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

项目摘要/摘要 视网膜由神经回路集合组成，它们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，使这种交流脱轨 并阻断从视网膜到大脑的信息流。严重的先天性静止性夜盲 特别令人感兴趣的是，尽管通过视网膜上通路的信号传输完全被抑制 发出光增量的信号，ON神经回路在解剖学上是完整的。阿尔法神经节细胞，主要输出 视网膜通路神经元编码特定的视觉特征，接受兴奋性和抑制性突触 输入，将这些输入整合到它们的树枝状隔间，并产生和传输行动序列 对大脑的潜在影响。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 然而，细胞和突触因素容易发生变化 在此期间，人们对视网膜疾病还没有很好的了解。 这项提议试图解决有关神经补偿机制的重要未解问题 这是由于明确定义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方法，这些实验将定义内在特性和 视网膜神经节细胞的突触计算在突触输入和 神经元接受的兴奋/抑制是被干扰的。两个CRISPR编辑的主体淘汰赛模型 视网膜上通路的谷氨酸受体mGluR6将用于研究视网膜内部的神经补偿 视网膜跨越纯合子(100%阻塞)和杂合子(50%阻塞)条件。我们将把单个细胞关联起来 电生理学和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。总而言之，拟议中的实验将显著深化 我们对视网膜内部神经补偿底物的机械理解，并定义了细胞 以及严重先天性静止性夜盲的突触缺陷。

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.