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）是非遗传性智力残疾的主要原因，包括 行为、感觉和认知缺陷。尽管妊娠期酒精摄入是一个重大威胁， 据报道，在美国，每10名孕妇中就有1名饮酒， 在过去的30天里喝了33杯酒怀孕期间的暴饮暴食特别危险，因为 血液中酒精含量突然过高虽然FASD需要产后诊断， 潜在的胚胎病因学，特别是皮质生成，还没有得到充分的研究。切向迁移 GABA能中间神经元和多巴胺能原始锥体神经元的径向迁移是错综复杂的 调节皮质生成的关键过程。众所周知，在子宫内暴饮暴食式暴露于 乙醇导致切向迁移的异常，其对径向迁移的影响尚不清楚。很长的- 该项目的长期目标是帮助我们了解FASD中皮质发育如何受到影响。 短期目标是研究宫内暴饮暴食型暴露于乙醇对放射性的影响。 原锥体神经元的迁移，以及对锥体神经元形态和功能的持久影响， 躯体感觉皮层这些目标将体现在两个具体目标中： 目标1.检验产前暴露于乙醇会破坏原始细胞放射状迁移的假设。 锥体神经元在胚胎皮质发生。免疫组织化学和器官型切片培养 结合实时视频显微镜将研究胚胎发育过程中放射状迁移的变化， 发展 目标2.检验产前暴露于乙醇对迁移的影响在产后持续存在的假设 神经解剖学/功能性处置和锥体细胞上兴奋性/抑制性突触平衡的改变 神经元结合免疫组织化学、形态学、电生理学和光遗传学 方法将用于出生后早期和年轻成年小鼠，以研究狂欢的持续影响， 型暴露于乙醇对锥体神经元的配置和功能特性。这将包括 在突触发生和成年期，兴奋性和抑制性皮层回路之间的平衡。 这个项目的发现将填补我们关于细胞和分子生物学知识的一个关键空白。 FASD的潜在机制。这将为未来的研究提供信息，重点是进一步阐明 子宫内暴露于乙醇对未出生婴儿的神经发育后果及其管理。