Neural circuits and synapses for early visual processing

用于早期视觉处理的神经回路和突触

• 批准号: 8002002
• 负责人: Jonathan B Demb
• 金额: $ 13.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8002002
• 关键词: AMPA Receptors; Alpha Cell; Amacrine Cells; Biological; Blindness; Caliber; Cell Death; Cells; Data; Dependence; Development; Eye diseases; Frequencies; Glaucoma; Glutamates; Goals; Inner Plexiform Layer; Interneurons; Ischemia; Kinetics; Lead; Leber' s disease; Ligands; Light; Location; Measures; Mediating; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neural Pathways; Neurons; Night Blindness; Output; Pathway interactions; Photoreceptors; Physiological; Process; Property; Prosthesis; Retina; Retinal; Retinal Cone; Retinal Diseases; Role; Signal Transduction; Stratification; Synapses; Testing; Tissues; Trees; Vertebrate Photoreceptors; Vision; Visual; base; cell type; desensitization; excitotoxicity; ganglion cell; information processing; neural circuit; presynaptic; public health relevance; receptor; response; retinal rods; visual information; visual process; visual processing; voltage

DESCRIPTION (provided by applicant): My long-term goal is to understand the biological basis of visual processing at the level of neural circuits and synapses. I am pursuing this goal in the mammalian retina, a tissue comprised of ~70 cell types: ~3-4 photoreceptors (depending on species), ~50 interneurons (horizontal, bipolar and amacrine cells) and ~20 output neurons (ganglion cells). Over the past period, we focused on two types of ganglion cell (ON and OFF Alpha cell) and elucidated fundamental components of their synaptic inputs and mechanisms for contrast adaptation. These accomplishments allow us to now expand our studies to a dozen types of ganglion cell that we recognize based on a combination of functional properties (light-evoked synaptic conductance) and structural properties (dendritic tree diameter and stratification level in the inner plexiform layer). Aim 1 will reveal fundamental circuit mechanisms for night vision, by determining how rod signals are transmitted, via an identified neural pathway, to each ganglion cell type. Rods synapse with rod bipolar cells, which in turn excite the AII amacrine cell; the AII cell signals directly certain ganglion cell types and indirectly others by synapsing with the presynaptic cone bipolar terminal. Preliminary data suggest that a small group of OFF ganglion cell types receives direct AII cell synapses; another group receives indirect synapses, whereas a third group lacks connection to the circuit and loses function in dim light. To encode visual signals in daylight, each ganglion cell type receives glutamatergic synapses from one or more types of cone bipolar cell, but we need to test which ganglion cell types encode glutamate release with an NMDA receptor (Aim 2). Compared to the other major type, AMPA receptors, NMDA receptors have a conductance that is voltage-dependent, lacks desensitization and has relatively slow kinetics. We want to understand the role of NMDA receptors in visual processing, and as a first step we will identify which ganglion cell types express them. For each type, we will test for functional expression by applying NMDA directly; we will test further whether these receptors contribute to high contrast responses under normal physiological conditions. Finally, we will test quantitatively the role of NMDA receptors in visual processing (Aim 3). We will model ligand-gated receptor contributions to contrast responses and test whether NMDA receptors are used preferentially for encoding low versus high contrast. We will test further whether the slow kinetics of the NMDA receptor-mediated response encodes preferentially low temporal frequencies. Proposed studies will yield basic understanding of how retinal circuits and synapses process information and provide background for understanding retinal diseases that either compromise the rod pathway or involve NMDA receptor-mediated excitotoxicity. PUBLIC HEALTH RELEVANCE: Proposed studies will provide background for understanding the impact of eye diseases that impair night vision (i.e., retinitis pigmentosa, congenital stationary night blindness) and eye diseases that involve cell death caused by excitotoxicity (i.e., glaucoma, ischemia). Studies will lead to a better understanding of how the retina processes visual information, which could facilitate the development of prosthetic devices for stimulating preserved retinal cells in certain forms of blindness.

描述(申请人提供)：我的长期目标是在神经回路和突触水平上了解视觉处理的生物学基础。我正在哺乳动物的视网膜上追求这个目标，这个组织由大约70种细胞类型组成：~3-4个光感受器(视物种而定)，~50个中间神经元(水平、双极和无长突细胞)和~20个输出神经元(神经节细胞)。在过去的一段时间里，我们重点研究了两种类型的神经节细胞(On和Off Alpha细胞)，并阐明了它们突触输入的基本成分和对比度适应的机制。这些成就使我们现在可以将我们的研究扩展到十几种类型的神经节细胞，这些细胞是根据功能属性(光诱发的突触电导)和结构属性(树突树直径和内丛状层的层叠水平)识别的。目标1将通过确定视杆信号如何通过已识别的神经通路传递到每种神经节细胞类型来揭示夜视的基本电路机制。视杆细胞与视杆双极细胞突触，继而刺激AII无长突细胞；AII细胞通过与突触前锥体双极终末突触，直接向某些类型的神经节细胞发出信号，并间接向其他类型的神经节细胞发出信号。初步数据表明，一小部分节外细胞类型接受直接的AII细胞突触；另一组接受间接突触，而第三组缺乏与电路的连接，在昏暗的光线下失去功能。为了在白天编码视觉信号，每种神经节细胞类型都从一种或多种类型的锥体双极细胞接收谷氨酸能突触，但我们需要测试哪些神经节细胞类型与NMDA受体一起编码谷氨酸释放(目标2)。与另一种主要类型的AMPA受体相比，NMDA受体的电导是电压依赖的，缺乏脱敏作用，动力学相对较慢。我们想要了解NMDA受体在视觉处理中的作用，作为第一步，我们将确定哪些神经节细胞类型表达它们。对于每种类型，我们将通过直接应用NMDA来测试功能表达；我们将进一步测试这些受体在正常生理条件下是否有助于高对比度反应。最后，我们将定量测试NMDA受体在视觉处理中的作用(目标3)。我们将模拟配基门控受体对对比反应的影响，并测试NMDA受体是否优先用于编码低对比与高对比。我们将进一步测试NMDA受体介导的反应的缓慢动力学是否优先编码低时间频率。拟议的研究将对视网膜回路和突触如何处理信息产生基本的理解，并为理解视网膜疾病提供背景，这些疾病要么危及视杆通路，要么涉及NMDA受体介导的兴奋性毒性。 与公众健康相关：拟议的研究将为了解损害夜间视力的眼病(即视网膜色素变性、先天性静止性夜盲)和涉及兴奋性毒性引起的细胞死亡的眼病(即青光眼、缺血)的影响提供背景资料。研究将导致对视网膜如何处理视觉信息的更好理解，这可能有助于开发假体设备来刺激某些形式失明的保存的视网膜细胞。