Genes and visual pigments of red-green color vision

描述（由申请人提供）：一项巨大的投资正在用于开发恢复或提供盲人视网膜光敏性的治疗方法。包括干细胞、基因治疗和视网膜假体在内的几个领域的技术进步显示出巨大的希望；然而，对日光视觉基本电路的理解落后于恢复光敏性的技术。令人兴奋的技术进步重新激发了理解视觉通路回路的需求，以便确定最佳的恢复光敏性的治疗策略和最有效的实施方法。对处理视觉信息的电路细节的全面了解将为开发治疗致盲性视力障碍的复杂策略带来丰富的机会。这个应用程序专注于灵长类视觉系统中一个独特的子系统，在那里有特殊的机会来发现负责特定感知的神经回路的工作。人们普遍认为，s-锥输入到s-锥双极细胞，然后再输入到小的双层神经节细胞——即所谓的“S-ON/koniocellular通路”——是蓝黄色觉的重要电路；然而，生理上测量的小双层神经节细胞的光谱响应特性与感知上测量的蓝黄对手通道的光谱响应特性不匹配，这一事实是一个未解决的问题，因为小双层神经节是蓝色感知的生物基质。关于视网膜S-OFF神经节细胞的信息较少。对于唯一在灵长类动物中被解剖和生理学表征的S-OFF神经节细胞，使用ON通路阻断剂2-氨基-4 -磷酸丁酸（AP-4）完全阻断S-OFF光反应，表明S-OFF和S-cone信号都通过ON S-cone双极细胞传递到视网膜内部，并且视网膜内部电路中ON信号的信号反转对于产生S-OFF反应至关重要。因此，就像棒状双极细胞为开和关神经节细胞反应提供底物一样，ON S锥双极细胞似乎为具有开和关成分的完整S锥系统提供了第一级。人类已经发现基因突变完全中断了s -锥和s -锥双极细胞之间的直接信号传递。这些患者为研究S-ON/S-OFF/孔细胞通路在感知中的作用提供了前所未有的机会。具体目标1：利用视网膜电图、功能磁共振成像和视觉心理物理学，通过对具有阻断S-ON/S-OFF/koniocellular通路的突变的人类患者的研究，研究其在感知中的作用。具体目标2：利用电生理学、生理学和功能性磁共振成像技术分离和研究动物模型中颜色通路的特定成分，以探索高水平的视觉处理如何从光敏光感受器中提取可用信息。

DESCRIPTION (provided by applicant): A huge investment is being made to develop treatments to restore or provide light sensitivity to the retinas of the blind. Technological advancements in several areas including stem cells, gene therapy, and retinal prostheses show great promise; however, understanding of the basic circuitry for daylight vision lags behind technology to restore light sensitivity. Exciting technological advances reinvigorate the need to understand the circuitry of visual pathways in order to identify the best light-sensitivity-restoring therapeutic strategies and the most effective implementations of them. A complete understanding of the details of the circuitry for processing visual information will bring a wealth of opportunities for developing sophisticated strategies for treating blinding vision disorders. This application focuses on a unique sub system within the primate visual system where there are exceptional opportunities to discover the workings of neural circuitry responsible for specific percepts. It is widely accepted that S-cone input to S-cone bipolar cells and in turn to small bistratified ganglion cells--the so called "S-ON/koniocellular pathway"-- is the important circuit for blue-yellow color vision; however, the fact that the spectral response properties of small bistratified ganglion cells measured physiologically do not match those of the blue-yellow opponent channel measured perceptually is an unresolved problem for the idea that the small bistratified ganglion is the biological substrate blue perception. There is less information about retinal S-OFF ganglion cells. For the only S-OFF ganglion cells that have been characterized anatomically and physiologically in primate, bath application of the ON-pathway blocker 2-amino- 4-phosphonobutyric acid (AP-4) completely blocks the S-OFF light response, suggesting that both ON and OFF S-cone signals are transmitted to the inner retina via the ON S-cone bipolar cell and that a sign inversion of the ON signal in the inner retinal circuitry is critical for generating the S-OFF response. Thus, in much the same way that rod bipolar cells provide the substrate for both ON and OFF ganglion cell responses, the ON S- cone bipolar cells appear to provide the first stage for a complete S-cone system with both ON and OFF components. Gene mutations in humans have been discovered that completely interrupt the direct transmission of signals between S-cones and the S-cone bipolar cells. These patients offer an unprecedented opportunity to study the role of the S-ON/S-OFF/koniocellular pathways in perception. Specific Aim 1: To study the role of the S-ON/S-OFF/koniocellular pathways in perception through the study of human patients with mutations that block them, using the electroretinogram, functional magnetic resonance imaging and visual psychophysics. Specific Aim 2: To isolate and study specific components of chromatic pathways in animal models using electrophysiology, physiology, and functional magnetic resonance imaging to explore how higher levels of visual processing extract usable information from the light sensitive photoreceptors. PUBLIC HEALTH RELEVANCE: Technological advancements in stem cells, gene therapy, and retinal prostheses show great promise for restoring or providing new light sensitivity to retinas of the blind; however, understanding of the basic circuitry for daylight vision lags behind the technology to provide light sensitivity. Exciting technological advances reinvigorate the need to understand the circuitry of visual pathways in order to identify the best therapeutic strategies and the most effective implementations of them. A complete understanding of the details of the circuitry for processing visual information will bring a wealth of opportunities for developing sophisticated strategies for treating blinding vision disorders. The major objective of this grant is to provide a new understanding of the circuitry responsible for a specific visual capacity--blue-yellow color vision.