In utero ethanol exposure & development of GABAergic cortical interneurons

子宫内乙醇暴露

• 批准号: 7321656
• 负责人: Verginia Carmella Cuzon Carlson
• 金额: $ 4.2万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321656
• 关键词: Affect; Age; Alcohol consumption; Appearance; Behavioral; Biological; Brain; Cells; Chronic; Coculture Techniques; Computer information processing; Defect; Dependence; Development; Diet; Disruption; Dose; Embryo; Embryonic Development; Environmental Risk Factor; Ethanol; Fetal Alcohol Exposure; Fetal Alcohol Syndrome; Genes; Green Fluorescent Proteins; Height; Hydrocephalus; In Vitro; Interneurons; Kinetics; Liquid substance; Medial; Microcephaly; Molecular; Morphology; Mutate; Neocortex; Numbers; Patient currently pregnant; Pattern; Population; Positioning Attribute; Predisposition; Pregnancy; Regulation; Rodent; Running; Seizures; Sensory; Slice; Source; Staging; System; Testing; Time; Transgenic Mice; Video Microscopy; alcohol consumption during pregnancy; alcohol exposure; chronic alcohol ingestion; day; extracellular; feeding; gamma-Aminobutyric Acid; in utero; in vivo; migration; neuronal circuitry; postnatal; prenatal; receptor; research study

Consumption of ethanol during pregnancy can be detrimental to the offspring, the most severe detriment being the developmental defects collectively referred to as fetal alcohol syndrome (FAS). In brain, FAS is hallmarked by defects in gross morphology (e.g., microcephaly, hydrocephaly, porencephaly, hydroanencephaly) that have been attributed to insult during corticogenesis. Prenatal chronic ethanol exposure compromises the GABAergic system in the immature brain and, thus, inhibitory regulation, contributing to increased susceptibility to seizures and deficits in sensory information processing associated with FAS. In this proposal, we ask whether chronic ethanol consumption (1-6% EtOH) during pregnancy leads to abnormal development of the GABAergic system in the offspring. The overriding hypothesis is that the abnormal disposition of the postnatal and mature cortex seen in FAS manifests itself early on in corticogenesis by affecting the migration of primordial GABAergic interneurons to their usual laminar positions within the neocortex. In rodent, these GABAergic interneurons arise extracortically primarily from the medial ganglionic eminence (MGE) and migrate tangentially into the developing neocortex. In Specific Aim 1, we will quantitatively assess the patterns and kinetics of the tangential migration of MGE-derived cells with the specific hypothesis that the disruption of tangential migration is dependent on the dose and time of ethanol insult in utero. Specific Aim 2 will employ real-time videomicroscopy in heterotypic and heterochronic telencephalic slice cocultures to test the specific hypothesis that both cell intrinsic and extrinsic mechanisms contribute to alter the pattern of tangentil migration with in utero ethanol. Specific Aim 3 will incorporate electrophysiological, gene profiling, and immunohistochemical approaches to test the hypothesis that in utero ethanol exposure interacts with the GABAergic system to exert its effect on tangential migration of MGE-derived cells. Overall, this project will for the first time define the effect of ethanol consumption during early stages of pregnancy on the embryonic development of a specific and important population of cells in the neocortex, notably the GABAergic cortical interneurons. In the long run, the proposed studies will lay the groundwork for assessing how disruptions of the cortical neuronal circuitry underlie many of the behavioral abnormalities seen in FAS.

怀孕期间摄入酒精可能对后代有害，这是最严重的损害 这些发育缺陷统称为胎儿酒精综合征(Fas)。在大脑中，Fas是 以大体形态缺陷为特征(例如，小头畸形、脑积水、多孔性脑畸形、 积水性无脑症)，被归因于皮质生成过程中的侮辱。产前慢性酒精 暴露会损害未成熟大脑中的GABA能系统，从而抑制调节， 增加对癫痫的易感性和相关的感觉信息处理缺陷 和Fas一起。 在这项建议中，我们询问怀孕期间长期摄入乙醇(1-6%乙醇)是否会导致 子代GABA能系统发育异常。压倒一切的假设是 Fas的出生后和成熟皮质的异常处置在早期就表现出来了 影响原始GABA能中间神经元向其正常板层迁移的皮质生成 在大脑皮层内的位置。在啮齿动物中，这些GABA能中间神经元主要是从外部产生的 内侧神经节隆起(MGE)，并切向迁移到发育中的新皮质。具体而言 目标1，我们将定量评估MGE衍生的切向迁移的模式和动力学 具有特定假设的细胞，即切向迁移的中断依赖于剂量和 酒精在宫内侮辱的时间。特定目标2将使用实时视频显微镜在异型和 异时端脑切片共培养，以检验细胞固有的和 外在机制有助于改变子宫内乙醇的切线迁移模式。特定目标 3将结合电生理学、基因图谱和免疫组织化学方法来测试 宫内酒精暴露与GABA能系统相互作用的假说 MGE来源细胞的切向迁移。 总体而言，该项目将首次确定#年早期阶段乙醇消费的影响。 妊娠对胚胎发育的一种特定而重要的新皮质细胞群， 值得注意的是GABA能皮质中间神经元。长远来说，拟议的研究将会奠定基础。 为了评估皮层神经元回路的中断是如何导致许多行为异常的 在Fas上见过。