Synaptic and circuit mechanisms of compensation following loss of cone inputs in themature mouse retina

成熟小鼠视网膜视锥细胞输入丢失后的突触和电路补偿机制

• 批准号: 10561666
• 负责人: Felice A Dunn
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561666
• 关键词: Ablation; Adult; Affect; Afferent Neurons; Aging; Alzheimer' s Disease; Axon; Categories; Cell Death; Cell physiology; Cells; Cellular Structures; Central Nervous System; Cessation of life; Clinical; Compensation; Cone; Diagnostic; Disease; Drops; Early Diagnosis; Excitatory Synapse; Exhibits; Genetic; Glutamate Receptor; Goals; Human; Inhibitory Synapse; Injections; Injury; Knowledge; Light; Light Adaptations; Light Cell; Maps; Masks; Measures; Mediating; Methods; Minor; Modeling; Mus; Neuronal Plasticity; Onset of illness; Output; Parkinson Disease; Pathway interactions; Photoreceptors; Property; Public Health; Reaction; Research; Resolution; Retina; Retinal Cone; Retinal Diseases; Retinitis Pigmentosa; Sensory; Site; Stimulus; Structure; Synapses; Synaptic Transmission; Testing; Vision; Visual; Visual Acuity; Visual Cortex; Visual Pathways; Work; cell type; diphtheria toxin receptor; effective therapy; flexibility; ganglion cell; genetic manipulation; in vivo; innovation; insight; loss of function; macular dystrophy; neuronal excitability; presynaptic; receptive field; response; spatial integration; statistics; therapy design; voltage

There is a gap in knowledge of how loss of 50-80% of cone photoreceptors produces almost no change in visual acuity or sensitivity. While contributions from cortex have been examined, those from retina have been underappreciated. The long-term goal to understand how the retina functions robustly in the face of photoreceptor death will generate transformative insights into how neural plasticity compensates for cell death. Understanding this compensation is likely to lead to earlier diagnostics and more effective treatments. The overall objective of this proposal is to elucidate the fundamental synaptic and circuit-level mechanisms that allow the retina to function while compensating for photoreceptor death. This proposal focuses on the well-characterized circuit of the ON sustained alpha ganglion cell in mouse retina, a strong model circuit with identified cell types, maps of specific connections, accessibility to genetic manipulation, and quantifiable structure and function. Following genetic ablation of 50-75% of cones in adult retina with the diphtheria toxin receptor, these ganglion cells adjust receptive field structures and spike responses. The observations are congruent with adaptation, which adjusts integration and gain for stimulus statistics, e.g., greater integration and gain at lower light levels, or homeostatic plasticity, which involves remodeling circuitry or channel expression. The central hypothesis is that the retina can compensate for cone loss via mechanisms of adaptation and/or homeostatic plasticity that we will determine in two specific aims: (Aim 1) identify the extent and sites of compensation within the retinal circuit following partial cone loss in the adult and (Aim 2) determine the contributions of partial stimulation, mean adaptation and homeostatic plasticity to the retina's reaction to cone loss. The results of the first aim will identify the structural and functional consequences of cone loss on the direct excitatory pathway from cones to type 6 cone bipolar cells to ON alpha ganglion cells. The results of the second aim will determine how adaptation, changes in excitatory and inhibitory circuits, and intrinsic excitability contribute to changes in ganglion cell spatial and intensity encoding following partial cone loss. The approach is innovative for the genetic control over cone ablation in mature retina, the stage at which most human retinal diseases occur; functional and structural examination with cell-type specific resolution; and focus on synaptic and circuit mechanisms underlying a well known discrepancy between photoreceptor loss and visual function. The research is significant for (1) uncovering mechanisms that may mask visual deficits in early stages of photoreceptor loss; (2) suggesting diagnostics that could detect earlier onset of diseases causing cone loss; (3) establishing knowledge about the flexibility of a sensory circuit and how this flexibility pertains to a surviving circuit; (4) providing direct measures of how retinal function after partial cone loss is distinct from or similar to that in control retina—thus potentially influencing the design of treatments to restore retinal function following photoreceptor loss.

关于50-80%的视锥细胞光感受器的损失如何在视觉上几乎没有变化， 敏锐度或灵敏度。虽然已经检查了来自皮层的贡献，但是已经检查了来自视网膜的贡献。 被低估了长期目标是了解视网膜如何在面对 光感受器死亡将对神经可塑性如何补偿细胞死亡产生变革性的见解。 死亡了解这种补偿可能会导致更早的诊断和更有效的治疗。 这个建议的总体目标是阐明基本的突触和电路水平的机制 使视网膜在补偿感光细胞死亡的同时发挥功能。该提案的重点是 小鼠视网膜中ON持续的α神经节细胞的良好表征的电路， 确定的细胞类型，特定连接的地图，遗传操作的可访问性，以及可量化的 结构和功能。在用白喉毒素对成人视网膜中50-75%的视锥细胞进行基因消融后， 受体，这些神经节细胞调整感受野结构和尖峰反应。观察结果 与适应一致，适应调整刺激统计的积分和增益，例如，更大的整合 和增益在较低的光水平，或稳态可塑性，这涉及重塑电路或通道 表情中心假设是视网膜可以通过以下机制补偿视锥细胞损失： 适应和/或稳态可塑性，我们将确定在两个具体目标：（目标1）确定 成人部分视锥细胞丧失后视网膜回路内代偿的范围和部位，以及（目标2） 确定部分刺激，平均适应和稳态可塑性对视网膜的贡献， 对锥形损失的反应。第一个目标的结果将确定结构和功能的后果， 从视锥细胞到6型视锥双极细胞再到ON α神经节细胞的直接兴奋性通路上的视锥细胞损失。 第二个目标的结果将决定如何适应，兴奋和抑制回路的变化， 内源性兴奋性对部分视锥细胞空间和强度编码变化影响 损失该方法对于成熟视网膜中视锥消融的遗传控制是创新的， 大多数人类视网膜疾病的发生;功能和结构检查与细胞类型的具体决议; 并专注于突触和电路机制的基础上，一个众所周知的差异感光器之间 丧失和视觉功能。该研究对于揭示视觉掩蔽机制具有重要意义 光感受器丧失早期阶段的缺陷;（2）建议诊断，可以检测早期发病的 导致视锥细胞损失的疾病;（3）建立有关感觉回路灵活性的知识，以及这种灵活性如何影响神经元的功能。 灵活性与存活电路有关;（4）提供部分切除后视网膜功能如何的直接测量 视锥细胞丢失与对照视网膜中的视锥细胞丢失不同或相似，从而潜在地影响视网膜的设计。 治疗以恢复感光细胞丧失后的视网膜功能。