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

关于50%-80%的视锥细胞感光细胞的丧失如何导致视觉几乎没有变化，目前还存在一个知识空白 敏锐或敏感。虽然已经检查了来自皮质的贡献，但来自视网膜的贡献已经被 被低估了。长期的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。 这项建议的总体目标是阐明基本的突触和电路水平的机制 这使得视网膜能够在补偿感光细胞死亡的同时发挥作用。这项提案的重点是 描述了小鼠视网膜上持续的阿尔法神经节细胞的回路，这是一个具有 确定的细胞类型、特定连接的图谱、遗传操作的可及性以及可量化的 结构和功能。用白喉毒素对成人视网膜50%-75%的视锥细胞进行遗传切割后 这些神经节细胞通过受体调节感受野结构和棘波反应。观察到的是 与适应一致，后者调整刺激统计的整合和增益，例如，更大的整合 以及在较低光照水平下的增益，或涉及重塑电路或通道的动态平衡可塑性 表情。中心假设是视网膜可以通过以下机制来补偿视锥细胞的丢失 适应和/或动态平衡可塑性，我们将在两个具体目标中确定：(目标1)确定 成人部分视锥丢失后视网膜环路的代偿范围和位置(目标2) 确定部分刺激、平均适应和动态平衡可塑性对视网膜的贡献 对视锥丢失的反应。第一个目标的结果将确定以下方面的结构和功能后果 从视锥细胞到6型视锥双极细胞再到阿尔法神经节细胞的直接兴奋通路上的视锥细胞丢失。 第二个目标的结果将决定适应、兴奋和抑制回路的变化，以及 内源性兴奋性参与部分锥体损伤后神经节细胞空间和强度编码的变化 损失。该方法在成熟视网膜视锥细胞切除的遗传控制方面是创新的，在这一阶段 大多数人类视网膜疾病发生；细胞类型特定分辨率的功能和结构检查； 并将重点放在众所周知的光感受器之间差异背后的突触和回路机制上 丧失视觉功能。这项研究对于(1)揭示可能掩盖视觉的机制具有重要意义 光感受器丧失早期阶段的缺陷；(2)提示可以检测到更早发病的诊断 导致视锥细胞丢失的疾病；(3)建立关于感觉回路灵活性的知识，以及如何做到这一点 灵活性与存活的回路有关；(4)提供部分视网膜功能的直接测量。 视锥细胞丢失不同于或类似于对照视网膜--因此可能会影响 光感受器丧失后恢复视网膜功能的治疗。

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.