NICOTINIC RECEPTORS IN CEREBRAL CORTICAL DEVELOPMENT

大脑皮质发育中的烟碱受体

• 批准号: 6231388
• 负责人: ALLAN S SCHNEIDER
• 金额: $ 7.9万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6231388
• 关键词: acetylcholine; astrocytes; calcium flux; cell component structure /function; cerebral cortex; chemical kinetics; confocal scanning microscopy; developmental neurobiology; embryo /fetus; embryo /fetus drug adverse effect; gestational age; immunocytochemistry; laboratory mouse; neurogenesis; neurons; nicotinic receptors; oligodendroglia; pharmacology; protein localization; protein structure function; smoking; stimulant /agonist; tissue /cell culture; voltage /patch clamp

DESCRIPTION: (Adapted from the applicant's Description) There is an extensive literature showing that fetal nicotine exposure, due to maternal smoking, alters embryonic brain development and results in a variety of pathological effects in the neonate that fall under the heading of the "fetal nicotine syndrome". Although the mechanisms involved are not well understood, they are thought to be mediated in part by nicotinic acetylcholine receptors in the fetal brain. Yet neither the existence of functional nicotinic receptors in early fetal mammalian brain nor their role in development are well established. The investigators have obtained preliminary evidence that functional nicotinic receptors are expressed on mouse cerebral cortical cells at early embryonic ages when the cortex consists mainly of dividing stem and progenitor cells. Initial results show that nicotinic agonist activation of these receptors evokes characteristic electrophysiological responses and cytosolic Ca++ signals in the E10 cells. These early findings now open up an interesting set of questions concerning the role nicotinic receptors play in early cortical development and how chronic fetal nicotine exposure may alter such development. Before one can address these long term issues, however, it is first necessary to resolve the more focused issues concerning the acquisition, properties, and cellular localization of functional nicotinic receptors in the developing cerebral cortex. Thus, the investigators' specific aims are to answer the following two questions: at what stages of embryonic development do mouse cerebral cortical cells acquire functional nicotinic Ach receptors? And which subtypes of nicotinic receptors are present in the mouse cortex at different stages of development and which neural cells types are they on? Isolated mouse cerebral cortical cells derived from E10, E13, and E18 embryos will be used. Receptor functionality will be assessed by nicotinic agonist-induced Ca++ signaling and patchclamp electrophysiology. Receptor subtypes will be identified by pharmacological and kinetic analysis of functional responses. Immunocytochemistry will also be used to identify receptor subtypes and the different neural cell types they may be on. The results of this project will lay the groundwork for further exploration of the role of nicotinic receptors in normal development and that of nicotine as a neuroteratogen.

描述：（根据申请人的描述进行了改编） 广泛的文献表明，由于母亲而导致胎儿尼古丁的暴露 吸烟，改变胚胎脑发育并导致多种 属于“胎儿的标题”的新生儿的病理影响 尼古丁综合征”。尽管所涉及的机制尚不清楚，但 人们认为它们是由烟碱乙酰胆碱受体部分介导的 在胎儿大脑中。 然而，功能性烟碱的存在 早期胎儿哺乳动物大脑的受体或其在发育中的作用是 良好。 调查人员已经获得了初步证据 功能性烟碱受体在小鼠脑皮质细胞上表达 在早期胚胎时代，当皮质主要由茎和 祖细胞。 初始结果表明烟碱激动剂激活 这些受体唤起了特征性的电生理反应和 E10细胞中的胞质Ca ++信号。 这些早期发现现在打开了 关于烟碱受体起作用的有趣的问题 早期皮质发育以及慢性胎儿尼古丁暴露如何改变 这样的发展。 但是，在解决这些长期问题之前， 首先需要解决有关该问题的更集中的问题 功能性烟碱的获取，特性和细胞定位 发育中的脑皮质中的受体。 因此，调查人员的 具体目的是回答以下两个问题：在什么阶段 胚胎发育DO小鼠脑皮质细胞获得功能 烟碱ACH受体？ 以及哪些烟碱受体的亚型是 在不同的开发阶段存在于小鼠皮层中 神经细胞类型吗？ 孤立的小鼠脑皮质细胞 将使用源自E10，E13和E18胚胎的胚胎。 受体功能 将通过烟碱激动剂诱导的Ca ++信号和PatchClamp评估 电生理学。 受体亚型将通过药理学鉴定 和功能响应的动力学分析。 免疫细胞化学也将 用于识别受体亚型和不同的神经细胞类型 可能会打开。 该项目的结果将为进一步的基础奠定基础 探索烟碱受体在正常发育中的作用，并 尼古丁作为神经染料。