Mechanisms of Visual Plasticity

视觉可塑性机制

• 批准号: 6779175
• 负责人: Thomas E Krahe
• 金额: $ 26.95万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779175
• 关键词: NMDA receptors; amblyopia; antisense nucleic acid; binocular vision; cAMP response element binding protein; early embryonic stage; electrophysiology; ferrets; gel electrophoresis; gene expression; genetic manipulation; immunocytochemistry; microinjections; molecular cloning; neural plasticity; neural transmission; polymerase chain reaction; receptor expression; receptor sensitivity; synapses; transcription factor; vision tests; visual cortex; voltage /patch clamp; western blottings

DESCRIPTION (adapted from applicant's abstract): Degradation of the visual characterized by a decrease of visual acuity that cannot be improved by corrective lenses. Amblyopia is relatively common in the general population and constitutes a major cause of visual disability. In this condition, connections relaying information from the deprived eye to the visual cortex withdraw and connections relaying information from the experienced eye expand, with most cortical neurons responding only to stimulation of the experienced eye. As a consequence, visual function mediated by the deprived eye can be completely and irreversibly lost. Recovery of binocular function can be obtained, however, if normal visual stimulation to the deprived eye is restored promptly after deprivation has been initiated. In view of the substantial scientific and clinical relevance of these types of neural plasticity, there is an urgent need to elucidate the underlying cellular and molecular mechanisms. Neurophysiological activity involving the N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be required for the loss of connections from the deprived eye. The prevailing hypothesis is that the voltage-dependent magnesium blockade of the NMDA receptor enables it to act as a correlation detector. Inputs from the non-deprived eye that can drive correlated pre-and post-synaptic activity are strengthened, while synaptic inputs from the deprived eye that exhibit uncorrelated firing with the post-synaptic cell are lost. In addition, calcium influx through the NMDA receptor associated channel regulates intracellular kinases that activate the transcription factor cAMP/Calcium-dependent response element binding protein (CREB). Although this cascade of events has provided a framework for understanding the mechanisms of cortical plasticity, several important questions have remained unanswered concerning the role of NMDA receptors and CREB in ocular dominance plasticity: I) do NMDA receptors function as correlation detectors in ocular dominance plasticity? ii) is activation of CREB required for the loss of cortical binocularity during monocular deprivation?, iii) do NMDA receptors have a function in recovery of cortical binocularity following re-establishment of visual stimulation to the deprived eye?, and iv) what function does CREB have in recovery of cortical binocularity? The proposed studies will use molecular-genetic manipulations to answer these important questions. Antisense reagents will be used to reduce expression of individual genes, and viral mediated gene transfer will be used to induce overexpression of individual genes or expression of mutated genes in the visual cortex. Use of these complementary techniques will provide a new and exciting opportunity to examine the molecular mechanisms of loss and recovery of visual cortical function. Collectively the results of the proposed studies will place us in a position to start tracing the sequence of molecular events leading to loss and recovery of cortical function in monocular deprivation amblyopia. A better understanding of these mechanisms should provide specific targets to develop novel therapeutic approaches in the treatment of amblyopia.

描述（改编自申请人的摘要）：视觉的退化 特征是视力下降，无法改善 矫正镜头。弱视在普通人群中相对普遍 构成视觉障碍的主要原因。在这种情况下，连接 从被剥夺的眼睛传达信息到视觉皮层的提取和 连接从经验丰富的眼睛扩展的信息扩展，大多数 皮质神经元仅对刺激有经验的眼睛有反应。作为 结果，被剥夺的眼睛介导的视觉功能可以是完全的，并且 不可逆转地迷失了。但是，如果可以获得双眼功能的恢复 在剥夺眼睛的正常视觉刺激之后迅速恢复 剥夺已开始。鉴于实质的科学和 这些类型的神经可塑性的临床相关性，迫切需要 阐明潜在的细胞和分子机制。 涉及N-甲基-D-天冬氨酸（NMDA）类型的神经生理活性 谷氨酸受体被认为是失去连接所必需的 被剥夺的眼睛。普遍的假设是电压依赖性 NMDA受体的镁阻塞使其能够充当相关性 探测器。来自非剥夺眼睛的输入，可以驱动相关的前和 突触后活性得到加强，而突触的输入 剥夺了与后突触细胞不相关发射的眼睛是 丢失的。此外，通过NMDA受体相关通道的钙涌入 调节激活转录因子的细胞内激酶 CAMP/钙依赖性响应元件结合蛋白（CREB）。虽然这个 一系列事件为理解机制提供了一个框架 皮质可塑性，几个重要问题仍未解决 关于NMDA受体和CREB在眼部优势可塑性中的作用： i）DO NMDA受体在眼部优势中充当相关检测器 可塑性？ ii）是损失皮质所需的CREB的激活 单眼剥夺期间的双眼？，iii）NMDA受体是否具有 重新建立后皮质双向性的恢复功能 视觉刺激被剥夺的眼睛吗？和IV）CREB具有什么功能 在恢复皮质双向性方面？拟议的研究将使用 分子遗传操作回答这些重要问题。反义 试剂将用于减少单个基因的表达和病毒 介导的基因转移将用于诱导个体过表达 视觉皮层中突变基因的基因或表达。使用这些 互补技术将为检查一个新的激动人心的机会 视觉皮质功能丧失和恢复的分子机制。 拟议的研究的总体结果将使我们处于 开始追踪分子事件的序列，导致丢失和恢复 单眼剥夺弱视中的皮质功能。更好地理解 这些机制应提供特定的靶标以开发新的治疗性 在治疗弱视方面的方法。