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

项目总结 胎儿接触酒精会导致广泛的神经功能障碍，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老年人的生活质量 但早期发现是有效治疗的关键。宫内磁共振受益于最近的 对三维图像重建中回溯性运动校正方法的改进，是一种很有前途的非 用于识别与胎儿酒精暴露相关的大脑发育异常的侵入性技术。我们 最近开发出一种恒河猴FASD模型，类似于人类在怀孕早期饮酒， 在意识到怀孕之前，但在意识到怀孕时停止。大脑发育异常是显而易见的 孕期(G)135天口服1.5g/kg猕猴胎儿的MRI研究 (约6杯)怀孕前60天每日饮用酒精。与对照组相比，乙醇- 暴露的胎儿大脑较小，白质纤维系统发育较差 与运动和认知功能有关。G135的体外电生理记录 胎儿证明，核磁共振识别的异常与功能性损害有关 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，并进一步扩大MRI和 这种FASD模型的电生理特征。12只恒河猴每日暴露于 孕妇在怀孕前60天饮用1.5g/kg酒精将与12只对照组动物进行比较。在……里面 子宫核磁共振将在G135进行，后代将存活到出生后(P)180天(大约 6个月大)。将在P3和P180上进行更多的MRI实验。本提案的目标1将 使用胎儿(G135)和出生后MRI(P3和P180)来确定酒精暴露对大脑的长期影响 发展。这一目标包括一项主要分析，重点放在被确定为不同于 G135和全脑分析，以确定额外的大脑区域对胎儿酒精暴露敏感。这些 结果将有助于AIMS 2和AIMS中与其他实验模式相结合的分析的数据简化 3.目标2将检查胎儿酒精暴露造成的运动行为障碍，并确定潜在的 神经回路。目标3将定义以下因素引起的认知功能和情绪调节障碍 并确定胎儿酒精暴露的发育过程和特定的脑区 这些损伤。

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.