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.

项目概要 胎儿接触酒精会导致一系列神经系统缺陷，统称为胎儿酒精 谱系障碍（FASD）。这种普遍存在的神经发育障碍目前影响多达 1-5% 的人 美国的学龄儿童。现有的干预策略可以改善人们的生活质量 受影响的个体，但早期发现对于有效治疗至关重要。子宫内 MRI 受益于最近的 3D 图像重建中回顾性运动校正方法的改进，是一种有前途的非 用于识别与胎儿接触酒精相关的异常大脑发育的侵入性技术。我们 最近开发了一种 FASD 的恒河猴模型，类似于人类在妊娠早期饮酒， 在意识到怀孕之前，但在确认怀孕后停止。大脑发育异常明显 妊娠日 (G)135 通过 MRI 对口服 1.5 g/kg 的恒河猴胎儿进行检测 （大约 6 杯）在怀孕的前 60 天内每天饮用乙醇。与对照相比，乙醇 暴露的胎儿的大脑小脑较小，白质纤维系统较不发达 参与运动和认知功能。在 G135 上进行的离体电生理记录 胎儿证明 MRI 识别的异常与胎儿的功能障碍有关 谷氨酸能传递。本申请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 MRI 和 该 FASD 模型的电生理学特征。十二只恒河猴每天暴露在 将在妊娠前 60 天饮用 1.5 g/kg 乙醇的母亲与 12 只对照动物进行比较。在 子宫 MRI 将在 G135 进行，后代将存活到出生后天 (P)180（大约 6个月大）。将在 P3 和 P180 上进行额外的 MRI 实验。该提案的目标 1 将 使用胎儿 (G135) 和产后 MRI（P3 和 P180）来确定乙醇暴露对大脑的长期影响 发展。该目标包括针对被识别为不同的大脑结构的主要分析。 G135 和全脑分析以确定对胎儿乙醇暴露敏感的其他大脑区域。这些 结果将有助于减少与目标 2 和其他实验方式的组合分析的数据 3. 目标 2 将检查由于胎儿乙醇暴露导致的运动行为损伤，并确定潜在的原因 神经回路。目标 3 将定义由以下因素引起的认知功能和情绪调节障碍： 胎儿乙醇暴露并确定与相关的发育过程和特定大脑区域 这些障碍。