Retinal Circuitry Response to Nerve Injury

项目摘要/摘要 健康的视觉需要神经视网膜中平行的细胞和突触通路的功能。电路 由不同类型的细胞构成的细胞为编码不同的视觉提供了解剖学和生理学基础 场景。事实上，小鼠视网膜的视觉输入通过光感受器转换为电信号(1个视杆，2个 锥体型)，由中间神经元整合(1种水平细胞，~15种双极细胞，~60种无长突细胞)，并传递到 大脑由视网膜神经节细胞(&gt；40种)组成，其轴突形成视神经。在神经外科模型中 视网膜神经节细胞(RGCs)的轴突受损，称为视神经挤压(ONC)。在……里面 对ONC的反应，70%-80%的RGC在两周内死亡。然而，RGC的死亡是有偏见的，而且 视乎研资局类型而定。一群有弹性的RGC类型在崩溃后持续并存活了数周， 而其他易受影响的研资局类型则在几天内死亡。ONC模式的一个长期目标是拯救 损伤的视网膜节细胞并使轴突再生，以靶向大脑区域，恢复功能性视力。这一领域有 确定了促进RGC存活的转录和组织水平的机制。此外，研资局的存活率 和轴突再生通过RGC电活动(例如，动作电位激发)而增强。然而，还有 我们对(1)不同类型的研资局活动如何在ONC之后受到影响的理解上的主要差距；(2)如何 活动的变化与RGC类型的弹性/敏感类别一致；以及(3)是否存在细胞性 或受ONC影响的突触机制，并禁止增强某些RGC的活动 受伤后的类型。因此，我将利用电生理和共聚焦显微镜技术来 直接回答我的假设：视神经挤压后视网膜节细胞功能障碍和放电减少 取决于RGC的类型，反映了突触和细胞内在机制的组合。这就做 测量对ONC和ONC具有弹性或易感性的特定RGC类型的解剖和生理 确定突触或内在机制对ONC后RGC活性低下的贡献。 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，会导致视网膜节细胞功能障碍和死亡，并可能有助于设计 理性疗法。

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.