Ethanol exposure in utero: effects on radial migration, form, and function of pyramidal neurons in the somatosensory cortex.

子宫内乙醇暴露：对体感皮层锥体神经元径向迁移、形态和功能的影响。

• 批准号: 9358322
• 负责人: Laurie Christine Delatour
• 金额: $ 4.4万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9358322
• 关键词: ARHGEF5 gene; Adult; Affect; Alcohol consumption; Alcohols; Behavioral; Blood alcohol level measurement; Brain; Bromodeoxyuridine; Cell Proliferation; Cells; Cellular Morphology; Characteristics; Cognitive deficits; Complement; Dangerousness; Development; Diagnosis; Electrophysiology (science); Embryo; Embryonic Development; Equilibrium; Ethanol; Etiology; Face; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Food; Functional disorder; Glutamates; Goals; Height; Immunohistochemistry; Incubated; Intellectual functioning disability; Internal Ribosome Entry Site; Interneurons; Investigation; Kinetics; Knowledge; Label; Liquid substance; Long-Term Effects; Molecular; Morphology; Mus; Neuroglia; Neurons; Pattern; Physiologic pulse; Pregnancy; Pregnant Women; Problem behavior; Process; Property; Pyramidal Cells; Radial; Reporting; Research; Risk; Sensory; Slice; Somatosensory Cortex; Staining method; Stains; Synapses; Teratogens; Testing; Time; Training; Transgenic Mice; United States; Ventricular; Video Microscopy; Woman; alcohol exposure; cell type; drinking; experimental study; fetal; hippocampal pyramidal neuron; in utero; in vivo; insight; migration; neurobiotin; neurotransmission; non-genetic; offspring; optogenetics; patch clamp; postnatal; postsynaptic; pregnant; prenatal exposure; response; scaffold; stressor; synaptogenesis; transcription factor; unborn child; young adult

Project Summary Fetal Alcohol Spectrum Disorder (FASD) is a leading cause of non-genetic intellectual disability, including behavioral, sensory, and cognitive deficits. Even though gestational ethanol consumption is a significant threat to the unborn child, it has been reported that 1 pregnant woman in 10 in the United States drinks alcohol, and 1 in 33 binge drinks in the past 30 days. Binge-type drinking during pregnancy is particularly dangerous due to abrupt and exceedingly high blood alcohol levels. While FASD necessitates a postnatal diagnosis, the underlying embryonic etiology, specifically corticogenesis, is understudied. The tangential migration of GABAergic interneurons and the radial migration of glutamatergic primordial pyramidal neurons are intricately regulated processes that are key to corticogenesis. While is it known that in utero binge-type exposure to ethanol results in aberrances in tangential migration, its effects on radial migration are not known. The long- term goal of this project is to contribute to our understanding of how cortical development is affected in FASD. The short-term objectives are to investigate the effects of in utero binge-type exposure to ethanol on the radial migration of primordial pyramidal neurons, and the enduring effects on pyramidal neuron form and function in the somatosensory cortex. These objectives will be embodied in two specific aims: Aim 1. Test the hypothesis that prenatal exposure to ethanol disrupts the radial migration of primordial pyramidal neurons during embryonic corticogenesis. Immunohistochemistry and organotypic slice culture paired with real-time videomicroscopy will investigate changes in radial migration during embryonic development. Aim 2. Test the hypothesis that the effects of prenatal exposure to ethanol on migration persist postnatally as altered neuroanatomical/functional disposition and excitatory/inhibitory synaptic balance on pyramidal neurons. A combination of immunohistochemical, morphological, electrophysiological, and optogenetic approaches will be used in early postnatal and young adult mice to investigate the persistent effects of binge- type exposure to ethanol on the disposition and functional properties of pyramidal neurons. This will include the balance between the excitatory and inhibitory cortical circuits during the time of synaptogenesis and adulthood. The findings from this project will fill a critical void in our knowledge regarding the cellular and molecular mechanisms underlying FASD. This will inform future research focused on further elucidating the neurodevelopmental consequences of in utero exposure to ethanol on the unborn child and their management.

项目摘要 胎儿酒精谱系障碍（FASD）是非遗传智力障碍的主要原因，包括 行为，感觉和认知缺陷。即使妊娠乙醇消耗是一个重大威胁 对于未出生的孩子，据报道，美国10名孕妇饮酒，1个 在过去的30天中，在33次暴饮暴食中。由于怀孕期间的暴饮暴食型饮酒特别危险 突然和极高的血液酒精水平。尽管FASD需要产后诊断，但 潜在的胚胎病因，特别是皮质生成。切向迁移的 GABA能中间神经元和谷氨酸能原始锥体神经元的径向迁移错综复杂 调节过程是皮质生成的关键。虽然知道在子宫暴饮暴食中暴露于 乙醇会导致切向迁移的异常，其对径向迁移的影响尚不清楚。长期 该项目的术语目标是为我们理解FASD中的皮质开发的理解做出贡献。 短期目标是调查子宫内暴饮体中乙醇对径向的影响 原始锥体神经元的迁移，以及对锥体神经元形式和功能的持久影响 体感皮质。这些目标将体现在两个具体目标中： 目标1。检验以下假设：产前暴露于乙醇会破坏原始的径向迁移 胚胎皮质发生过程中的锥体神经元。免疫组织化学和器官切片培养 与实时视频显微镜配对，将调查胚胎期间径向迁移的变化 发展。 目标2。检验以下假设：产前暴露于乙醇对迁移的影响持续存在 随着神经解剖学/功能性的改变以及金字塔上的兴奋性/抑制性突触平衡 神经元。免疫组织化学，形态学，电生理和光遗传学的组合 方法将在产后和成年小鼠早期使用，以研究暴饮暴食的持续作用 在金字塔神经元的处置和功能特性上暴露于乙醇。这将包括 在突触发生和成年期间，兴奋性和抑制性皮质回路之间的平衡。 该项目的发现将填补我们有关细胞和分子的知识的关键空隙 FASD的机制。这将为未来的研究提供信息，重点是进一步阐明 子宫内对未出生的孩子及其管理的神经发育后果。