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: 6629698
• 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/6629698
• 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异常 新皮层功能和可塑性是这些缺陷的基础。但是， 细胞和分子机制，从而破坏了产前酒精 新皮质发展仍然难以捉摸。神经元电生理活性 认为涉及N-甲基-D-天冬氨酸（NMDA）类型的谷氨酸受体 在电路重排中具有关键功能，以表征 发展新皮层。此外，通过NMDA钙的流入 受体激活转录因子cAMP/钙依赖性响应 元素结合蛋白（CREB），该蛋白调节所需的基因表达 神经可塑性。已知酒精会阻止NMDA受体，并且有 越来越多的证据表明慢性酒精后CREB激活减少 接触。拟议的研究将检查一系列相互关联的假设 专注于酒精对NMDA受体和CREB依赖性机制的影响 新皮质发展和可塑性。研究将使用分子 技术，包括体内反义技术和基因病毒载体 转移，检查酒精破坏的分子机制 皮质发育和可塑性。第一个目标是表征 暴露于酒精的动物的感觉新皮层功能异常 在第三个妊娠中，相当于人类妊娠。动物会 在一个周期之后，在电生理和行为上进行了研究 无酒精月份。第二个目标是检查酒精的影响是否 NMDA受体是皮质发育破坏的基础。酒精是 已知会降低但不完全阻断NMDA受体功能。相似地 饮酒，反义DNA抑制但不会阻断皮质NMDA受体 功能。因此，对物体注射的反义DNA将用于 验证皮质NMDA受体功能的部分阻断是否为 足以破坏皮层发育。这些研究的第三个目标是 为了阐明降低CREB激活是否构成降低 FAS中的皮质可塑性。为了检查这一假设，单纯疱疹病毒 向量将用于诱导Creb的过表达，以补偿 慢性酒精治疗引起的下调。电生理学 然后，录音将用于确定皮质可塑性是否为 通过CREB的过表达恢复至正常水平。最后，这些 研究将检查酒精是否影响外围部位的发展 这会影响皮质发展。视觉皮层将用作模型 在这些研究中，因为它是新皮层研究最多的领域。 此外，视觉皮质可塑性被认为共享一些基本机制 有了学习和记忆，并且有大量证据表明NMDA受体 和Creb参与了这种可塑性。该系统的研究 通常应该评估酒精对产前皮质可塑性的影响 并且结果不应仅限于视觉皮层。此信息 可能有一天有助于制定预防或 减轻FAS的发病率。