Structure and Function of Primate Retinal Circuits

描述（由申请人提供）：侏儒和阳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，是我们感知颜色、形状和运动的基础。侏儒（持续性）神经节细胞对光强度的缓慢变化反应最佳，而伞（短暂性）神经节细胞可以检测到更快速的波动，这是一个特征。 增强了对运动的敏感性本研究的目的是确定不同类型的双极细胞，二级神经元，如何处理锥信号，以产生这些不同的时间响应特性。由于灵长类动物锥双极细胞的功能记录很少，因此调节时间调谐的机制仍不清楚。此外，我们的初步数据表明，以前提出的时间调谐模型，从工作在较低的哺乳动物，可能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。在目的1中，我们将测试的假设，在红藻氨酸受体亚基组成的异质性，和红藻氨酸受体辅助蛋白，形状的时间响应特性的OFF双极细胞。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的OFF锥双极细胞类型调谐到更高的时间频率的假设。在目标3中，我们将确定新鉴定的OFF双极细胞类型是否向OFF阳伞细胞输入，并将测试OFF侏儒神经节细胞回路中是否存在偏心依赖性变化。我们将使用免疫组织化学，共聚焦和超分辨率显微镜，膜片钳电生理学的组合来解决这些目标。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，也应该揭示有关侏儒和阳伞神经节细胞电路的新细节。因此，该建议解决了国家眼科研究所确定的两个明确需求：1）了解“结构， 视网膜神经元的“功能和电路”和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，因此本研究的结果对于开发恢复或治疗视网膜疾病所致视力丧失的方法以及解释视觉功能测试将是非常宝贵的。

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.