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Mechanisms of Visual Plasticity

视觉可塑性机制

基本信息

批准号：
7038166
负责人：
Ary S Ramoa
金额：
$ 3.86万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2005-07-30
项目状态：
已结题

项目摘要

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）：视觉退化其特征是视力下降且无法通过以下方法改善矫正镜片。弱视在普通人群中相对常见是造成视力障碍的重要原因。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传递信息的连接会扩展，大多数皮层神经元仅对有经验的眼睛的刺激做出反应。作为一个因此，由被剥夺的眼睛介导的视觉功能可以完全并且不可挽回地丢失。双眼功能是可以恢复的，但是，如果被剥夺的眼睛的正常视觉刺激在术后立即恢复剥夺已经开始。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失去连接所必需的被剥夺的眼睛。普遍的假设是电压相关镁对 NMDA 受体的阻断使其能够发挥相关作用探测器。来自非剥夺眼睛的输入可以驱动相关的预和突触后活动得到加强，同时来自突触的输入与突触后细胞表现出不相关放电的被剥夺的眼睛是丢失的。此外，钙通过 NMDA 受体相关通道流入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理解机制的框架皮质可塑性，几个重要的问题仍未得到解答关于 NMDA 受体和 CREB 在眼优势可塑性中的作用： I) NMDA 受体是否充当眼优势相关检测器可塑性？ ii) CREB 的激活是皮质丧失所必需的单眼剥夺期间的双眼性？，iii) NMDA 受体是否具有重建后皮质双眼恢复的功能对被剥夺的眼睛进行视觉刺激？以及 iv) CREB 有什么功能皮质双眼恢复？拟议的研究将使用分子遗传学操作来回答这些重要问题。反义试剂将用于减少单个基因和病毒的表达介导的基因转移将用于诱导个体的过度表达视觉皮层中的基因或突变基因的表达。使用这些互补技术将提供一个新的、令人兴奋的机会来检查视觉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序列单眼剥夺性弱视的皮质功能。更好地理解这些机制应该提供具体的目标来开发新的治疗方法治疗弱视的方法。