Neural circuits and synapses for early visual processing

描述（由申请人提供）：我的长期目标是在神经回路和突触的层面上了解视觉处理的生物学基础。我正在哺乳动物视网膜中追求这个目标，这是一个由大约70种细胞类型组成的组织：大约3-4个感光细胞（取决于物种），大约50个中间神经元（水平、双极和无突细胞）和大约20个输出神经元（神经节细胞）。在过去的一段时间里，我们专注于两种类型的神经节细胞（on和OFF α细胞），并阐明了它们的突触输入的基本组成部分和对比适应的机制。这些成就使我们现在能够将我们的研究扩展到十几种神经节细胞，我们基于功能特性（光诱发突触电导）和结构特性（树突树直径和内丛状层的分层水平）的组合来识别这些细胞。目的1将揭示夜视的基本电路机制，通过确定视杆信号如何通过已识别的神经通路传递到每个神经节细胞类型。杆状体与杆状双极细胞发生突触，杆状双极细胞反过来刺激AII无分泌细胞；AII细胞直接向某些神经节细胞发出信号，并通过与突触前锥体双极端突触间接向其他细胞发出信号。初步数据表明，一小部分OFF神经节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接受来自一种或多种锥双极细胞的谷氨酸能突触，但我们需要测试哪种神经节细胞类型用NMDA受体编码谷氨酸释放（Aim 2）。与其他主要类型的AMPA受体相比，NMDA受体的电导依赖于电压，缺乏脱敏性，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来检测功能表达；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受体在视觉加工中的作用（目的3）。我们将模拟配体门控受体对对比度反应的贡献，并测试NMDA受体是否优先用于编码低对比度和高对比度。我们将进一步测试NMDA受体介导的反应的慢动力学是否优先编码低时间频率。拟议的研究将产生对视网膜回路和突触如何处理信息的基本理解，并为理解损害杆通路或涉及NMDA受体介导的兴奋毒性的视网膜疾病提供背景。

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.