Neuroanatomical/Functional Correlates in an FASD Model

FASD 模型中的神经解剖学/功能相关性

• 批准号: 8016629
• 负责人: Scott Parnell
• 金额: $ 9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016629
• 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; public health relevance; pup; research study

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.

描述（由申请人提供）：产前乙醇暴露最常见但最具破坏性的影响之一是涉及发育中的大脑。虽然胎儿酒精综合症 (FAS)/胎儿酒精谱系障碍 (FASD) 患者的大脑结构和功能异常均已被描述，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差距。继其他人之前的工作以及申请人最近的研究之后，本文提出的实验旨在检查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；相当于人类受精后第四周）接触乙醇会导致大脑畸形和神经功能缺陷的相关模式，并持续到成年期。拟议的工作将采用小鼠 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极大地增强申请人对旨在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 和 M Styner 博士）的指导和合作，以及申请人之前的 FASD 研究经验，为成功完成这项工作提供了保证。阐述了高分辨率 MRI 在发现乙醇诱导的胎儿小鼠大脑畸形方面的效用（Parnell 等人，2009），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来进行，如下所示： 具体目标 #1 将测试 GD 8 急性乙醇暴露将对小鼠大脑特定区域产生长期形态学影响的假设。为此目的的实验将利用高分辨率 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：相同的乙醇暴露范例将改变大脑的互连神经通路。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 将检验以下假设：急性 GD 8 乙醇暴露将导致青少年和成年小鼠神经功能异常，这与观察到的形态异常一致。这些研究的结果将提供有关妊娠早期乙醇暴露的长期后果的重要数据，并且无疑将为 FASD 的诊断和预防工作提供信息。此外，该提案中描述的研究和培训将为未来有关乙醇致畸的研究以及候选人追求院士职业的目标提供坚实的基础。 公共健康相关性：该项目的实验将使用 MRI 和行为测试来检查乙醇对胎儿酒精谱系障碍 (FASD) 小鼠模型在妊娠早期的影响。这项工作的目标是加深我们对乙醇影响范围的了解，以帮助预防和更好地诊断 FASD。