Functional consequences of fetal-alcohol-induced brain growth abnormalities identified with in utero MRI

子宫内 MRI 发现胎儿酒精引起的大脑生长异常的功能后果

• 批准号: 10590615
• 负责人: Verginia Carmella Cuzon Carlson
• 金额: $ 67.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590615
• 关键词: Achievement; Affect; Age; Age Months; Alcohol consumption; Alcohols; Anatomy; Animal Model; Animals; Awareness; Axon; Behavior; Behavior assessment; Behavioral; Brain; Brain region; Cells; Cerebellum; Child; Control Animal; Data; Development; Developmental Process; Early Diagnosis; Electrophysiology (science); Equilibrium; Ethanol; Exhibits; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Fetus; Fiber; First Pregnancy Trimester; Functional Magnetic Resonance Imaging; Gestational Age; Glutamates; Grant; Growth; Histology; Human; Immunohistochemistry; Impaired cognition; Impairment; Incidence; Individual; Infant; Intervention; Investments; Lead; Longevity; Macaca mulatta; Magnetic Resonance Imaging; Measurement; Measures; Methods; Modality; Modeling; Monkeys; Motion; Motor; Nervous System Trauma; Neuroanatomy; Neurodevelopmental Disorder; Neurologic Deficit; Neurons; Oral; Outcome; Pregnancy; Prevalence; Prevention; Procedures; Process; Quality of life; Research; Rhesus; Risk Reduction; School-Age Population; Self Administration; Severities; Slice; Somatosensory Cortex; Structure; Synapses; System; Techniques; Testing; Therapeutic Intervention; Three-Dimensional Image; United States; Validation; Work; adverse outcome; alcohol exposure; behavior measurement; behavioral impairment; binge drinking; brain abnormalities; clinically relevant; cognitive development; cognitive function; comparison control; data reduction; detection method; drinking; early drinking; economic cost; efficacious treatment; emotion regulation; experimental study; fetal; functional disability; image reconstruction; improved; in utero; motor behavior; motor impairment; neonatal magnetic resonance imaging; neural; neural circuit; neuroimaging; nonhuman primate; novel; offspring; older women; patch clamp; postnatal; postsynaptic; prenatal exposure; putamen; socioeconomics; transmission process; white matter

PROJECT SUMMARY Fetal exposure to alcohol leads to a wide range of neurological deficits collectively termed fetal alcohol spectrum disorder (FASD). This prevalent neurodevelopmental disorder currently affects as many as 1-5% of school-aged children in the United States. Existing intervention strategies can improve the quality of life in affected individuals, but early detection is critical for efficacious therapy. In utero MRI has benefited from recent improvements in retrospective motion correction methods in 3D image reconstruction, and is a promising non- invasive technique for identifying abnormal brain development associated with fetal exposure to alcohol. We have recently developed a rhesus macaque model of FASD that resembles human drinking early in gestation, prior to pregnancy awareness, but ceases upon recognition of pregnancy. Abnormal brain growth is apparent at gestation day (G)135 by MRI in fetuses of rhesus macaques that orally self-administered 1.5 g/kg (approximately 6 drinks) daily ethanol over the first 60 days of pregnancy. Compared to controls, ethanol- exposed fetuses possessed brains with smaller cerebellums and less developed white matter fiber systems involved in motor and cognitive function. Ex vivo electrophysiological recordings performed on the G135 fetuses demonstrated that the MRI-identified abnormalities are associated with functional impairments in glutamatergic transmission. The experiments proposed in this application will determine the behavioral consequences of these anatomical and functional abnormalities, and further extend the MRI and electrophysiological characterization of this model of FASD. Twelve rhesus macaques exposed to daily maternal 1.5 g/kg ethanol drinking over the first 60 days of gestation will be compared to 12 control animals. In utero MRI will be performed at G135, and the offspring will be survived to postnatal day (P)180 (approximately 6 months of age). Additional MRI experiments will be performed on P3 and P180. Aim 1 of this proposal will use fetal (G135) and postnatal MRI (P3 and P180) to define the long-term impact of ethanol exposure on brain development. This Aim includes a primary analysis focused on brain structures identified to be different at G135 and whole-brain analysis to define additional brain regions sensitive to fetal ethanol exposure. These results will facilitate data reduction for the combined analyses with other experimental modalities in Aims 2 and 3. Aim 2 will examine impairments in motor behavior due to fetal ethanol exposure and define the underlying neural circuitry. Aim 3 will define the impairments in cognitive function and emotional regulation induced by fetal ethanol exposure and identify the developmental processes and specific brain regions associated with these impairments.

项目摘要 胎儿暴露于酒精会导致广泛的神经缺陷统称为胎儿酒精 频谱障碍（FASD）。这种普遍的神经发育障碍目前影响多达1-5％ 美国的学龄儿童。现有的干预策略可以改善生活质量 受影响的人，但早期发现对于有效的治疗至关重要。在Utero MRI中，MRI受益于最近 3D图像重建中回顾性运动校正方法的改进，是一个有希望的非 - 用于识别与胎儿暴露于酒精有关的脑发育异常的侵入性技术。我们 最近开发了一种恒河猕猴的FASD模型，类似于妊娠早期饮酒， 在怀孕意识之前，识别怀孕后停止。脑生长异常显而易见 在妊娠日（g）135在恒河猕猴的胎儿中，口腔自我管理1.5 g/kg （大约6饮料）在怀孕的前60天内每天乙醇。与对照组相比 裸露的胎儿拥有较小的小脑和较少发达的白质纤维系统的大脑 参与运动和认知功能。在G135上进行的体内电生理记录 胎儿表明，MRI识别的异常与功能障碍有关 谷氨酸能传输。本应用程序中提出的实验将确定行为 这些解剖和功能异常的后果，并进一步扩展了MRI和 该FASD模型的电生理表征。每天暴露于每天暴露的十二个恒河猕猴 在妊娠的前60天，将母体1.5 g/kg乙醇饮用与12只对照动物进行比较。在 子宫MRI将在G135进行，后代将幸存到产后日（P）180（大约 6个月大）。将在P3和P180上进行其他MRI实验。该提议的目标1将 使用胎儿（G135）和产后MRI（P3和P180）来定义乙醇暴露对脑的长期影响 发展。该目标包括针对大脑结构的主要分析 G135和全脑分析，以定义对胎儿乙醇暴露敏感的其他大脑区域。这些 结果将促进AIM 2和AIM 2和其他实验方式的合并分析的数据降低 3. AIM 2将检查由于胎儿乙醇暴露而导致的运动行为障碍，并定义了基础 神经电路。 AIM 3将定义认知功能和情绪调节的损害 胎儿乙醇暴露并确定与 这些障碍。