High-resolution diffusion tensor imaging in mouse models relevant to autism

与自闭症相关的小鼠模型的高分辨率扩散张量成像

基本信息

批准号：
7935407
负责人：
Harish Poptani
金额：
$ 19.97万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7935407
关键词：
Amygdaloid structure Animal Model Animals Anisotropy Anxiety Area Autistic Disorder BALB/cJ Mouse Behavior Behavioral Behavioral Symptoms Biological Birth Brain Brain Diseases Candidate Disease Gene Cerebellum Controlled Environment Corpus Callosum Development Diagnosis Diagnostic Diffusion Magnetic Resonance Imaging Disease Exhibits FMR1 Family Study Fiber Follow-Up Studies Fragile X Syndrome Functional Imaging Functional Magnetic Resonance Imaging Gene Mutation Genes Genetic Hippocampus (Brain)Human Image Imaging Techniques Impairment Inbred Mouse Inbred Strain Inbred Strains Mice Knock-out Knockout Mice Laboratories Lead Measurement Measures Methodology Methods Metric Modeling Molecular Monitor Monozygotic Twinning Monozygotic twins Mouse Strains Mus Mutant Strains Mice Mutation Pathogenesis Pathology Patients Pattern Phenotype Physiological Posterior Commissure Property Protein Family Reporting Research Resolution Rett Syndrome Rodent Rodent Model Role Schizophrenia Social Behavior Social Interaction Stereotyped Behavior Structure Study models Surrogate Markers Testing Time Tissues Twin Multiple Birth autism spectrum disorder base behavior change behavior test brain size cost efficient early childhood emerging adult endophenotype gain of function human subject improved in vivo indexing mouse model mutant nervous system disorder neuroligin 3 relating to nervous system social social communication theories trait water diffusion white matter

项目摘要

DESCRIPTION (provided by applicant): Structural and functional imaging studies have significantly impacted our understanding of the neural basis of developmental and neurological disorders. However, despite recent advancements, anatomical imaging in autistic patients has generally revealed little evidence of pathology, except evidence of transient increase in brain size along with some evidence of reduced corpus callosum and cerebellum size. These anatomical features and some fMRI studies have hypothesized a state of disrupted connectivity in the autistic brain that may be responsible for the behavioral traits observed in autism. To test this hypothesis, and to better understand the mechanistic role of brain connectivity in autism-related behavioral phenotypes, we will employ diffusion tensor imaging (DTI) techniques in mouse models as a surrogate for better diagnosis of the disorder. While DTI has been extensively used in human subjects, it would be extremely useful to develop this methodology for rodents as the mouse is an excellent model to probe the relationship between brain structure and social/behavioral patterns in a well controlled environment and provides tissue for histological confirmation. While, a true animal model of autism may be impossible to achieve, both inbred mice and mice with specific genetic mutations have been suggested to exhibit some endophenotypical behaviors observed in autistic patients indicative of their utility as relevant models for studying autism spectrum disorders. We will study the DTI properties in an inbred (BALB/cJ) and a mutant (neuroligin-3) strain of mice as these models have been shown to exhibit multiple behavioral and brain phenotypes relevant to autism, including reduced sociability and underdevelopment of the corpus callosum. We will test the overall hypothesis that longitudinal changes in DTI parameters can detect specific anatomical disruptions that underlie autism-relevant behavioral phenotypes in mouse models. The following specific aims will be achieved in order to support this hypothesis: Aim 1: To determine the utility of DTI as surrogate markers for assessing developmental changes (from prepubescence to early adulthood) in brain connectivity and social-behavior patterns of BALB/cJ mice. Aim 2: To determine the correlation between DTI features and social behaviors associated with the Nl-3 gene knockin mice and their longitudinal changes over pubescence. Longitudinal in vivo DTI studies (from pre-pubescence to early adulthood) will be performed to measure the changes in DTI metrics from the brain using a voxel based analysis. Correlations between DTI metrics and sociability will be tested in each group. After each in vivo session, some mice will be sacrificed and brains will be isolated and high- resolution ex vivo DTI studies will be performed and correlated with histological measurements. Successful implementation of the DTI techniques in the mouse in vivo will not only be helpful in understanding the biological and physiological basis of autism spectrum disorders, but will also benefit studies of other mouse models of developmental and psychiatric brain disorders, such as schizophrenia. PUBLIC HEALTH RELEVANCE: In this proposal high-resolution diffusion tensor imaging of the mouse brain will be developed as surrogate markers to assess the social behavioral abnormalities in mouse models relevant to autism. Successful implementation of the proposed DTI techniques in these models will not only be helpful in understanding the biological and physiological basis of autism spectrum disorders, but will also benefit studies of other mouse models of developmental and psychiatric brain disorders, such as schizophrenia.

描述（由申请人提供）：结构和功能成像研究严重影响了我们对发育和神经系统疾病神经基础的理解。然而，尽管最近进步，自闭症患者的解剖学成像通常显示出病理学的证据很少，除了证据表明脑大小的短暂增加以及一些疾病的call体和小脑大小的证据。这些解剖学特征和一些功能磁共振成像的研究假设自闭症大脑中连通性的连通性中断状态，这可能是自闭症中观察到的行为特征的原因。为了检验这一假设，并更好地理解大脑连通性在自闭症相关行为表型中的机械作用，我们将在小鼠模型中采用扩散张量成像（DTI）技术，作为更好地诊断疾病的替代物。尽管DTI已在人类受试者中广泛使用，但为啮齿动物开发这种方法非常有用，因为小鼠是一个很好的模型，可以在良好的控制环境中探测大脑结构与社会/行为模式之间的关系，并为组织学确认提供组织。尽管可能无法实现真正的自闭症动物模型，但已经提出，具有特定遗传突变的近交小鼠和小鼠都表现出在自闭症患者中观察到的某些内型型行为，以表明其效用是研究自闭症谱系疾病的相关模型。我们将研究小鼠的近交（BALB/CJ）和突变体（Neuroligin-3）菌株中的DTI特性，因为这些模型已显示出与自闭症相关的多种行为和脑表型，包括降低社交性和collosusum callosum的开发不足。我们将测试总体假设，即DTI参数的纵向变化可以检测小鼠模型中与自闭症相关的行为表型的特定解剖学破坏。为了支持这一假设，将实现以下具体目标：目标1：确定DTI作为脑连通性和Balb/CJ小鼠的社会行为模式评估发育变化（从预次脱离到成年早期）的替代标记的效用。目标2：确定与NL-3基因敲击蛋白小鼠相关的DTI特征与社会行为之间的相关性，以及它们在短柔毛上的纵向变化。将使用基于体素的分析进行纵向体内DTI研究（从青春期前到成年早期），以测量大脑DTI指标的变化。 DTI指标与社交性之间的相关性将在每个组中进行测试。每次体内疗程后，将处死一些小鼠并将大脑分离，并将进行高分辨率的EX VIVO DTI研究，并与组织学测量结果相关。成功实施了体内小鼠中DTI技术的实施不仅有助于理解自闭症谱系疾病的生物学和生理基础，而且还将有益于对精神分裂症等发育和精神病脑疾病的其他小鼠模型的研究。公共卫生相关性：在此提案中，将开发出小鼠大脑的高分辨率扩散张量成像作为替代标记，以评估与自闭症相关的小鼠模型中的社会行为异常。这些模型中提出的DTI技术的成功实施不仅有助于理解自闭症谱系疾病的生物学和生理基础，而且还将有益于对精神分裂症等发育和精神病脑疾病的其他小鼠模型的研究。