Neural circuits and synapses for early visual processing

摘要：我的长期目标是了解视觉处理的生物学基础 神经回路和突触。我正在哺乳动物的视网膜上追求这个目标，视网膜是一种由以下物质组成的组织 ~70种细胞类型：~3-4个感光细胞(视种类而定)，~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，我们重点关注了两个 神经节细胞的类型(On和Off Alpha细胞)及其基本成分的阐明 突触输入和对比适应机制。这些成就使我们现在能够 将我们的研究扩展到十几种类型的神经节细胞，这些细胞是基于 功能特性(光诱发突触电导)和结构特性(树突 内丛状层的直径和层积)。目标1将揭示基本电路 夜视的机制，通过确定视杆信号如何通过已识别的神经传递 每种神经节细胞类型的通路。视杆与视杆双极细胞突触，进而刺激AII 无长突细胞；AII细胞直接向某些类型的神经节细胞发出信号，并通过 与突触前锥体两极终末的突触。初步数据显示，一小部分人 节外细胞类型接受直接AII细胞突触；另一组接受间接突触， 而第三组缺少与电路的连接并且在昏暗的光中丧失功能。对可视内容进行编码 在白天，每种神经节细胞类型从一种或多种类型接收谷氨酸能突触 但我们需要测试哪些神经节细胞类型编码谷氨酸释放 NMDA受体(AIM 2)。与另一种主要类型的AMPA受体相比，NMDA受体具有 电导依赖于电压，缺乏减敏作用，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，我们将测试函数表达式 通过直接应用NMDA；我们将进一步测试这些受体是否有助于高对比度 在正常生理条件下的反应。最后，我们将定量测试NMDA的作用 视觉处理中的受体(目标3)。我们将模拟配基门控受体对对比的影响 反应和测试NMDA受体是否优先用于编码低和高 对比度。我们将进一步测试NMDA受体介导的反应的缓慢动力学 优先编码低时间频率。拟议的研究将产生对以下方面的基本了解 视网膜回路和突触如何处理信息并为理解提供背景 损害视杆通路或涉及NMDA受体介导的视网膜疾病 兴奋性毒性。

Abstract: 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.