Retinal circuits for precise signaling

描述（由申请人提供）：在本申请中，视网膜回路功能方面的专家提出研究哺乳动物视网膜中用于夜视的视杆通路内的信号处理和适应机制。视杆和视锥双极细胞对于夜间和白天视觉是必不可少的，因为它们将来自外部视网膜中的光感受器的信号传输到内部视网膜进行处理。了解视杆细胞通路如何编码信息是一个基本问题，适用于所有的感觉通路，包括锥双极通路和皮层回路。视杆双极细胞与A17无长突细胞形成突触带接触，A17无长突细胞与视杆双极细胞形成相互抑制反馈接触。在过去的十年中，许多实验室研究了这种突触连接，产生了大量与其功能相关的生物物理细节。然而，神经生理学的细节显得如此复杂，以至于其功能作用难以把握。最近的研究发现，在杆双极带状突触的几种机制，使其适应背景水平和对比度。然而，来自A17无长突细胞的反馈抑制被认为对这种适应没有贡献。A17中的其他几个信号处理机制已经被确定为调节其反馈。这些机制是基本的和重要的，因为它们与大脑中许多其他神经元中发现的机制相似。我们推测，在夜间，A17无长突细胞的分裂感受野环绕调节视杆双极细胞的突触释放，以改善其信号质量，并且A17根据背景水平调节环绕的later程度。我们拟研究无长突反馈对视杆和视锥双极细胞进行突触加工的影响。使用现实的计算模型的视网膜电路，我们将描绘可能的作用，反馈和前馈机制参与杆双极- A17相互突触。在目标1中，我们将建立一个详细的模型，突触前和突触后的生物物理机制，不包括形态学的细节。我们将研究如何通过杆双极带调节囊泡释放的已知机制可以限制或增强其信号的信息内容。目的2将测试的假设，负反馈杆双极细胞产生分裂的空间环绕，增强对比度响应曙光信号。在这一目标中，我们将采用目标1的反馈模型，并添加A17无长突的精细放射树突的细节，包括其电压门控钠和钾通道。总的来说，拟议的研究将提高我们对视网膜视觉通路在不同背景水平下进行的信号处理的理解。由于视杆细胞和视锥细胞通路对视力至关重要，这项研究将提高我们对一系列眼部疾病的理解。由于这些通路是视觉假体和遗传方法刺激恢复一系列眼病所致视力丧失的关键目标，因此在此获得的知识将有助于推动此类设备和治疗的发展。

DESCRIPTION (provided by applicant): In this application, an expert in the function of retinal circuitry proposes to investigate mechanisms of signal processing and adaptation within the rod pathway for night vision in the mammalian retina. Rod and cone bipolar cells are essential for night and day vision because they transmit and signals from photoreceptors in the outer retina for processing to the inner retina. Understanding how the rod pathway encodes information is a fundamental problem that applies to all sensory pathways, including cone bipolar pathways and cortical circuits. The rod bipolar makes a synaptic ribbon contact onto the A17 amacrine cell, which then makes a reciprocal inhibitory feedback contact onto the rod bipolar cell. Over the past decade, this synaptic connection has been studied by many laboratories, producing a wealth of biophysical details relevant to its function. However, the neurophysiological detail appears so complex that its functional role is difficult to grasp. Recent studies have discovered several mechanisms in the rod bipolar ribbon synapse that cause it to adapt to the background level and to contrast. However the feedback inhibition from the A17 amacrine cell is not thought to contribute to this adaptation. Several other signal processing mechanisms in the A17 have been identified that regulate its feedback. These mechanisms are fundamental and significant because they are similar to those found in many other neurons in the brain. We hypothesize that at night, a divisive receptive field surround from the A17 amacrine cell regulates synaptic release by the rod bipolar cell to improve its signal quality, and that the A17 regulates the laterl extent of the surround according to the background level. We propose to study the effect of amacrine feedback on the synaptic processing performed by the rod and cone bipolar cells. Using realistic computational models of retinal circuitry, we will delineate the possible roles of feedback and feedforward mechanisms involved at the rod bipolar - A17 reciprocal synapse. In Aim 1, we will develop a detailed model of the presynaptic and postsynaptic biophysical mechanisms excluding the details of morphology. We will examine how the known mechanisms for modulating vesicle release by the rod bipolar ribbon can limit or enhance the information content of its signal. Aim 2 will test the hypothesis that negative feedback to the rod bipolar cel generates a divisive spatial surround that enhances the contrast response to twilight signals. In this aim, we will take the model of feedback from Aim 1 and add details of the fine radiating dendrites of the A17 amacrine, including its voltage-gated sodium and potassium channels. Overall, the proposed research will improve our understanding of the signal processing at different background levels performed by visual pathways of the retina. As the rod and cone pathways are critical for vision, the research will improve our understanding of a range of eye diseases. Because these pathways are critical targets for stimulation by visual prostheses and genetic approaches to restoring vision loss from a range of eye diseases, the knowledge gained here will help to advance the development of such devices and treatments.