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：
10090603
负责人：
NICHOLAS C. BRECHA
金额：
$ 54.23万
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/10090603
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 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.

光感受器突触复合物非常重要，因为它是处理视觉的关键站点信号以及这些信号从感光体转移到视网膜中下游神经元。重点该应用在水平细胞上，抑制性中间神经元向光感受器发送反馈抑制，对双极细胞的饲料抑制作用，以及对自己的自动信号。水平细胞的流行视图功能是这些细胞介导光感受器之间的横向抑制作用，从而有助于拮抗作用在下游神经元中发现的接收场环绕。但是，依据的细胞机制水平细胞对哺乳动物双极和神经节细胞中接受场特性的贡献已被证明由于缺乏水平细胞信号传导的基本信息，因此很难确定。该程序的目的是了解视网膜中的视觉处理，重点是突触和视力初始阶段的基础的细胞机制。我们将通过确定和测试通过GABA向光感受器介导水平细胞信号传导的突触和细胞机制和双极细胞以及自身。特定目标1：确定介导水平细胞信号传导到感光体的机制。实验将测试水平细胞如何通过a）识别补体来测试水平细胞如何介导对感光体的信号传导由水平细胞表达的补品gabaar和gabacr亚基，b）表征间接的 GABA对抑制和抑制光感受器CAV通道的作用。具体目标2：确定介导水平细胞前馈信号传导到双极细胞的机制。实验将测试水平细胞如何通过A提供滋补性GABA介导的信号传导，以通过A）确定在on-的树突上表达的补品gabaar和gabacr亚基的补充和双极细胞和b）表征GABA能信号的生理特性由光遗传控制的水平细胞提供给双极细胞。特定目标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。实验会测试代表性双极细胞类型的光响应的特征如何由水平细胞塑造使用halotagtm和Ampa-dart的信号传导，这是一种沉默水平细胞输出的新型化学生成工具。拟议的研究将进一步了解介导早期视野的基本过程。这目标与国家眼睛研究所的健康相关目标是一致的电路以及治疗方法和诊断工具的开发对于治疗和预防视网膜疾病。