Structure and Function of Primate Retinal Circuits

灵长类动物视网膜回路的结构和功能

• 批准号: 8670611
• 负责人: Teresa Puthussery
• 金额: $ 34.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670611
• 关键词: AMPA Receptors; Address; Biological Models; Blindness; Calcium; Cells; Clinical; Color; Color Perception; Cone; Data; Dendrites; Diffuse; Drug or chemical Tissue Distribution; Electrophysiology (science); Employee Strikes; Eye; Form Perception; Frequencies; Gated Ion Channel; Glutamate Receptor; Goals; Heterogeneity; Human; Immunohistochemistry; Kainic Acid Receptors; Knowledge; Light; Macaca; Mammals; Maps; Measures; Mediating; Methods; Microscopy; Modeling; Motion; National Eye Institute; Neural Pathways; Neurons; Ocular Prosthesis; Output; Pathway interactions; Patients; Pattern; Peripheral; Physiological; Pilot Projects; Primates; Process; Property; Proteins; Resolution; Retina; Retinal; Retinal Cone; Retinal Diseases; Shapes; Signal Transduction; Sodium; Structure; Testing; Vision; Work; base; cell type; ganglion cell; insight; kainate; light intensity; neuromechanism; patch clamp; presynaptic; programs; public health relevance; response; restoration; retinal neuron; selective expression; signal processing; skills; visual information; voltage; voltage gated channel

DESCRIPTION (provided by applicant): The midget and parasol ganglion cells are the most abundant output neurons in the primate retina, and are fundamental for our perception of color, form and motion. Midget (sustained) ganglion cells respond optimally to slow changes in light intensity, whereas parasol (transient) ganglion cells can detect more rapid fluctuations, a feature that enhances sensitivity to motion. The objective of this study is to determine how the various types of bipolar cells, the second- order neurons, process cone signals to generate these distinct temporal response properties. Since few functional recordings have been made from primate cone bipolar cells, the mechanisms that mediate temporal tuning remain unclear. Moreover, our preliminary data indicate that previously proposed models for temporal tuning, from work in lower-order mammals, may not directly apply to primates. In preliminary studies, we have found that, unlike other mammals, all macaque OFF cone bipolar cells receive input primarily through kainate- type glutamate receptors. In Aim 1, we will test the hypothesis that heterogeneity in kainate receptor subunit composition, and kainate receptor auxiliary proteins, shapes the temporal response properties of OFF bipolar cells. In Aim 2, we will test the hypothesis that selective expression of voltage-gated channels tunes specific OFF cone bipolar cell types to higher temporal frequencies. In Aim 3, we will determine whether a newly identified OFF bipolar cell type makes input to OFF parasol cells, and will test whether there are eccentricity-dependent changes in OFF midget ganglion cell circuitry. We will address these aims using a combination of immunohistochemistry, confocal and super-resolution microscopy, and patch-clamp electrophysiology. These studies will provide new insights into the functional mechanisms of temporal processing in the primate retina, and should also reveal new details regarding the circuitry of midget and parasol ganglion cells. Thus, this proposal addresses two explicit needs identified by the National Eye Institute which are; 1) to understand the "structure, function and circuitry" of retinal neurons and 2) to "decode the electrical patterns used by retina neurons to transmit visual information". The macaque is an ideal model system for the human retina, and thus the results of this study will be invaluable for developing methods to restore or treat vision loss from retinal disease, and for interpreting tests of visual function.

描述（由申请人提供）：侏儒神经节细胞和伞神经节细胞是灵长类动物视网膜中最丰富的输出神经元，对于我们对颜色、形状和运动的感知至关重要。小型（持续）神经节细胞对光强度的缓慢变化做出最佳反应，而伞状（瞬时）神经节细胞可以检测到更快速的波动，这是一个特征 增强对运动的敏感性。本研究的目的是确定各种类型的双极细胞（二阶神经元）如何处理视锥细胞信号以产生这些不同的时间响应特性。由于灵长类视锥双极细胞的功能记录很少，介导时间调谐的机制仍不清楚。此外，我们的初步数据表明，之前在低阶哺乳动物中提出的时间调整模型可能并不直接适用于灵长类动物。在初步研究中，我们发现，与其他哺乳动物不同，所有猕猴 OFF 视锥双极细胞主要通过红藻氨酸型谷氨酸受体接收输入。在目标 1 中，我们将检验以下假设：红藻氨酸受体亚基组成和红藻氨酸受体辅助蛋白的异质性决定了 OFF 双极细胞的时间响应特性。在目标 2 中，我们将测试电压门控通道的选择性表达将特定关闭锥体双极细胞类型调整到更高时间频率的假设。在目标 3 中，我们将确定新识别的 OFF 双极细胞类型是否向 OFF 伞细胞输入，并将测试 OFF 侏儒神经节细胞电路中是否存在偏心率依赖性变化。我们将结合免疫组织化学、共聚焦和超分辨率显微镜以及膜片钳电生理学来解决这些目标。这些研究将为灵长类动物视网膜时间处理的功能机制提供新的见解，并且还应该揭示有关侏儒和伞神经节细胞电路的新细节。因此，该提案解决了国家眼科研究所确定的两个明确需求： 1）理解“结构， 视网膜神经元的功能和电路”以及2）“解码视网膜神经元用于传输视觉信息的电模式”。猕猴是人类视网膜的理想模型系统，因此这项研究的结果对于开发具有无价的价值。恢复或治疗视网膜疾病引起的视力丧失的方法，以及解释视功能测试的方法。