Horizontal cell signaling in the mammalian retina

哺乳动物视网膜中的水平细胞信号传导

• 批准号: 10331735
• 负责人: NICHOLAS C. BRECHA
• 金额: $ 53.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331735
• 关键词: Address; Blindness; Cell physiology; Cells; Complement; Complex; Coupled; Dendrites; Diagnostic; Disinhibition; Feedback; GABA transporter; Goals; Health; Image Analysis; Interneurons; Knowledge; Lateral; Light; Mediating; Modeling; Molecular; National Eye Institute; Nervous system structure; Neurons; Output; Pathology; Photoreceptors; Physiological; Presynaptic Terminals; Prevention; Process; Property; Proteins; Regulation; Retina; Retinal Diseases; Role; SNAP receptor; Shapes; Signal Pathway; Signal Transduction; Site; Structure; Synapses; Testing; Vesicle; Vision; Visual; cell type; cellular targeting; diagnostic tool; experimental study; gamma-Aminobutyric Acid; ganglion cell; horizontal cell; neurotransmission; novel; optogenetics; outer plexiform layer; prevent; programs; receptive field; receptor; receptor expression; response; retinal neuron; screening; sight restoration; therapeutic development; therapy development; tool; visual information; visual photoreceptor; visual processing; voltage

The photoreceptor synaptic complex is of great importance as it is a key site for the processing of visual signals, and the transfer of these signals from photoreceptors to downstream neurons in the retina. The focus of this application is on horizontal cells, inhibitory interneurons that send feedback inhibition to photoreceptors, feedforward inhibition to bipolar cells, and autaptic signals to themselves. The prevailing view of horizontal cell function is that these cells mediate lateral inhibition between photoreceptors, contributing to the antagonistic receptive field surrounds found in downstream neurons. However, the cellular mechanisms underlying the contribution of horizontal cells to receptive field properties in mammalian bipolar and ganglion cells has proven quite difficult to determine due in major part to the lack of fundamental information on horizontal cell signaling. The objective of this program is to understand visual processing in the retina with a focus on the synaptic and cellular mechanisms that underlie the initial stages of vision. We will address this objective by determining and testing the synaptic and cellular mechanisms mediating horizontal cell signaling via GABA to photoreceptors and bipolar cells, as well as to themselves. Specific Aim 1: Determine the mechanisms mediating horizontal cell signaling to photoreceptors. Experiments will test how horizontal cells mediate signaling to photoreceptors by A) identifying the complement of tonic GABAAR and GABACR subunits expressed by horizontal cells and B) characterizing the indirect action of GABA on inhibition and disinhibition of photoreceptor Cav channels. Specific Aim 2: Determine the mechanisms mediating horizontal cell feedforward signaling to bipolar cells. Experiments will test how horizontal cells provide tonic GABA-mediated signaling to bipolar cell types by A) identifying the complement of tonic GABAAR and GABACR subunits expressed on the dendrites of ON- and OFF-bipolar cells and B) characterizing the physiological properties of the GABAergic signal provided by optogenetically controlled horizontal cells to bipolar cells. Specific Aim 3: Determine the functional influence of horizontal cell signaling on bipolar cell visual processing. Experiments will test how features of the light responses of representative bipolar cell types are shaped by horizontal cell signaling using HaloTagTM and AMPA-DART, a novel chemogenetic tool to silence horizontal cell output. Proposed studies will further the understanding of fundamental processes mediating early vision. This objective is consistent with the health-related goals of the National Eye Institute for the understanding of retinal circuits and the development of therapeutic approaches and diagnostic tools essential for the treatment and prevention of retinal disease.

光感受器突触复合体是视觉加工的关键部位，具有重要意义 信号，以及这些信号从光感受器到视网膜下游神经元的转移。焦点 这种应用是在水平细胞上，向光感受器发送反馈抑制的抑制性中间神经元， 对双极细胞的前馈抑制，以及对自身的自动信号。水平单元格的主流观点 功能是这些细胞介导光感受器之间的侧向抑制，有助于拮抗 在下游神经元中发现感受野周围。然而，潜在的细胞机制 水平细胞对哺乳动物双极细胞和神经节细胞感受野特性的贡献已被证明 很难确定，主要是因为缺乏关于水平细胞信号的基本信息。 这个项目的目标是了解视网膜的视觉处理，重点是突触和 构成视觉初始阶段的细胞机制。我们将致力于实现这一目标，确定和 检测水平细胞通过GABA向光感受器传递信号的突触和细胞机制 和双极细胞，以及它们自己。 具体目标1：确定水平细胞向光感受器传递信号的机制。 实验将测试水平细胞如何通过A)识别补体来传递信号给光感受器 由水平细胞表达的强直性GABAAR和GABACR亚基以及B)特征的间接 GABA在光感受器Cav通道抑制和解除抑制中的作用具体目标2： 确定水平细胞前馈信号传递给双极细胞的机制。 实验将测试水平细胞如何通过A向双极细胞类型提供紧张性GABA介导的信号。) 鉴定On-1树突上表达的强直GABAAR和GABACR亚基的补体 以及B)表征GABA能信号的生理特性 由光基因控制的水平细胞提供给双极细胞。具体目标3：确定 水平细胞信号对双极细胞视觉加工的功能影响。实验将会 测试具有代表性的双极细胞类型的光响应特征如何受水平细胞的影响 使用HaloTagTM和AMPA-DART的信号传递，AMPA-DART是一种新的化学发生工具，可以静默水平细胞输出。 拟议的研究将进一步了解调节早期视觉的基本过程。这 目标与国家眼科研究所了解视网膜的健康相关目标是一致的 电路和治疗方法和诊断工具的发展对治疗和 预防视网膜疾病。