Functional analysis of retinal inhibitory processes

视网膜抑制过程的功能分析

• 批准号: 7736295
• 负责人: Jozsef Vigh
• 金额: $ 32.26万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7736295
• 关键词: Affect; Amacrine Cells; Architecture; Area; Axon; Binding Sites; Bypass; Calcium; Calcium Channel; Cells; Characteristics; Code; Color; Complex; Data; Dendrites; Detection; Devices; Electric Capacitance; Environment; Equilibrium; Feedback; Glutamates; Glycine; Goals; Goldfish; Human; Image; In Situ; Ion Channel; Kinetics; Lateral; Light; Light Adaptations; Measurement; Measures; Mediating; Membrane; Membrane Potentials; Motion; N-Methyl-D-Aspartate Receptors; Output; Photoreceptors; Physiological; Preparation; Presynaptic Terminals; Process; Prosthesis; Receptor Activation; Regulation; Research; Resolution; Retina; Retinal; Role; Shapes; Signal Transduction; Slice; Synapses; Synaptic Potentials; Testing; Time; Translating; Vision; Visual; Visually Impaired Persons; Work; cell preparation; computerized data processing; design; gamma-Aminobutyric Acid; ganglion cell; information processing; interest; neural circuit; neuronal cell body; patch clamp; public health relevance; receptive field; receptor function; relating to nervous system; research study; response; visual information; voltage; voltage gated channel

DESCRIPTION (provided by applicant): Retinal inhibitory inputs shape the kinetics of graded, sustained photoreceptor signals as they pass through the retina. At the network level, retinal inhibition mediates the antagonistic center-surround organization of the bipolar cell's receptive field, and in turn, that of the ganglion cell. This retinal circuit underlies contrast detection, a fundamental feature of signal processing by the retina. The goal of the proposed research is to study the distribution, functional characteristics and regulation of inhibitory inputs targeting an identified retinal bipolar cell. I will take advantage of a unique preparation made from the goldfish retina, in which patch-clamp recordings of light evoked membrane currents can be made either from the soma or the axon terminal of an ON-type, Mb bipolar cell in a slice preparation. Stable recordings from these compartments is possible even after axon severing, thus outer or inner retinal inhibitory inputs can be separately studied. Using this preparation I will revisit fundamental questions of visual information processing in the vertebrate retina. My preliminary data show that light evokes different responses at the bipolar cell soma compared to the axon terminal, due to differences in their respective synaptic inputs and voltage-gated channels. The first specific aim will characterize the light-evoked responses of the axon terminal in intact Mb bipolar cells and will study with high time-resolution capacitance measurements how these physiological responses trigger glutamate release. The second specific aim will focus on separating outer and inner retinal inhibition targeting Mb bipolar cells. I will determine how each influence the glutamate output, and separate their contributions to the antagonistic surround response. I recorded light-evoked inhibitory synaptic currents from bipolar axon terminals with severed axons, which represents pure lateral inhibition. I will characterize electrophysiologically and pharmacologically these synaptic inputs at various light adaptation levels, and determine their underlying synaptic circuitry. I have preliminary evidence that NMDA receptors provide enough calcium to trigger GABA release from amacrine cells directly and locally, bypassing voltage-gated calcium channels. The last specific aim will test the hypothesis that NMDA receptor regulation in amacrine cells influences synaptically triggered GABA release and in turn, bipolar cell output. Overall, these experiments will use a combination of capacitance, membrane potential/ current measurements and pharmacological manipulations to determine how the excitatory visual information reaching the ganglion cells is regulated by progressive levels of inhibition as the signal passes through the retinal network. PUBLIC HEALTH RELEVANCE: Images of the environment are translated into neural codes by all vertebrate retinas, including that of humans, in a very similar manner: the retina codes for contours, colors and motion. The proposed research investigates the natural mechanisms underlying contour detection. The results can be used to guide the design of prosthetic vision devices to restore some sight to blind people.

描述（由申请人提供）：视网膜抑制输入在通过视网膜时形成分级、持续的光感受器信号的动力学。在网络水平上，视网膜抑制介导双相细胞接受野的拮抗中心-环绕组织，进而介导神经节细胞的接受野。这种视网膜回路是对比度检测的基础，是视网膜信号处理的基本特征。本研究的目的是研究针对已识别的视网膜双极细胞的抑制输入的分布、功能特征和调控。我将利用由金鱼视网膜制成的一种独特的制备方法，在这种制备方法中，光诱发膜电流的膜片钳记录可以从on型双极细胞的体细胞或轴突末端进行，在切片制备中。即使在轴突切断后，这些隔室的稳定记录也是可能的，因此可以分别研究外部或内部视网膜抑制输入。利用这些准备，我将重新审视脊椎动物视网膜中视觉信息处理的基本问题。我的初步数据表明，由于各自的突触输入和电压门控通道的差异，光在双极细胞体和轴突末端唤起不同的反应。第一个具体目标将表征完整Mb双极细胞轴突末端的光诱发反应，并将通过高时间分辨率电容测量研究这些生理反应如何触发谷氨酸释放。第二个具体目标将集中在分离外部和内部视网膜抑制针对Mb双极性细胞。我将确定每一种影响谷氨酸输出的方式，并将它们对拮抗周围反应的贡献分开。我记录了来自双极轴突终端的光诱发抑制性突触电流，这代表了纯粹的侧抑制。我将在电生理学和药理学上描述这些突触输入在不同的光适应水平，并确定其潜在的突触电路。我有初步的证据表明，NMDA受体提供足够的钙，直接和局部地触发无毛细胞释放GABA，绕过电压门控钙通道。最后一个具体目标将测试假设，即NMDA受体调节无毛细胞影响突触触发的GABA释放，进而影响双极细胞输出。总的来说，这些实验将使用电容、膜电位/电流测量和药理学操作的组合来确定到达神经节细胞的兴奋性视觉信息是如何在信号通过视网膜网络时受到渐进抑制水平的调节的。公共卫生相关性：所有脊椎动物（包括人类）的视网膜都以非常相似的方式将环境图像转换为神经编码：视网膜编码轮廓、颜色和运动。本研究探讨了轮廓检测的自然机制。研究结果可用于指导义肢视觉装置的设计，以恢复盲人的部分视力。