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: 6509419
• 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 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6509419
• 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)的特征是 儿童的行为和生理异常，包括学习， 感觉和运动障碍。越来越多的证据表明， 新皮质功能和可塑性是这些缺陷的基础。然而， 产前酒精暴露扰乱的细胞和分子机制 新皮质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)类型的谷氨酸受体被认为 在电路重排中具有关键作用，这是 发育中的感觉新皮质。此外，通过NMDA的钙流入 受体激活转录因子cAMP/钙依赖反应 元件结合蛋白(CREB)，它调节所需的基因表达 神经可塑性。众所周知，酒精可以阻断NMDA受体，而且有 越来越多的证据表明慢性酒精导致CREB活性降低 曝光。拟议的研究将检验一系列相互关联的假设。 重点阐述了酒精对NMDA受体和CREB依赖机制的影响 新皮质发育和可塑性。这些研究将使用分子 技术包括体内反义技术和基因的病毒载体 转移，以检查酒精破坏的分子机制 皮质发育和可塑性。第一个目标是刻画 酒精对动物感觉新皮质功能的影响 在相当于人类妊娠的第三个三个月期间。动物将会是 经过一段时间的电生理学和行为学研究 戒酒月。第二个目标是研究酒精对人体健康的影响 NMDA受体是大脑皮质发育受阻的基础。酒精是 已知会降低NMDA受体的功能，但不是完全阻断。类似 对于酒精，反义DNA抑制但不阻断大脑皮层NMDA受体 功能。因此，皮内注射的反义DNA将被用于 验证皮质NMDA受体功能的部分阻断是否 足以扰乱大脑皮层发育。这些研究的第三个目标是 为了阐明CREB活性降低是否是导致CREB活性降低的原因 Fas中的皮质可塑性。为了检验这一假设，一种单纯疱疹病毒 载体将被用来诱导CREB的过度表达，补偿 慢性酒精治疗引起的基因表达下调。电生理学 然后将使用录音来确定皮质可塑性是否 CREB过表达使其恢复到正常水平。最后，这些 研究将检查酒精是否会影响周围部位的发育 影响大脑皮层发育的物质。视皮层将被用作模型 因为它一直是新大脑皮层研究最多的区域。 此外，视觉皮质可塑性被认为具有一些基本的机制 与学习和记忆有关，有大量证据表明，NMDA受体 和CREB参与了这种类型的可塑性。关于这一制度的研究 应评估酒精对产前皮质可塑性的影响 研究结果不应仅限于视觉皮质。此信息 可能有一天有助于设计出治疗干预措施，以防止或 减轻Fas的发病率。