Structure and Function of Neurons in the Primate Retina

描述(申请人提供)：这些实验的目的是了解灵长类动物视网膜中视觉信息的处理。这一资助期间的重点将放在侏儒神经节细胞上，它既调节高敏锐度视觉，又调节红绿颜色视觉。侏儒神经节细胞是灵长类动物视网膜中最常见的类型，但尽管进行了多年的研究，关于提供其输入的神经回路的一些重要问题仍然没有答案。其中两个问题将在拟议的解剖学实验中得到解决。第一个问题涉及从视杆到侏儒神经节细胞的输入来源。目前还不确定侏儒神经节细胞是否通过突触从杆状突触接受从局部回路神经元到侏儒双极细胞的高度敏感的信息输入，如果是的话，这第一次出现在视网膜的什么地方。侏儒双极细胞和AII无长突细胞将使用完整的猕猴视网膜制剂进行标记，它们的接触将使用化学或电突触的第三种标记进行标记。工作假说是，这些突触正好出现在无视杆的中央中心凹外面。另一种假说是，中央侏儒神经节细胞仅通过相对不敏感的视杆-锥体缝隙连接接受视杆输入，而外围小视神经节细胞通过AII细胞接受更敏感的视杆输入。第二个问题涉及小神经节细胞对红色和绿色锥体刺激产生相反反应的神经回路。在中央视网膜，这种兴奋是选择性的，因为侏儒神经节细胞通过单个侏儒双极细胞接受来自单个红色或绿色锥体的输入。但目前还不确定如何在外围产生选择性兴奋，在那里，侏儒神经节细胞接受来自不止一个侏儒双极细胞的输入。目前尚不清楚选择性抑制是如何在视网膜的任何地方产生的，因为抑制性局部回路神经元，水平细胞和无长突细胞，在它们的连接中是非选择性的。解释侏儒神经节细胞反应选择性的工作假说是基于其他哺乳动物视网膜的生理实验结果，以及在最后一次授予期间开发的神经回路的线性模型。根据该模型，无长突细胞具有相对较窄的树突区域和遍及内丛状层的分支，使得侏儒神经节细胞的反应比红色和绿色锥体的分布预测的更具特异性。虽然单个无长突细胞使用抑制性神经递质甘氨酸，在它们的连接中是非选择性的，但它们的净作用是增强对一个锥体型刺激的小神经节细胞的兴奋。工作假说是，潜在的机制是抑制第二种类型的无长突细胞的紧张性、抑制性输入。这一假说将通过鉴定与侏儒双极细胞和侏儒神经节细胞突触前的甘氨酸能无长突细胞，并研究它们与回路中其他无长突细胞的相互作用来验证。由于人类和猕猴的视网膜如此相似，拟议中的实验结果将与人类视觉相关。 与公共健康相关：这项研究涉及产生侏儒神经节细胞光反应的神经回路。到目前为止，这些神经节细胞是人类和其他灵长类动物中最常见的神经节细胞类型，它们同时调节高敏锐度视觉和红绿颜色视觉。在视杆细胞和视锥细胞都活跃的情况下，有关视杆细胞传入侏儒神经节细胞的起源的实验将有助于理解弱光下的视觉。在美国，这对夜间驾驶尤其重要，而在昏暗的光线下视力问题是许多眼病的早期征兆。这些实验还将有助于解释视网膜电信号的潜在机制，视网膜电信号是一种广泛使用的诊断眼病和监测治疗效果的方法。

DESCRIPTION (provided by applicant): The goal of these experiments is to understand the processing of visual information in primate retinas. The focus in this grant period will be on midget ganglion cells, which mediate both high acuity vision and red-green color vision. Midget ganglion cells are the most common type in primate retinas, but despite many years of research, a number of important questions about the neural circuit providing their input remain unanswered. Two of these questions will be addressed in the proposed anatomical experiments. The first question deals with the source of the input from rods to midget ganglion cells. It is uncertain whether midget ganglion cells receive highly-sensitive input from rods via synapses from local circuit neurons, AII amacrine cells, onto midget bipolar cells and if so, where in the retina this first appears. Midget bipolar cells and AII amacrine cells will be labeled using whole mount preparations of macaque retina, and their contacts will be labeled using a third marker for either chemical or electrical synapses. The working hypothesis is that these synapses appear just outside the rod-free, central fovea. An alternative hypothesis is that central midget ganglion cells receive rod input only via relatively insensitive rod-cone gap junctions, but peripheral midget ganglion cells receive more sensitive rod input via AII cells. The second question deals with neural circuit that generates opposing responses of midget ganglion cells to stimulation of red and green cones. In the central retina, the excitation is selective because midget ganglion cells receive input from a single red or green cone via a single midget bipolar cell. But it is uncertain how selective excitation would be generated in the periphery, where midget ganglion cells receive input from more than one midget bipolar cell. It is unclear how selective inhibition arises anywhere in the retina because the inhibitory local circuit neurons, horizontal cells and amacrine cells, are unselective in their connections. The working hypothesis to account for the selectivity of midget ganglion cell responses is based on results from physiological experiments in other mammalian retinas and a linear model of the neural circuit developed during the last grant period. According to the model, amacrine cells with relatively narrow dendritic fields and branches throughout the inner plexiform layer make the responses of midget ganglion cells more specific than would be predicted by the distribution of the red and green cones. Although individual amacrine cells use the inhibitory neurotransmitter glycine and are unselective in their connections, their net effect is to enhance excitation of the midget ganglion cell in response to stimulation of one cone type. The working hypothesis is that the underlying mechanism is inhibition of a tonic, inhibitory input by a second type of amacrine cell. This hypothesis will be tested by identifying the glycinergic amacrine cells presynaptic to midget bipolar cells and midget ganglion cells and studying their interactions with other amacrine cells in the circuit. Because the retinas of humans and macaques are so similar, the results of the proposed experiments would be relevant to human vision. PUBLIC HEALTH RELEVANCE: This research deals with the neural circuit that generates the light responses of midget ganglion cells. These are, by far, the most common type of ganglion cells in humans and other primates, and they mediate both high acuity vision and red-green color vision. The experiments on the origin of rod inputs to midget ganglion cells would help to understand vision in dim light, when both rods and cones are active. In the United States, this is particularly important for driving at night, and problems with vision in dim light are an early sign for many eye diseases. These experiments would also help to explain the mechanism underlying the electroretinogram, a widely-used method to diagnose eye diseases and monitor the effects of treatments.