Thresholds, sites, and contributions of circuit compensation following rod photoreceptorloss in mature retina

成熟视网膜视杆细胞感光损失后电路补偿的阈值、部位和贡献

• 批准号: 9913554
• 负责人: Felice A Dunn
• 金额: $ 36.3万
• 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: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913554
• 关键词: Ablation; Address; Affect; Afferent Neurons; Amacrine Cells; Axon; Cell Death; Cells; Cessation of life; Cone; Data; Degenerative Disorder; Dendrites; Event; Exhibits; Financial compensation; Functional disorder; Future; Generations; Genes; Genetic; Glutamates; Goals; Human; Impairment; Individual; Injury; Investigation; Knowledge; Light; Link; Measures; Mediating; Modeling; Molecular; Mus; Neurons; Output; Pathway interactions; Patients; Photons; Photoreceptors; Population; Prosthesis; Proteins; Public Health; Reaction; Research; Resolution; Retina; Rod; Signal Transduction; Site; Structure; Synapses; Visual; Visual system structure; Work; base; cell type; diphtheria toxin receptor; effective therapy; ganglion cell; in vivo; innovation; insight; knock-down; mouse model; neural circuit; neuron loss; neuronal circuitry; normal aging; novel; postsynaptic; quantum; response; retinal neuron; retinal rods; stem cells; tool

There is critical need to understand the causes, extent, and mechanisms of reactions to cell death so that effective treatments most appropriate for the state of the remaining circuit can be employed, and so that constructive compensation can be harnessed as a potential treatment in conditions where a portion of the circuit endures. Our long-term goal is to salvage neuronal circuits. Here, we will define the effects of controlled cell death on specific circuits, cell types, synapses, and proteins for the purpose of understanding the conditions that result in constructive (e.g., compensation through increasing synaptic gain) vs. destructive (e.g., aberrant spontaneous activity that corrupts signal) response. The mouse retina is an exceptional platform for this study because the primary sensory neurons, photoreceptors, can be manipulated under genetic control; cell types within specific circuits are identifiable and accessible; and the functional readout can be interpreted as visual sensitivity. We propose to ablate variable populations of rods in mature retina and determine the structural and functional effects on the primary rod bipolar cell pathway, the most sensitive retinal pathway: rods→rod bipolar cells→AII amacrine cells→ON cone bipolar cells→ON sustained alpha ganglion cells (abbr. ON alpha). ON alpha ganglion cells receive the greatest number of rod inputs, thus would be the most sensitive to rod loss. Our central hypothesis is that the retina has constructive reactions to input loss with the capacity to recover normal function up to an undefined threshold; beyond this threshold, destructive reactions begin. Unknown is this tipping point. Our preliminary data show that despite loss of half the rods, rod- mediated light responses in ON alpha ganglion cell spikes are comparable to control, suggesting compensation within the primary rod bipolar cell pathway. Thus, the premise is strong for constructive compensation within the retina following rod loss, and we will determine the induction parameters, sites, and contributions of this compensation to maintaining function in the following aims: (Aim 1) to determine the degree of input loss that induces constructive vs. destructive structural and functional changes, and (Aim 2) to locate the site(s) and mechanism(s) of compensation within a well-defined neural circuit. The approach is innovative for genetic control over the timing and degree of rod death; synaptic- and cell-type specific structural and functional investigation of a well-defined retinal circuit; and molecular tools to distinguish between cell ablation and synapse disassembly in triggering compensatory mechanisms. The results will be significant for (1) determining the degree of rod death that triggers the remaining circuit to undergo destructive or constructive responses, (2) identifying the sites and contributions of structural and functional compensation to maintaining retinal function, and (3) providing knowledge essential to the optimization and deployment of therapies to treat dysfunctional photoreceptors involving stem cells, genes, and prostheses, all of which rely on a stable retinal circuit and/or extensive knowledge of the state of the surviving retinal circuit.

迫切需要了解对细胞死亡的反应的原因，程度和机制，以便可以采用最适合其余电路状态的有效治疗方法，以便在电路持久的一部分条件下，可以将建设性补偿作为潜在的治疗方法。我们的长期目标是挽救神经元电路。在这里，我们将定义受控细胞死亡对特定电路，细胞类型，突触和蛋白质的影响，目的是了解导致建设性（例如，通过增加突触增益而获得的补偿）与破坏性（例如，异常发起人的发起人的活动损坏信号的赔偿）的影响。小鼠视网膜是本研究的特殊平台，因为可以在遗传控制下操纵主要的感觉神经元，感光体。特定电路中的细胞类型是可识别和可访问的；功能读数可以解释为视觉灵敏度。我们建议在成熟的视网膜中消除杆的可变种群，并确定对原代杆双极细胞途径的结构和功能作用，这是最敏感的视网膜途径：杆→杆双极性细胞→AII II无链氨基细胞→锥双极性细胞上的双极细胞→对持续的Alpha神经节细胞（ABBR）（ABBR）（ABBR）。在α神经节细胞上，收到最大数量的杆输入，因此对杆损耗最敏感。我们的中心假设是，视网膜对输入损失具有建设性反应，其能力恢复正常功能至不确定的阈值。除了这个阈值之外，破坏性反应开始了。这个转折点未知。我们的初步数据表明，目的地损失了一半的杆，杆 - Alpha神经节细胞尖峰上的介导的光反应与对照相媲美，表明补偿 在主杆双极细胞通路内。这一点，前提对于杆损失后视网膜内的建设性补偿是强大的，我们将确定该薪酬对维持功能的归纳参数，站点和贡献：（目标1）确定诱导建设性与毁灭性结构和功能的造成建设性和（赔偿目标2）的输入损失程度，以及在位置上的中等范围（s）和机械依赖（S）和机械态度（s）的方法（S）用于对杆死亡的时间和程度的遗传控制；明确定义的视网膜电路的突触和细胞类型特异性结构和功能投资；和分子工具，以区分细胞消融和突触在触发补偿机制中脱离脱层。结果对于（1）确定触发剩余电路的杆死亡程度将很重要视网膜电路和/或广泛了解生存视网膜电路状态。