问题。朝着治愈 疾病，我们需要更多地了解神经肌肉电路的细节。长期以来对 外部肌肉纤维一直是它们有两种主要类型：多发纤维（MIF） 沿其整个长度接收大量神经肌肉连接，并单感染纤维（SIF） 在其中部地区接收一个神经肌肉连接。它是最近在灵长类动物中发现的 这两种类型的肌肉纤维由不同的运动神经元组提供，表明MIF VS。 SIF的区别延伸到完整的电动机单元。 MIFS及其运动神经元的解剖学特征建议 他们控制缓慢的双眼比对（Gergence和固定），而SIF及其运动神经元控制 更快，定位运动（扫视和平滑追击）。总体目标是检验双重假设 眼睛的运动控制。这将使用线性阵列记录和光遗传学来研究MIF 和SIF运动神经元在行为猕猴中。飞行员工作表明，猕猴的外眼运动神经元可以是 病毒转导至表达外源基因，为光遗传学方法奠定了基础。第一个目的是 在猕猴运动神经元中实现可靠的，可靠的病毒转导和OPSIN表达。三个病毒向量 将在不同的体积和滴度下注入轨道肌肉。随之而来的转基因表达 运动神经元，以及任何神经毒性的证据，将在组织学上进行1年的组织学分析 确定最佳参数。第二个目的是区分MIF和SIF的功能作用 运动神经元。利用灵长类动眼动物中MIF和SIF运动神经元的单独的colinear位置 细胞核，我们将角度线性阵列电极同时采样两个种群。运动神经元活动 将根据猕猴进行的Gergence，Saccade和平稳的追求运动进行分析。米夫 运动神经元将通过体内光遗传学光吸收和组织学分析来鉴定。结果 该研究将解决MIF和SIF电机单元是否构成用于控制该系统的双运动系统 眼睛。如预测的那样 斜视的破坏，为治疗提供了特定的靶标。更一般地，这项工作将提供新的 用于研究灵长类动物神经元的病毒和神经生理技术，为灵长类动物建立新颖的测试 光遗传学，并为神经肌肉疾病的基因疗法的安全性和功效提供了信息。