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

项目摘要 胎儿暴露于酒精导致广泛的神经功能缺损统称为胎儿酒精 谱系障碍（FASD）。这种普遍的神经发育障碍目前影响多达1-5%的 美国的学龄儿童。现有的干预策略可以改善生活质量， 受影响的个体，但早期发现是有效治疗的关键。子宫内MRI受益于最近 在3D图像重建中回顾性运动校正方法的改进，并且是一种有前途的非运动校正方法。 一种侵入性技术，用于识别与胎儿暴露于酒精相关的异常大脑发育。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，但在意识到怀孕后停止。大脑发育异常很明显 经口自我给药1.5 g/kg的恒河猴胎仔在妊娠第135天（G）的MRI 在怀孕的前60天，每天喝大约6杯乙醇。与对照组相比，乙醇- 暴露的胎儿具有较小的小脑和较不发达的白色纤维系统 参与运动和认知功能。在G135上进行的离体电生理记录 胎儿表明MRI鉴定的异常与胎儿的功能障碍有关， 电磁波传输。在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，并进一步扩大MRI和 该FASD模型的电生理特征。12只恒河猴每天暴露在 将在妊娠前60天饮用1.5 g/kg乙醇的母体与12只对照动物进行比较。在 将在G135进行子宫MRI，并且后代将存活至出生后（P）180天（约 6个月）。将对P3和P180进行额外的MRI实验。本提案的目标1将 使用胎儿（G135）和出生后MRI（P3和P180）确定乙醇暴露对大脑的长期影响 发展该目标包括主要分析，重点是确定不同的大脑结构， G135和全脑分析，以确定对胎儿乙醇暴露敏感的其他脑区。这些 结果将有助于与目标2中的其他实验模式进行组合分析的数据简化， 3.目标2将检查由于胎儿乙醇暴露引起的运动行为障碍，并确定潜在的 神经回路目标3将定义认知功能和情绪调节的损害， 胎儿乙醇暴露，并确定发育过程和特定的大脑区域与 这些缺陷。

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.