Alcohol in Neocortex Development and Plasticity

酒精在新皮质发育和可塑性中的作用

• 批准号: 6711646
• 负责人: Ary S Ramoa
• 金额: $ 32.31万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711646
• 关键词: NMDA receptors; alcohols; antisense nucleic acid; behavior test; biological models; cAMP response element binding protein; developmental neurobiology; electrical measurement; electrophysiology; embryo /fetus toxicology; ferrets; fetal alcohol syndrome; gene expression; genetic regulation; gestational age; immunocytochemistry; muscle contraction; neocortex; neural plasticity; neurogenesis; transfection; vision; vision tests; visual cortex; western blottings

DESCRIPTION: Fetal alcohol syndrome (FAS) is characterized by a constellation of behavioral and physiological abnormalities in children, including learning, sensory and motor deficits. There is growing evidence that abnormalities of neocortical function and plasticity underlie these deficits. However, the cellular and molecular mechanisms by which prenatal alcohol exposure disrupts neocortical development remain elusive. Neuronal electrophysiological activity involving the N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to have a critical function in the circuit rearrangements that characterize the developing sensory neocortex. Moreover, inflow of calcium through the NMDA receptor activates the transcription factor cAMP/Calcium-dependent response element binding protein (CREB), which regulates gene expression required in neural plasticity. Alcohol is known to block NMDA receptors and there is increasing evidence that CREB activation is reduced following chronic alcohol exposure. The proposed studies will examine a series of interrelated hypotheses focused on effects of alcohol on NMDA receptor- and CREB-dependent mechanisms of neocortical development and plasticity. The studies will use molecular techniques, including in vivo antisense techniques and viral vectors for gene transfer, to examine the molecular mechanisms by which alcohol disrupts cortical development and plasticity. The first goal is to characterize abnormalities of function in sensory neocortex of animals exposed to alcohol during the third trimester equivalent of human gestation. Animals will be studied electrophysiologically and behaviorally following a period of one alcohol-free month. The second goal is to examine whether effects of alcohol on NMDA receptors underlie the disruption of cortical development. Alcohol is known to decrease, but not completely block, NMDA receptor function. Similarly to alcohol, antisense DNA suppresses but does not block cortical NMDA receptor function. Therefore, antisense DNA injected intracortically will be used to verify whether a partial blockade of cortical NMDA receptor function is sufficient to disrupt cortical development. The third goal of these studies is to elucidate whether reduction of CREB activation underlies the decreased cortical plasticity in FAS. To examine this hypothesis, a herpes simplex viral vector will be used to induce overexpression of CREB, compensating for the downregulation caused by the chronic alcohol treatment. Electrophysiological recordings will then be used to determine whether cortical plasticity is restored to its normal level by the overexpression of CREB. Finally, these studies will examine whether alcohol affects development of peripheral sites that influence cortical development. The visual cortex will be used as a model in these studies because it has been the most studied area of the neocortex. Moreover, visual cortical plasticity is thought to share some basic mechanisms with learning and memory, and there is substantial evidence that NMDA receptors and CREB are involved in this type of plasticity. The studies on this system should assess the effects of alcohol on prenatal cortical plasticity in general and the results should not be restricted to the visual cortex. This information may one day contribute to devise therapeutic interventions that will prevent or alleviate morbidity in FAS.

描述：胎儿酒精综合征（FAS）的特点是一个星座， 儿童的行为和生理异常，包括学习， 感觉和运动缺陷。越来越多的证据表明， 新皮层功能和可塑性是这些缺陷的基础。但 产前酒精暴露干扰胎儿发育的细胞和分子机制 新皮层的发育仍然难以捉摸。神经元电生理活动 涉及N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的 在电路重组中发挥关键作用， 发育中的感觉皮层此外，通过NMDA的钙内流 受体激活转录因子cAMP/钙依赖性反应 元件结合蛋白（CREB），它调节基因表达所需的， 神经可塑性已知酒精会阻断NMDA受体， 越来越多的证据表明，慢性酒精后CREB激活减少 exposure.拟议的研究将审查一系列相互关联的假设 专注于酒精对NMDA受体和CREB依赖机制的影响 大脑皮层的发育和可塑性这些研究将使用分子 技术，包括体内反义技术和用于基因表达的病毒载体。 转移，以检查酒精破坏的分子机制， 皮质发育和可塑性。第一个目标是描述 酒精暴露动物感觉新皮层功能异常 在相当于人类怀孕的第三个三个月。动物将 在一段时间后， 无酒精月第二个目标是研究酒精对 NMDA受体是皮质发育中断的基础。醇是 已知降低但不完全阻断NMDA受体功能。类似地 对酒精，反义DNA抑制但不阻断皮层NMDA受体 功能因此，皮质内注射的反义DNA将用于 验证皮质NMDA受体功能的部分阻断是否 足以破坏皮质发育这些研究的第三个目标是 为了阐明CREB激活的减少是否是 皮质可塑性。为了验证这一假设， 载体将用于诱导CREB的过表达，补偿CREB的表达。 慢性酒精治疗引起的下调。电生理 记录将用于确定皮层可塑性是否 通过CREB的过度表达恢复到正常水平。最后这些 研究将检查酒精是否影响周围部位的发育 影响皮层发育的神经系统视觉皮层将被用作模型 在这些研究中，因为它是新皮层中研究最多的区域。 此外，视觉皮层可塑性被认为共享一些基本机制 与学习和记忆有关，有大量证据表明NMDA受体 和CREB参与了这种可塑性。对该系统的研究 应该评估酒精对产前皮质可塑性的影响 研究结果不应该局限于视觉皮层。这些信息 有一天可能有助于设计治疗干预措施， 降低FAS的发病率。