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: 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
• 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

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，因为它是处理视觉信息的关键部位。 信号，以及将这些信号从光感受器传递到视网膜中的下游神经元。重点 是水平细胞，抑制性中间神经元，其向光感受器发送反馈抑制， 对双极细胞的前馈抑制和对自身的自适应信号。水平细胞的流行观点 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 下游神经元的感受野包围。然而，细胞机制的基础上， 在哺乳动物的双极细胞和神经节细胞中，水平细胞对感受野特性的贡献已被证明 很难确定，这主要是由于缺乏关于水平小区信令的基本信息。 这个项目的目的是了解视网膜的视觉处理，重点是突触和 视觉最初阶段的细胞机制。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，以及它们自己。 具体目标1：确定介导水平细胞信号传导至光感受器的机制。 实验将测试水平细胞如何通过以下方式来介导光感受器的信号传导：A）识别补体 和B）表征水平细胞表达的紧张性GABAAR和GABACR亚基的间接 GABA对光感受器Cav通道的抑制和解除抑制的作用。具体目标二： 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）向双极细胞类型提供紧张性GABA介导的信号传导。 鉴定ON-1树突上表达的紧张性GABAAR和GABACR亚基的补体， 和关闭双极细胞，以及B）表征GABA能信号的生理特性 由光遗传学控制的水平细胞向双极细胞提供。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 测试代表性双极细胞类型的光响应特征如何被水平细胞塑造 使用HaloTagTM和AMPA-DART进行信号传导，这是一种新型的化学遗传学工具，可以沉默水平细胞输出。 拟议的研究将进一步了解调解早期视力的基本过程。这 目的与国家眼科研究所的健康相关目标一致，以了解视网膜病变。 电路和治疗方法的发展和诊断工具的治疗和 预防视网膜疾病。