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

 描述(由申请人提供)：人类视觉系统具有非凡的能力来检测对比度的差异(即，跨空间或时间的亮度差异)，最小可达 1：500。这种能力是日常视觉任务，如阅读、驾驶和人脸识别的基础。事实上，对比敏感度的缺陷被用作 评估视网膜疾病。尽管它很重要，但编码和限制对比敏感度的潜在细胞和网络机制仍然难以捉摸。过去的工作认为光感受器频率响应是限制时间对比敏感度(TCS)的一种机制；然而，这一点还没有得到经验证明。这项建议的目的是确定在中间视觉条件下，当杆光感受器整合多个光异构化的反应时，杆光响应动力学如何对视觉TCS做出贡献。基本的假设是，棒的失活动力学通过限制棒对光衰减的反应速度来限制TCS。为了验证这一假设，开发了一种新的可操作的行为测试，它在小鼠身上建立了一个符合人类视觉心理物理学基本特性的人类时间视觉模型。在可操作的测试中，小鼠被训练来检测并对闪烁的视觉刺激做出反应，这一动作需要皮质INPT和决策。操作行为分析收集的初步数据表明，具有快速杆灭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。结合标准电生理学工具和转基因模型，行为测试可以剖析视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，以及适应机制对中间视觉光照水平对不同频率刺激的敏感性的影响。目的2检测视杆光反应动力学对视觉(行为)对比敏感度的贡献。目的3在视紫红质P23H小鼠视网膜色素变性模型中测试视网膜和视觉时间对比敏感度，以验证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P23H视紫红质突变的患者和小鼠模型比对照受试者表现出更快的视杆恢复反应。这一目的的结果可以很好地为早期和实用的视觉功能测试提供原则证明，该测试可以诊断某些形式的常染色体显性遗传性视网膜色素变性。这个项目将具有重要意义，因为它将有助于了解视杆动力学对正常和病变视网膜的视觉TCS的贡献，以及2)深入了解视杆和视锥信号之间的动态视网膜相互作用，这些相互作用决定了中间视觉的时间、空间和光谱敏感性。这项拟议的研究是创新的，因为它使用了我们研究小组开发的一种新的操作行为分析方法来检查老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.