Neuroanatomical/Functional Correlates in an FASD Model

描述（由申请人提供）：在最常见的，但毁灭性的，产前乙醇暴露的影响是那些涉及到发育中的大脑。虽然胎儿酒精综合征(FAS)/胎儿酒精谱系障碍（FASD）患者的大脑结构和功能异常已经被描述，但我们对这些缺陷的全部范围以及预期的结构/功能相关性的理解仍然存在空白。在前人研究和申请人近期研究的基础上，本文提出的实验旨在研究妊娠早期暴露对大脑结构和功能的长期影响，并提供相关数据。总的来说，本研究将验证妊娠早期（小鼠妊娠期[GD] 8，相当于人类受精后第四周）乙醇暴露会导致持续到成年期的脑畸形和神经功能缺陷的相关模式。这项工作将采用小鼠FASD模型、最先进的高分辨率磁共振成像（MRI）、弥散张量成像（DTI），以及一系列认知、感觉、运动和其他行为测试。除了进一步加强申请人在MRI/DTI技术，分析和解释方面的培训外，本提案中概述的实验和教育机会将大大提高候选人对设计表征神经功能表型的方法的知识和理解。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（S Moy博士）和成像技术（A Johnson博士和M Styner博士）的指导和合作，以及申请人以前的FASD研究经验，为这项工作的成功完成提供了希望。在阐释了高分辨率MRI在发现乙醇诱导的胎儿小鼠脑畸形方面的效用之后（Parnell等人，2009），这项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来进行：具体目标#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形态学影响。为此目的的实验将利用高分辨率核磁共振成像，并将对出生后12、30和90只小鼠的大脑进行分析。SPECIFIC AIM #2将测试同样的乙醇暴露模式将改变大脑相互连接的神经通路的假设。PD 12、PD 30和PD 90小鼠的大脑纤维束将利用DTI进行评估。SPECIFIC AIM #3将测试急性GD 8乙醇暴露将导致青春期和成年小鼠神经功能异常的假设，这与观察到的畸形相一致。这些研究的结果将提供关于妊娠早期乙醇暴露的长期后果的重要数据，毫无疑问，将为FASD的诊断和预防工作提供信息。此外，本提案中描述的研究和培训将为未来关于乙醇致畸的研究和候选人追求院士职业生涯的目标奠定坚实的基础。

DESCRIPTION (provided by applicant): 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. Additionally, the research and training described in this proposal will provide a solid foundation for both future studies regarding ethanol's teratogenesis, and the candidate's goal of pursuing a career as an academician. PUBLIC HEALTH RELEVANCE: The experiments in this project will use MRI and behavioral tests to examine the effects of ethanol during early pregnancy in a mouse model of Fetal Alcohol Spectrum Disorders (FASD). The goal of this work is to increase our understanding of the spectrum of ethanol's effects in order to aid in the prevention and better diagnosis of FASD.