Computation at retinal synapses

描述（由申请人提供）：我们的长期目标是了解视网膜回路如何执行健康视力的计算。这项提议的直接目标是了解视网膜回路如何根据视觉场景的对比度调整其特性。对比度适应对于眼睛注视和不同环境之间的视觉处理很重要：它在低对比度下增加灵敏度以改善信噪比，并且它 在高对比度下降低灵敏度，以防止响应饱和。目前，我们对哺乳动物视网膜对比度适应的细胞和突触基础知之甚少。该建议包括两个具体的目标，将产生新的见解突触机制的对比度适应整合突触和电路水平的分析视网膜信号。在一种方法中，对光感受器的对比刺激的反应将记录在通过荧光蛋白的遗传表达鉴定的特定类型的视网膜中间神经元中，并通过双光子激光扫描显微镜观察。在第二种方法中，我们将使用中间神经元亚型的光遗传学控制来检查特定突触处的传输。使用这些互补的方法，具体目标1将通过探测杆视觉的专门途径来确定昏暗光线下的对比度适应机制。具体目标2将通过探测锥体视觉的平行路径来确定在更明亮的光水平下的对比度适应机制。与公共卫生的相关性：了解视网膜突触和电路如何实现对比度适应，可以产生有关视觉神经基础的基本信息，并为视网膜修复术的设计和人类视网膜疾病动物模型的研究提供信息。视觉研究的一个目标是开发基于基因的疗法来治疗由感光细胞变性引起的失明（例如，视网膜色素变性）。这种有前景的疗法是使用病毒介导的通道视紫红质-2（ChR 2）（一种光门控阳离子通道）的表达在视网膜中间神经元中产生光敏性。我们将在中间神经元中表达ChR 2，以研究视网膜回路中的突触相互作用;通过设计，我们将比较光感受器和ChR 2介导的回路输出。因此，我们将产生关于视觉信号范围的关键信息，这些信号可以由视网膜编码，其中ChR 2是唯一的光传感器。 我们提出了国家眼科和视力研究计划中视网膜疾病项目的三个目标：1）确定治疗视网膜色素变性的潜在治疗策略，2） 增加对感光后适应的理解（即，神经回路中的增益控制），以及3）增加对神经网络中的细胞间相互作用如何生成可解释为视觉图像的信号的理解。

DESCRIPTION (provided by applicant): Our long-term goal is to understand how retinal circuits perform the computations underlying healthy vision. The immediate goal of this proposal is to understand how retinal circuits adjust their properties to the contrast of a visual scene. Contrast adaptation is important for visual processing across eye fixations and between different environments: it increases sensitivity at low contrast to improve the signal-to-noise ratio, and it decreases sensitivity at high contrast to prevent response saturation. Presently, we know relatively little about the cellular and synaptic basis for contrast adaptation in the mammalian retina. This proposal comprises two specific aims that will generate novel insights into the synaptic mechanisms underlying contrast adaptation by integrating synapse- and circuit-level analyses of retinal signaling. In one approach, responses to contrast stimulation of photoreceptors will be recorded in specific types of retinal interneurons identified by genetic expression of fluorescent proteins and visualized by two-photon laser-scanning microscopy. In a second approach, we will use optogenetic control of subtypes of interneurons to examine transmission at specific synapses. Using these complementary approaches, Specific Aim 1 will determine the mechanisms for contrast adaptation in dim light by probing a specialized pathway for rod vision. Specific Aim 2 will determine the mechanisms for contrast adaptation at brighter light levels by probing parallel pathways for cone vision. Relevance to Public Health: Understanding how contrast adaptation is implemented by retinal synapses and circuits generates fundamental information about the neural basis of vision and informs the design of retinal prosthetics and the study of animal models of human retinal diseases. A goal of vision research is the development of gene-based therapies for treating blindness caused by photoreceptor degeneration (e.g., retinitis pigmentosa). A promising therapy of this sort is the generation of light sensitivity in retinal interneurons using virally-mediated expression of channelrhodopsin-2 (ChR2), a light-gated cation channel. We will express ChR2 in interneurons to study synaptic interactions in retinal circuits; by design, we will compare photoreceptor- and ChR2-mediated circuit outputs. Thus, we will generate critical information about the range of visual signals that could be encoded by a retina in which ChR2 is the only light sensor. We address three goals of the Retinal Diseases Program in the National Plan for Eye and Vision Research: 1) determining potential therapeutic strategies for treatment of retinitis pigmentosa, 2) increasing understanding of post-photoreceptor adaptation (i.e., gain control in neural circuits), and 3) increasing understanding of how inter-cellular interactions in neural networks generate signals that are interpretable as visual images.