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

基本信息

  • 批准号:
    10636801
  • 负责人:
  • 金额:
    $ 36.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
有迫切需要了解的原因,程度和机制的反应,细胞死亡,使有效的治疗最适合的状态,其余电路可以采用,使建设性的补偿可以利用作为一个潜在的治疗条件下的一部分电路的持久性。我们的长期目标是挽救神经回路。在这里,我们将定义控制细胞死亡对特定回路,细胞类型,突触和蛋白质的影响,以了解导致建设性(例如,通过增加突触增益的补偿)与破坏性的(例如,破坏信号的异常自发活动)反应。小鼠视网膜是这项研究的一个特殊平台,因为初级感觉神经元,光感受器,可以在遗传控制下操纵;特定回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。我们建议在成熟视网膜中消融可变的视杆细胞群,并确定对主要视杆双极细胞通路的结构和功能影响,最敏感的视网膜通路:视杆细胞→视杆双极细胞→AII无长突细胞→ON锥双极细胞→ON持续α神经节细胞(abbr. ON alpha)。ON α神经节细胞接收最大数量的视杆输入,因此对视杆损失最敏感。我们的中心假设是,视网膜对输入损失有建设性的反应,有能力恢复正常功能,直到一个不确定的阈值;超过这个阈值,破坏性的反应开始。未知的是这个临界点。我们的初步数据显示,尽管失去了一半的棒,棒- ON α神经节细胞棘波介导的光反应与对照相当,表明补偿 在初级视杆双极细胞通路中。因此,前提是在视杆细胞丧失后视网膜内的建设性补偿是强有力的,我们将确定诱导参数,地点,以及这种补偿对维持功能的贡献,目的如下:(目的1)确定引起建设性与破坏性结构和功能变化的输入损失程度,以及(目标2)在明确定义的神经回路内定位补偿的位点和机制。该方法是创新的遗传控制杆死亡的时间和程度;突触和细胞类型的特定结构和功能的调查一个明确的视网膜电路;和分子工具,以区分细胞消融和突触解体触发补偿机制。这些结果对于(1)确定触发剩余回路进行破坏性或建设性反应的视杆死亡程度,(2)识别结构和功能补偿对维持视网膜功能的部位和贡献,以及(3)提供对治疗功能障碍的光感受器的治疗方法的优化和部署至关重要的知识,包括干细胞,基因和假体,所有这些都依赖于稳定的视网膜回路和/或对存活的视网膜回路状态的广泛了解。

项目成果

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Felice A Dunn其他文献

Felice A Dunn的其他文献

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{{ truncateString('Felice A Dunn', 18)}}的其他基金

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:
    10331742
  • 财政年份:
    2019
  • 资助金额:
    $ 36.34万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 36.34万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 36.34万
  • 项目类别:
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:
    10401796
  • 财政年份:
    2019
  • 资助金额:
    $ 36.34万
  • 项目类别:
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:
    10090475
  • 财政年份:
    2019
  • 资助金额:
    $ 36.34万
  • 项目类别:
Structure, function, and adaptability of parallel pathways in mammalian retina
哺乳动物视网膜平行通路的结构、功能和适应性
  • 批准号:
    8889375
  • 财政年份:
    2014
  • 资助金额:
    $ 36.34万
  • 项目类别:
Structure, function, and adaptability of parallel pathways in mammalian retina
哺乳动物视网膜平行通路的结构、功能和适应性
  • 批准号:
    9096817
  • 财政年份:
    2014
  • 资助金额:
    $ 36.34万
  • 项目类别:
Structure, function, and adaptability of parallel pathways in mammalian retina
哺乳动物视网膜平行通路的结构、功能和适应性
  • 批准号:
    8423488
  • 财政年份:
    2013
  • 资助金额:
    $ 36.34万
  • 项目类别:
Structure, function, and adaptability of parallel pathways in mammalian retina
哺乳动物视网膜平行通路的结构、功能和适应性
  • 批准号:
    8601079
  • 财政年份:
    2013
  • 资助金额:
    $ 36.34万
  • 项目类别:

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