Neuroanatomical/Functional Correlates in an FASD Model

产前酒精暴露最常见但最具破坏性的影响是涉及发育中的大脑。 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）/胎儿酒精谱系障碍（FASD），我们对这些疾病的全面理解仍存在差距。 缺陷和预期的结构/功能相关性。对其他人以前的工作以及 根据申请人最近的研究，本文提出的实验被设计为检查早期抗肿瘤治疗的长期效果。 妊娠期暴露对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 检验妊娠早期乙醇暴露（小鼠妊娠第8天[GD];相当于第4天） 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。拟议的工作将采用小鼠FASD模型，最先进的高分辨率磁 磁共振成像（MRI）、弥散张量成像（DTI）以及一系列认知、感觉、运动和其他行为检查。 试验.除了进一步培训申请人的MRI/DTI技术，分析和解释，实验 本建议书中概述的教育机会将大大提高候选人的知识和理解， 设计用于表征神经功能表型的方法。为保证这项工作的顺利完成， 由北卡罗来纳州-查佩尔山大学和杜克大学的特殊研究环境提供， 由FASD领域（K Sulik博士）、行为分析（S Moy博士）和成像领域的专家指导和合作 技术（Drs A约翰逊和M Styner），以及申请人以前的FASD研究经验。具有 举例说明了高分辨率MRI用于发现胎儿小鼠中乙醇诱导的脑畸形的效用（帕内尔等人， 2009年），拟议的工作将把这些分析扩展到产后阶段。这项工作将通过解决3 子假设和相关的具体目标如下：具体目标#1将检验急性乙醇 GD 8的暴露将对小鼠大脑的特定区域产生长期的形态学影响。的实验 这一目标将利用高分辨率MRI，并需要分析出生后12天、30天和90天的小鼠的大脑。 具体目标#2将检验这一假设，即相同的乙醇暴露范式将改变互连的神经元。 大脑的路径。将使用DTI评估PD 12、30和90小鼠的脑纤维束。具体目标#3 将检验急性GD 8乙醇暴露将导致青少年和成人神经功能异常的假设 与观察到的畸形学一致的小鼠。这些研究的结果将提供重要的数据 关于早期妊娠乙醇暴露的长期后果，毫无疑问，将承诺告知FASD 诊断和预防工作。此外，本提案中所述的研究和培训将提供一个坚实的 这是未来研究乙醇致畸作用的基础，也是候选人追求职业生涯的目标。 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.