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.

项目摘要/摘要 健康视力需要平行细胞和突触途径在神经视网膜中的功能。电路 由各种细胞类型构建的提供了解剖学和生理基础，用于编码各种视觉 场景。实际上，通过光感受器（1杆，2）将视觉输入转换为电信号 锥类型），由中间神经元（1个水平，〜15双极，〜60 amacrine细胞类型），并中继到 轴突形成视神经的视网膜神经节细胞（> 40种类型）的大脑。在神经外科模型中 损伤被称为视神经挤压（ONC），视网膜神经节细胞（RGC）的轴突受损。在 对ONC的反应，RGC中有70-80％在两周内死亡。但是，RGC的死亡是有偏见的，并且 取决于RGC类型。一组弹性的RGC类型持续存在，并在暗恋后存活数周， 而其他易感RGC类型在几天内死亡。 ONC模型的长期目标是营救 损伤的RGC并使轴突能够重新生长，以靶向大脑区域并恢复功能视觉。该领域有 鉴定出促进RGC存活的转录组和组织级机制。此外，RGC生存 RGC的电活动（例如，动作电势射击）增强了轴突再生。但是，有 我们对（1）ONC之后不同RGC类型的活性如何影响（1）的主要差距； （2）如何 活动的变化与RGC类型的弹性/易感类别保持一致； （3）是否有细胞 或受ONC影响并禁止增强某些RGC活性的能力的突触机制 受伤后的类型。因此，我将利用电生理和共聚焦显微镜技术 直接解决了我的假设，即RGC中的功能障碍和降低发射后视神经挤压 取决于RGC类型，并反映了突触和细胞内部机制的组合。我会 测量特定RGC类型的解剖学和生理学，这些类型具有弹性或容易受到ONC的影响 确定突触或固有机制对ONC后RGC不良性的贡献。 了解这些机制将产生有关自然疾病的影响 视神经，例如青光眼，引起RGC的功能障碍和死亡，可能有助于设计 理性疗法。