Mechanisms of Visual Plasticity

描述（改编自申请人摘要）：目视检查降解 以视力下降为特征，不能通过 矫正镜片弱视在一般人群中相对常见， 是视力残疾的主要原因。在这种情况下，连接 将信息从被剥夺的眼睛传递到视觉皮层， 从经验丰富的眼睛中继信息的连接扩展， 皮层神经元只对有经验的眼睛的刺激作出反应。作为 因此，由被剥夺的眼睛介导的视觉功能可以被完全和 不可逆转地失去。然而，如果 对被剥夺的眼睛的正常视觉刺激在 剥夺已经开始。鉴于大量的科学和 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连接丢失所必需的， 被剥夺的眼睛流行的假设是，电压依赖性 镁对NMDA受体的阻断使其能够作为一种相关性， 检测器来自非剥夺眼的输入，其可以驱动相关的前和 突触后活动得到加强，而突触输入从 表现出与突触后细胞不相关的放电的被剥夺的眼睛是 迷路了此外，通过NMDA受体相关通道的钙内流 调节激活转录因子的细胞内激酶 cAMP/钙依赖性反应元件结合蛋白（CREB）。虽然这 级联事件提供了一个框架，了解机制， 皮质可塑性，几个重要的问题仍然没有答案 关于NMDA受体和CREB在眼优势可塑性中的作用： NMDA受体是否在眼优势中起相关检测器的作用 可塑性？ii）CREB的激活是皮质功能丧失所必需的吗？ 单眼剥夺时的双眼视觉？iii）NMDA受体是否具有 功能恢复皮质双眼重建后， 视觉刺激的剥夺眼睛？，CREB有什么功能 恢复皮质双眼视功能拟议的研究将使用 分子遗传操作来回答这些重要的问题。反义 试剂将用于减少单个基因的表达， 介导的基因转移将用于诱导个体的过表达， 基因或视觉皮层中突变基因的表达。使用这些 互补技术将提供一个新的和令人兴奋的机会， 视皮层功能丧失和恢复的分子机制。 总的来说，拟议研究的结果将使我们能够 开始追踪导致损失和恢复的分子事件的顺序， 单眼剥夺性弱视的皮质功能更好地了解 这些机制将为开发新的治疗药物提供特定的靶点， 弱视的治疗方法。

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.