Horizontal cell signaling in the mammalian retina

哺乳动物视网膜中的水平细胞信号传导

基本信息

批准号：
10547806
负责人：
NICHOLAS C. BRECHA
金额：
$ 55.47万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547806
关键词：
Blindness Cell physiology Cells Complement Complex Coupled Dendrites Diagnostic Disinhibition Feedback Genetic Goals Health Image Analysis Interneurons Knowledge Lateral Light Mediating Modeling Molecular National Eye Institute Nervous System 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

项目摘要

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非常重要，因为它是视觉处理的关键部位信号，以及这些信号从光感受器到视网膜下游神经元的传递。焦点该应用的重点是水平细胞，抑制性中间神经元向光感受器发送反馈抑制，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，其背后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，这主要是由于缺乏水平细胞信号传导的基本信息。该计划的目标是了解视网膜的视觉处理，重点关注突触和视觉初始阶段的细胞机制。我们将通过确定和测试通过 GABA 介导水平细胞信号传导至光感受器的突触和细胞机制和双极细胞，以及它们本身。具体目标 1：确定介导水平细胞向光感受器发出信号的机制。实验将通过 A) 识别补体来测试水平细胞如何介导光感受器信号传导水平细胞表达的强直 GABAAR 和 GABACR 亚基的数量和 B) 表征间接 GABA 对光感受器 Cav 通道的抑制和去抑制作用。具体目标2：确定介导双极细胞水平细胞前馈信号的机制。实验将测试水平细胞如何向双极细胞类型提供强直性 GABA 介导的信号传导 A) 识别ON-树突上表达的补体GABAAR和GABACR亚基和 OFF-双极细胞和 B) 表征 GABA 信号的生理特性由光遗传学控制的水平细胞提供给双极细胞。具体目标 3：确定水平细胞信号传导对双极细胞视觉处理的功能影响。实验将测试代表性双极细胞类型的光响应特征如何由水平细胞塑造使用 HaloTagTM 和 AMPA-DART（一种新型化学遗传学工具来沉默水平细胞输出）进行信号传导。拟议的研究将进一步了解调节早期视力的基本过程。这目标与国家眼科研究所了解视网膜的健康相关目标一致电路以及治疗方法和诊断工具的开发对于治疗和治疗至关重要预防视网膜疾病。