Structure and Function of Primate Retinal Circuits

描述(申请人提供)：侏儒和伞状神经节细胞是灵长类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)神经节细胞对光线强度的缓慢变化做出最佳反应，而阳伞(瞬时)神经节细胞可以检测到更快的波动，这是一个特征 这增强了对运动的敏感性。这项研究的目的是确定不同类型的双极细胞，即二阶神经元，如何处理锥体信号来产生这些不同的时间反应特性。由于从灵长类锥体双极细胞中获得的功能记录很少，所以调节时间调谐的机制仍然不清楚。此外，我们的初步数据表明，以前提出的时间调整模型，来自低级哺乳动物的工作，可能不直接适用于灵长类。在初步研究中，我们发现，与其他哺乳动物不同，所有猕猴的视锥外双极细胞主要通过海人酸型谷氨酸受体接受输入。在目标1中，我们将检验红藻氨酸受体亚单位组成和红藻氨酸受体辅助蛋白的异质性塑造非双极细胞的时间反应特性的假说。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外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，我们将确定一种新发现的外双极细胞类型是否向外阴伞细胞输入，并将测试外侏儒神经节细胞电路是否存在偏心率依赖性的变化。我们将结合免疫组织化学、共聚焦显微镜和超分辨率显微镜以及膜片钳电生理学来解决这些问题。这些研究将为灵长类视网膜中时间处理的功能机制提供新的见解，也将揭示关于侏儒和副神经节细胞电路的新细节。因此，这项建议解决了国家眼科研究所确定的两个明确需求：1)理解“结构， 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恢复或治疗视网膜疾病造成的视力损失的方法以及解释视觉功能测试将具有非常重要的价值。

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.