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

描述（由申请人提供）：结构和功能成像研究显著影响了我们对发育和神经系统疾病神经基础的理解。然而，尽管最近取得了进展，自闭症患者的解剖成像通常显示很少的病理证据，除了大脑大小的短暂增加沿着胼胝体和小脑大小减少的证据。这些解剖学特征和一些功能磁共振成像研究假设自闭症患者大脑中的连接中断状态可能是导致自闭症患者行为特征的原因。为了验证这一假设，并更好地了解自闭症相关行为表型中大脑连接的机制作用，我们将在小鼠模型中采用弥散张量成像（DTI）技术作为更好诊断该疾病的替代品。虽然DTI已广泛用于人类受试者，但为啮齿动物开发这种方法将是非常有用的，因为小鼠是在良好控制的环境中探索脑结构与社会/行为模式之间关系的优秀模型，并提供组织学确认。虽然，真正的自闭症动物模型可能是不可能实现的，但近交系小鼠和具有特定基因突变的小鼠都被认为表现出在自闭症患者中观察到的一些内表型行为，表明它们作为研究自闭症谱系障碍的相关模型的实用性。我们将研究近交系（BALB/cJ）和突变（neuroligin-3）小鼠品系的DTI特性，因为这些模型已被证明表现出与自闭症相关的多种行为和大脑表型，包括社交能力降低和胼胝体发育不全。我们将测试的整体假设，DTI参数的纵向变化可以检测特定的解剖结构的破坏，孤独症相关的行为表型在小鼠模型的基础。为了支持这一假设，将实现以下具体目标：目的1：确定DTI作为替代标记物的效用，用于评估BALB/cJ小鼠脑连接和社会行为模式的发育变化（从青春期前到成年早期）。目标二：目的探讨N1 -3基因敲入小鼠的DTI特征与其社会行为的相关性及其在青春期的纵向变化。将进行纵向体内DTI研究（从青春期前到成年早期），以使用基于体素的分析测量大脑DTI指标的变化。将在每组中测试DTI指标和社交能力之间的相关性。在每个体内阶段后，将处死一些小鼠，分离脑，进行高分辨率离体DTI研究，并与组织学测量相关联。在小鼠体内成功实施DTI技术不仅有助于理解自闭症谱系障碍的生物学和生理学基础，而且还将有利于对其他发育和精神脑疾病（如精神分裂症）小鼠模型的研究。公共卫生相关性：在这项提案中，高分辨率的扩散张量成像的小鼠大脑将被开发作为替代标记，以评估社会行为异常的小鼠模型相关的自闭症。在这些模型中成功实施拟议的DTI技术不仅有助于理解自闭症谱系障碍的生物学和生理学基础，而且还将有利于其他发育和精神脑障碍（如精神分裂症）小鼠模型的研究。

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.