Neuroanatomical/Functional Correlates in an FASD Model

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的个体中描述了大脑的结构和功能异常 综合征(FAS)/胎儿酒精光谱障碍(FASD)，我们对这些疾病的全面了解仍然存在差距 缺陷和预期的结构/功能相关性。跟进其他人以前的工作，以及 申请者最近的研究，这里提出的实验旨在检查早期 孕期暴露对大脑结构和功能的影响，并提供相关数据。总体而言，拟议工作将 检验这样一种假设：在妊娠早期(小鼠妊娠第8天；相当于第4天)接触酒精 人类受精后一周)导致脑畸形和神经功能缺陷的相关模式， 一直持续到成年。建议的工作将使用鼠标FASD模型，最先进的高分辨率磁力 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者的MRI/DTI技术、分析和解释外，这些实验 这份提案中概述的教育机会将极大地增强候选人对以下方面的了解和理解 设计用于表征神经功能表型的方法。成功完成这项工作的承诺是 由北卡罗来纳大学教堂山分校和杜克大学卓越的研究环境提供， FASD领域(K Sulik博士)、行为分析(S Moy博士)和成像领域专家的指导和协作 技术(DRS A Johnson和M Styner)，以及申请人以前的FASD研究经验。拥有 说明了高分辨率MRI在发现酒精诱导的胎鼠脑畸形中的作用(Parnell等人， 2009年)，拟议的工作将把这些分析扩展到出生后阶段。这项工作将通过以下方式进行： 次级假设和相关的特定目标如下：特定目标1将检验急性酒精的假设 暴露于GD8会对小鼠大脑的特定区域产生长期的形态影响。针对以下问题的实验 这一目标将利用高分辨率核磁共振，并将需要分析出生后12天、30天和90天的小鼠的大脑。 特定的AIM#2将测试这样的假设，即同样的酒精暴露范例将改变相互连接的神经 大脑的路径。将使用DTI对PD 12、30和90小鼠的大脑纤维束进行评估。特定目标#3 将检验急性GD8酒精暴露将导致青少年和成人神经功能异常的假设 与观察到的畸形相一致的小鼠。这些研究的结果将提供重要的数据 关于怀孕早期接触酒精的长期后果，并将毫无疑问地承诺通知FASD 诊断和预防工作。此外，本提案中描述的研究和培训将提供坚实的 为未来关于乙醇致畸的研究以及候选人追求职业生涯的目标奠定了基础 院士。

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.