Neuroanatomical/Functional Correlates in an FASD Model

FASD 模型中的神经解剖学/功能相关性

基本信息

批准号：
8705968
负责人：
Scott Parnell
金额：
$ 23.38万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705968
关键词：
Acute Address Adolescence Adolescent Adult Adverse effects Attention Behavioral Biological Markers Birth Brain Brain region Cerebellum Cognitive Collaborations Corpus Callosum Data Defect Development Diagnosis Diffusion Magnetic Resonance Imaging Disease model Dose Dysmorphology Embryo Environment Ethanol Exhibits Exposure to Eye Fertilization Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome Fiber First Pregnancy Trimester Foundations Future Goals Growth Hippocampus (Brain)Human Imaging Techniques Imaging technology Individual Knowledge Learning Literature Long-Term Effects Magnetic Resonance Imaging Mentorship Methods Motor Mus Nervous system structure Neural Pathways North Carolina Pathology Pathway interactions Pattern Phenotype Pregnancy Prevention Reporting Research Research Training Resolution Sensory Severities Solid Specimen Staging Structure Testing Time Training Universities Work alcohol effect alcohol exposure behavior test brain pathway brain tract career design experience fetal mouse model offspring postnatal prenatal pup research study

项目摘要

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.

产前接触乙醇最常见但具有破坏性的影响之一是涉及发育中的大脑。虽然胎儿酒精患者的大脑结构和功能均出现异常综合症（FAS）/胎儿酒精谱系障碍（FASD），我们对这些综合症的全面理解仍然存在差距缺陷和预期的结构/功能相关性。跟进其他人之前的工作以及申请人最近的研究，本文提出的实验旨在检查早期的长期影响妊娠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，拟议的工作将检验以下假设：妊娠早期（小鼠妊娠第 8 天；相当于第四个人类受精后一周）会导致大脑畸形和神经功能缺陷的相关模式持续到成年。拟议的工作将采用小鼠 FASD 模型，即最先进的高分辨率磁性共振成像 (MRI)、弥散张量成像 (DTI) 以及一系列认知、感觉、运动和其他行为成像测试。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，实验本提案中概述的教育机会将极大地增强候选人的知识和理解旨在表征神经功能表型的方法。承诺圆满完成此项工作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）和影像学领域专家的指导和合作技术（A Johnson 博士和 M Styner 博士），以及申请人之前的 FASD 研究经验。拥有说明了高分辨率 MRI 在发现乙醇诱导的胎儿小鼠脑部畸形方面的用途（Parnell 等人， 2009），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 将检验以下假设：急性乙醇暴露于 GD 8 会对小鼠大脑的特定区域产生长期的形态学影响。实验为该目标将利用高分辨率 MRI，并对出生后 (PD) 12、30 和 90 只小鼠的大脑进行分析。具体目标 #2 将测试以下假设：相同的乙醇暴露范式将改变互连的神经元大脑的通路。将利用 DTI 评估 PD 12、30 和 90 只小鼠的大脑纤维束。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一致的小鼠。这些研究结果将提供重要数据关于妊娠早期乙醇暴露的长期后果，毫无疑问，我们承诺告知 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基础为未来有关乙醇致畸的研究以及候选人追求职业生涯的目标奠定基础院士。