Functional analysis of retinal inhibitory processes

视网膜抑制过程的功能分析

• 批准号: 8531940
• 负责人: Jozsef Vigh
• 金额: $ 29.13万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531940
• 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; Health; 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; 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）：当光感受器信号通过视网膜时，视网膜抑制输入形成分级的、持续的光感受器信号的动力学。在网络水平上，视网膜抑制介导双极细胞感受野的对抗性中心-周围组织，进而介导神经节细胞感受野的对抗性中心-周围组织。该视网膜电路是对比度检测的基础，这是视网膜信号处理的基本特征。拟议研究的目标是研究针对已识别的视网膜双极细胞的抑制输入的分布、功能特征和调节。我将利用由金鱼视网膜制成的独特制剂，其中可以从切片制剂中的 ON 型 Mb 双极细胞的体细胞或轴突末端进行光诱发膜电流的膜片钳记录。即使在轴突切断后，这些区室的稳定记录也是可能的，因此可以单独研究外部或内部视网膜抑制输入。利用这个准备工作，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，与轴突末端相比，光在双极细胞胞体处引起不同的反应，这是由于它们各自的突触输入和电压门控通道的差异。第一个具体目标将表征完整 Mb 双极细胞中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于分离针对 Mb 双极细胞的外部和内部视网膜抑制。我将确定每个因素如何影响谷氨酸输出，并将它们对对抗性环绕响应的贡献分开。我记录了来自带有切断轴突的双极轴突末端的光诱发抑制性突触电流，这代表纯粹的侧向抑制。我将从电生理学和药理学角度描述这些突触输入在不同光适应水平下的特征，并确定它们的潜在突触电路。我有初步证据表明 NMDA 受体提供足够的钙来触发无长突细胞直接局部释放 GABA，绕过电压门控钙通道。最后一个具体目标将检验以下假设：无长突细胞中的 NMDA 受体调节会影响突触触发的 GABA 释放，进而影响双极细胞输出。总体而言，这些实验将结合电容、膜电位/电流测量和药理学操作来确定当信号通过视网膜网络时，到达神经节细胞的兴奋性视觉信息如何受到渐进抑制水平的调节。公共健康相关性：环境图像被所有脊椎动物的视网膜（包括人类的视网膜）以非常相似的方式转化为神经代码：视网膜编码轮廓、颜色和运动。拟议的研究调查了轮廓检测背后的自然机制。研究结果可用于指导假肢视觉装置的设计，以帮助盲人恢复部分视力。

项目成果

Light-evoked S-nitrosylation in the retina.

• DOI: 10.1002/cne.23780
• 发表时间: 2015-10-01
• 期刊: The Journal of comparative neurology
• 作者: Tooker RE;Vigh J
• 通讯作者: Vigh J

Dopaminergic amacrine cells express opioid receptors in the mouse retina.

• DOI: 10.1017/s0952523812000156
• 发表时间: 2012-05
• 期刊: VISUAL NEUROSCIENCE
• 影响因子: 1.9
• 作者: Gallagher, Shannon K.;Anglen, Julia N.;Mower, Justin M.;Vigh, Jozsef
• 通讯作者: Vigh, Jozsef

Quantifying the effect of light activated outer and inner retinal inhibitory pathways on glutamate release from mixed bipolar cells.

量化光激活的外部和内部视网膜抑制途径对混合双极细胞谷氨酸释放的影响。

• DOI: 10.1002/syn.22028
• 发表时间: 2018
• 期刊: Synapse (New York, N.Y.)
• 作者: Lipin,MikhailY;Vigh,Jozsef
• 通讯作者: Vigh,Jozsef

Glycine transporter 1 modulates GABA release from amacrine cells by controlling occupancy of coagonist binding site of NMDA receptors.

甘氨酸转运蛋白 1 通过控制 NMDA 受体共激动剂结合位点的占用来调节无长突细胞释放 GABA。

• DOI: 10.1152/jn.00193.2013
• 发表时间: 2013
• 期刊: Journal of neurophysiology
• 影响因子: 2.5
• 作者: Rozsa,Eva;Vigh,Jozsef
• 通讯作者: Vigh,Jozsef

Nitric oxide mediates activity-dependent plasticity of retinal bipolar cell output via S-nitrosylation.

一氧化氮通过 S-亚硝基化介导视网膜双极细胞输出的活动依赖性可塑性。

• DOI: 10.1523/jneurosci.2792-13.2013
• 发表时间: 2013
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Tooker,RyanE;Lipin,MikhailY;Leuranguer,Valerie;Rozsa,Eva;Bramley,JayneR;Harding,JacquelineL;Reynolds,MelissaM;Vigh,Jozsef
• 通讯作者: Vigh,Jozsef