Retinal Circuitry Response to Nerve Injury

视网膜回路对神经损伤的反应

• 批准号: 10751621
• 负责人: Thomas Eugene Zapadka
• 金额: $ 4.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751621
• 关键词: Action Potentials; Acute; Address; Affect; Amacrine Cells; Anatomy; Area; Automobile Driving; Axon; Brain; Brain region; Categories; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Closure by clamp; Cone; Confocal Microscopy; Data; Detection; Disease; Electrophysiology (science); Frequencies; Functional disorder; Future; Glaucoma; Goals; Heterogeneity; In Vitro; Injury; Interneurons; Intervention; Ions; Kinetics; Learning; Light; Measures; Modeling; Morphology; Mus; Nerve Crush; Neural Retina; Operative Surgical Procedures; Optic Nerve; Optic Nerve Injuries; Outcome; Output; Pathway interactions; Patients; Pharmacology; Photoreceptors; Physiologic pulse; Physiological; Physiology; Potassium; Predisposition; Process; Property; Publishing; Ramp; Retina; Retinal Diseases; Retinal Ganglion Cells; Rod; Role; Signal Transduction; Sodium; Stimulus; Surgical Models; Synapses; Techniques; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Vision; Visual; Visual impairment; Work; axon growth; axon injury; axon regeneration; cell injury; cell regeneration; cell type; experimental study; extracellular; functional restoration; ganglion cell; human disease; improved; in vivo; injured; insight; lucifer yellow; nerve injury; neurotransmission; novel; patch clamp; postsynaptic; prophylactic; rational design; resilience; response; retinal axon; transcriptomics; visual processing; voltage

Project Summary/Abstract Healthy vision requires the function of parallel cellular and synaptic pathways in the neural retina. Circuits constructed from diverse cell types provide the anatomical and physiological basis for encoding diverse visual scenes. Indeed, visual inputs to the mouse retina are converted to electrical signals by photoreceptors (1 rod, 2 cone types), integrated by interneurons (1 horizontal, ~15 bipolar, ~60 amacrine cell types), and relayed to the brain by retinal ganglion cells (>40 types) whose axons form the optic nerve. In a surgical model of nerve injury, called the optic nerve crush (ONC), the axons of retinal ganglion cells (RGCs) are damaged. In response to ONC, 70-80% of RGCs die within two weeks. The death of RGCs is biased, however, and depends on the RGC type. A group of resilient RGC types persists and survives for weeks following the crush, whereas other susceptible RGC types die within a few days. A long-term goal of the ONC model is to rescue injured RGCs and enable regrowth of axons to target brain regions and restore functional vision. The field has identified transcriptomic and tissue-level mechanisms that promote RGC survival. Furthermore, RGC survival and axon regeneration are enhanced by RGC electrical activity (e.g., action potential firing). However, there is a major gap in our understanding of (1) how activity of different RGC types is affected following ONC; (2) how changes in activity align with the resilient/susceptible category of RGC types; and (3) whether there are cellular or synaptic mechanisms that are affected by ONC and prohibit the ability to enhance activity in certain RGC types following injury. I will therefore utilize electrophysiological and confocal microscopy techniques to directly address my hypothesis that dysfunction and reduced firing in RGCs post optic nerve crush depends on the RGC type and reflects a combination of synaptic and cell-intrinsic mechanisms. I will measure the anatomy and physiology of specific RGC types that are either resilient or susceptible to ONC and determine the contributions of either synaptic or intrinsic mechanisms to RGC hypoactivity after ONC. Understanding these mechanisms will generate insights into how naturally-occurring diseases that affect the optic nerve, such as glaucoma, cause dysfunction and death of RGCs and could contribute to the design of rational therapies.

项目总结/摘要 健康的视力需要神经视网膜中的平行细胞和突触通路的功能。电路 由不同的细胞类型构成的神经元为编码不同的视觉信号提供了解剖学和生理学基础。 场景事实上，对小鼠视网膜的视觉输入通过光感受器（1个杆，2个杆）转换成电信号。 视锥细胞类型），由中间神经元（1个水平，~15个双极，~60个无长突细胞类型）整合，并中继到 视网膜神经节细胞（>40种），其轴突形成视神经。在一个神经外科模型中， 损伤，称为视神经挤压（ONC），视网膜神经节细胞（RGC）的轴突受损。在 在对ONC的反应中，70-80%的RGC在两周内死亡。然而，RGC的死亡是有偏见的， 取决于RGC的类型。一组有弹性的RGC类型在挤压后持续存在并存活数周， 而其他易感的RGC类型在几天内死亡。ONC模式的一个长期目标是拯救 损伤的RGC，并使轴突重新生长到靶向大脑区域并恢复功能性视力。该领域 确定了促进RGC存活的转录组学和组织水平机制。此外，RGC生存 和轴突再生被RGC电活动增强（例如，动作电位放电）。不过有 我们对以下问题的理解存在重大差距：（1）不同类型的研资局在ONC后的活动如何受到影响;（2）ONC后的活动如何受到影响;（3）ONC后的活动如何受到影响。 活动的变化与RGC类型的弹性/敏感类别一致;以及（3）是否有细胞 或受ONC影响的突触机制，并禁止增强某些RGC活性的能力 受伤后的类型因此，我将利用电生理学和共聚焦显微镜技术， 直接解决了我的假设，即视神经挤压后RGCs功能障碍和放电减少 依赖于RGC类型，反映了突触和细胞内在机制的组合。我会 测量特定RGC类型的解剖学和生理学，这些RGC类型对ONC有弹性或敏感， 确定突触或内在机制对ONC后RGC活动减退的贡献。 了解这些机制将有助于深入了解自然发生的疾病如何影响 视神经，如青光眼，导致RGCs功能障碍和死亡，并可能有助于设计 理性疗法