Mechanisms of neural compensation in the retina and dysfunction in congenital stationary night blindness

项目总结/摘要 视网膜是由神经回路集合体组成的，这些神经回路集合体通过称为突触的连接进行通信， 产生视觉感知和行为。视网膜疾病导致信号缺陷，破坏这种沟通 阻碍信息从视网膜流向大脑。严重的先天性静止性夜盲症是 这是特别令人感兴趣的，因为尽管完全抑制了通过视网膜上通路的信号传输， 信号是轻微的增加，神经回路在解剖学上是完整的。阿尔法神经节细胞， 编码特定视觉特征的视网膜通路的神经元，接收兴奋性和抑制性突触 输入，将这些输入整合到它们的树突隔室中，并产生和传递一连串的动作 大脑的潜力。我们知道，神经回路可以采用不同的策略来进行精确的突触传递， 然而，细胞和突触因素容易改变， 视网膜疾病的发病原因还不太清楚。 这一建议旨在解决有关神经补偿机制的重要问题 这是由于在明确的阿尔法视网膜输出回路中的特定信号缺陷而发生的。使用一组 神经生理学和解剖学的方法，这些实验将定义如何内在的属性， 当突触的输入和平衡时，α视网膜神经节细胞的突触计算被改变， 神经元接收的兴奋/抑制受到干扰。两个CRISPR编辑的主要基因敲除模型 视网膜通路的谷氨酸受体mGluR 6将用于研究内皮层的神经补偿。 在纯合（100%阻断）和杂合（50%阻断）条件下的视网膜。我们将单个细胞 电生理学与高分辨率成像和视觉行为分析，以补充观察 细胞、突触和行为水平。总之，拟议的实验将大大深化 我们对视网膜内层神经补偿基质的机械理解， 和严重先天性静止性夜盲症的突触缺陷。

PROJECT SUMMARY/ABSTRACT The retina is comprised of neural circuit ensembles that communicate through connections called synapses to generate visual perception and behavior. Retinal diseases cause signaling deficits that derail this communication and block information flow traveling from the retina to the brain. Severe congenital stationary night blindness is of particular interest because despite complete suppression of signal transmission through the on retinal pathway that signals light increments, the on neural circuitry is anatomically intact. Alpha ganglion cells, the primary output neurons of retinal pathways that code for specific visual features, receive excitatory and inhibitory synaptic inputs, integrate these inputs across their dendritic compartments, and generate and transmit trains of action potentials to the brain. We know that neural circuits can adopt diverse strategies to conduct precise synaptic computations and generate response properties, however, the cellular and synaptic factors prone to alteration during retinal diseases are not well understood. This proposal seeks to address important unanswered questions about the mechanisms of neural compensation that occur in response to specific signaling deficits in well-defined alpha retinal output circuits. Using a set of neurophysiological and anatomical approaches, these experiments will define how intrinsic properties and synaptic computations of alpha retinal ganglion cells are altered when the synaptic inputs and balance of excitation/inhibition that a neuron receives is perturbed. Two CRISPR-edited knockout models of the principal glutamate receptor of the on retinal pathway, mGluR6, will be used to study neural compensation in the inner retina across homozygous (100% block) and heterozygous (50% block) conditions. We will correlate single cell electrophysiology with high resolution imaging and visual behavior assays to complement observations across the cellular, synaptic, and behavioral levels. Together, the proposed experiments stand to significantly deepen our mechanistic understanding of the substrates of neural compensation in the inner retina and define the cellular and synaptic deficits of severe congenital stationary night blindness.