NEUROANATOMICAL/FUNCTIONAL CORRELATES IN FASD MODEL

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 产前酒精暴露最常见但也是毁灭性的影响之一是那些涉及到发育中的大脑的影响。虽然在患有胎儿酒精综合征(FAS)/胎儿酒精谱系障碍(FASD)的个体中描述了大脑的结构和功能异常，但在我们对这些缺陷的全面范围以及预期的结构/功能相关性的理解方面仍然存在差距。在前人工作的基础上，以及申请人最近的研究，本文提出的实验旨在研究早期妊娠暴露对大脑结构和功能的长期影响，并提供相关数据。总体而言，这项拟议的工作将检验这样一种假设，即在早期妊娠阶段(小鼠怀孕第8天；相当于人类受精后第四周)接触乙醇会导致持续到成年的大脑畸形和神经功能缺陷的相关模式。这项拟议的工作将使用小鼠FASD模型、最先进的高分辨率磁共振成像(MRI)、扩散张量成像(DTI)以及一系列认知、感觉、运动和其他行为测试。除了进一步培训申请人的MRI/DTI技术，分析和解释，这项建议中概述的实验和教育机会将极大地提高候选人的知识和对旨在表征神经功能表型的方法的理解。北卡罗来纳大学教堂山分校和杜克大学卓越的研究环境、FASD领域专家(K Sulik博士)、行为分析专家(S Moy博士)和成像技术专家(DRS A Johnson和M Styner博士)的指导和合作，以及申请人以前的FASD研究经验，为成功完成这项工作提供了承诺。在说明了高分辨率MRI在发现酒精诱导的胎鼠脑畸形方面的作用后(Parnell等人，2009年)，拟议的工作将把这些分析扩展到出生后阶段。这项工作将通过解决3个子假设和相关的具体目标如下进行：特定目的#1将测试假设，即急性乙醇暴露于GD 8将对小鼠大脑的特定区域产生长期的形态影响。为此目的的实验将利用高分辨率核磁共振，并需要对出生后12天、30天和90天的小鼠的大脑进行分析。《特定目标2》将测试这一假设，即同样的酒精暴露范例将改变大脑相互连接的神经通路。将使用DTI对PD 12、30和90小鼠的大脑纤维束进行评估。特定的AIM#3将测试这样的假设，即急性GD8酒精暴露将导致青春期和成年鼠的神经功能异常，这与观察到的畸形形态一致。这些研究的结果将提供有关妊娠早期酒精暴露的长期后果的重要数据，并无疑将有望为FASD的诊断和预防工作提供信息。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Among the most common, yet devastating, effects of prenatal ethanol exposure are those that involve the developing brain. While both structural and functional abnormalities of the brain have been described in individuals with Fetal Alcohol Syndrome (FAS)/Fetal Alcohol Spectrum Disorders (FASD), gaps remain in our understanding of the full range of these defects and of expected structural/functional correlates. Following up on the previous work of others, as well as the applicant's recent research, the experiments proposed herein are designed to examine the long-term effects of early gestational exposure on both brain structure and function and to provide correlative data. Overall, the proposed work will test the hypothesis that ethanol exposure at early gestational stages (gestational day [GD] 8 in mice; equivalent to the fourth week post fertilization in humans) results in a correlative pattern of brain dysmorphology and neurofunctional deficits that persists into adulthood. The proposed work will employ a mouse FASD model, state of the art high-resolution Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), and a battery of cognitive, sensory, motor and other behavioral tests. In addition to furthering the applicant's training in MRI/DTI techniques, analyses and interpretation, the experiments and educational opportunities outlined in this proposal will greatly enhance the candidate's knowledge and understanding of methods designed to characterize neurofunctional phenotypes. Promise for the successful completion of this work is provided by the exceptional research environment of the University of North Carolina  Chapel Hill and of Duke University, mentorship by and collaboration with experts in the FASD field (Dr. K Sulik), behavioral analyses (Dr. S Moy), and imaging technologies (Drs A Johnson and M Styner), as well as the applicant's previous FASD research experience. Having illustrated the utility of high resolution MRI for discovery of ethanol-induced brain dysmorphology in fetal mice (Parnell et al, 2009), the proposed work will extend these analyses into postnatal stages. This work will be conducted by addressing 3 sub-hypotheses and the associated specific aims as follows: SPECIFIC AIM #1 will test the hypothesis that acute ethanol exposure on GD 8 will produce long-term morphological effects on specific regions of the mouse brain. The experiments for this aim will utilize high-resolution MRI and will entail analyses of the brains of postnatal day (PD) 12, 30, and 90 mice. SPECIFIC AIM #2 will test the hypothesis that this same ethanol exposure paradigm will alter the interconnecting neural pathways of the brain. Fiber tracts of the brains of PD 12, 30, and 90 mice will be assessed utilizing DTI. SPECIFIC AIM #3 will test the hypothesis that acute GD 8 ethanol exposure will result in neurofunctional abnormalities in adolescent and adult mice that are consistent with the observed dysmorphology. The results of these studies will provide important data regarding the long-term consequences of early gestational ethanol exposure and will, undoubtedly, promise to inform FASD diagnosis and prevention efforts.