Contribution of rod photoresponse inactivation kinetics to visual temporal contrast sensitivity in mesopic light

 描述（由申请人提供）：人类视觉系统具有显著的检测对比度差异的能力（即，空间或时间上的亮度差异）小到 一分五百。这种能力是日常视觉任务（如阅读、驾驶和面部识别）的基础。事实上，对比敏感度的缺陷被用作 视网膜疾病的评估。尽管其重要性，编码和限制对比敏感性的潜在细胞和网络机制仍然难以捉摸。过去的工作已经分配的感光器频率响应作为一种机制，限制时间对比敏感度（TCS），但是，这还没有被证明经验。这个建议的目标是确定如何杆光响应动力学有助于视觉TCS在中间视觉条件下，当杆光感受器集成的响应多个光异构化。潜在的假设是，杆失活动力学限制TCS的杆光减量的反应速度。为了验证这一假设，开发了一种新的操作性行为测定法，该测定法在小鼠中建立了与人类视觉心理物理学的基本性质相匹配的人类时间视觉模型。在操作性试验中，小鼠被训练来检测和响应闪烁的视觉刺激，这是一个需要皮层输入和决策的动作。初步的数据收集与操作行为分析表明，快速杆失活动力学的转基因小鼠比对照小鼠具有更高的时间对比敏感度。结合标准的电生理学工具和转基因模型，行为测定允许解剖杆动力学对视觉的贡献。目的1测试视杆细胞对动态刺激的反应，以及适应机制对不同频率刺激的敏感性的影响。目的2测试视杆细胞光反应动力学对视觉（行为）对比敏感度的贡献。目的3在视网膜色素变性的视紫红质P23 H小鼠模型中测试视网膜和视觉时间对比敏感度，以测试携带该突变的突变小鼠将表现出比对照小鼠更高的TCS的假设。我们预测这一点是因为携带P23 H视紫红质突变的患者和小鼠模型表现出比对照受试者更快的视杆细胞恢复反应。这一目标的结果很好地提供了一个早期和实用的视觉功能测试，i诊断某些形式的常染色体显性视网膜色素变性的原则证明。这个项目将是重要的，因为它将有助于理解1）在正常和患病视网膜中视杆动力学对视觉TCS的贡献，以及2）提供对视杆和视锥信号之间的动态视网膜相互作用的见解，这些信号决定了中间视觉的时间，空间和光谱敏感性。这项研究是创新的，因为它使用我们研究小组开发的一种新型操作性行为测定法来检查小鼠和人类共同的视觉特性。

 DESCRIPTION (provided by applicant): The human visual system has a remarkable capacity to detect differences in contrast (i.e., differences in luminance across space or time) as small as 1:500. This ability underlies the performance of everyday visual tasks such as reading, driving, and face recognition. Indeed, deficits in contrast sensitivity are used as diagnostic signs for the assessment of retinal disease. Despite its importance, the underlying cellular and network mechanisms that encode and limit contrast sensitivity remain elusive. Past work has assigned the photoreceptor frequency response as one mechanism that limits temporal contrast sensitivity (TCS); however, this has not been demonstrated empirically. The goal of this proposal is to determine how rod photoresponse kinetics contributes to visual TCS in mesopic conditions, when rod photoreceptors integrate the response of multiple photoisomerizations. The underlying hypothesis is that rod inactivation kinetics constrains TCS by limiting the speed of the responses of rods to light decrements. To test the hypothesis, a novel operant behavioral assay was developed which establishes in mouse a model of human temporal vision that matches fundamental properties of human visual psychophysics. In the operant assay, mice are trained to detect and respond to a flickering visual stimulus, an action that requires cortical inpt and decision-making. The preliminary data collected with the operant behavior assay suggest that transgenic mice with fast rod inactivation kinetics have higher temporal contrast sensitivity than control mice. Combined with standard electrophysiological tools and transgenic models, the behavioral assay allows dissection of the contributions of rod kinetics to vision. Aim 1 test how rods respond to dynamic stimuli and what impact adaptation mechanisms have on the sensitivity to different frequencies of stimulation in mesopic light levels. Aim 2 tests the contribution of rod photoresponses kinetics to visual (behavioral) contrast sensitivity. Aim 3 test retinal and visual temporal contrast sensitivity in a rhodopsin P23H mouse model of retinitis pigmentosa to test the hypothesis that mutant mice harboring this mutation will exhibit higher TCS than control mice. We predict this because patients and mouse models harboring the P23H rhodopsin mutation exhibit faster rod recovery responses than control subjects. Results of this aim may well provide proof-of-principle for an early and practical visual function test that i diagnostic of certain forms of autosomal dominant retinitis pigmentosa. This project will be significant because it will help understand 1) the contributions of rod kinetics to visual TCS in normal and diseased retinas, and 2) provide insights into the dynamic retinal interactions between rod and cone signals that determine the temporal, spatial, and spectral sensitivities of mesopic vision. The proposed research is innovative, because it examines visual properties common to mouse and humans using a novel operant behavioral assay developed by our research group.