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

描述(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障碍的神经基础的理解。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出很少的病理证据，除了有证据表明大脑大小一过性增加，以及一些证据表明穹隆体部和小脑大小缩小。这些解剖特征和一些功能磁共振研究假设自闭症患者大脑中的连接中断状态，这可能是自闭症患者观察到的行为特征的原因。为了验证这一假设，并更好地了解大脑连接在自闭症相关行为表型中的机制作用，我们将在小鼠模型中使用扩散张量成像(DTI)技术作为替代，以更好地诊断这种疾病。虽然DTI在人类受试者中得到了广泛的应用，但对于啮齿类动物来说，开发这一方法学将是非常有用的，因为小鼠是在受控良好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，并为组织学证实提供组织。虽然，自闭症的真实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，这表明它们作为研究自闭症谱系障碍的相关模型是有用的。我们将研究近交系小鼠(BALB/CJ)和突变小鼠(神经连接蛋白-3)的DTI特性，因为这些模型已被证明显示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良。我们将测试总体假设，即DTI参数的纵向变化可以检测到小鼠模型中与自闭症相关的行为表型背后的特定解剖破坏。为了支持这一假说，将实现以下特定目标：目标1：确定DTI作为替代标记物用于评估BALB/CJ小鼠大脑连通性和社会行为模式的发育变化(从青春期前到成年期早期)。目的：探讨NL-3基因敲击小鼠的DTI特征与社会行为的相关性及其在青春期的纵向变化。将进行纵向的体内DTI研究(从青春期前到成年早期)，以使用基于体素的分析来测量大脑DTI指标的变化。DTI指标和社交能力之间的相关性将在每组中进行测试。在每一次体内实验后，将处死一些小鼠，分离大脑，进行高分辨率的体外DTI研究，并与组织学测量相关联。DTI技术在小鼠体内的成功应用，不仅有助于了解自闭症谱系障碍的生物学和生理学基础，还将有助于其他发育和精神障碍小鼠模型的研究，如精神分裂症。与公共健康相关：在这项建议中，将开发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。在这些模型中成功实施所提出的DTI技术不仅将有助于了解自闭症谱系障碍的生物学和生理学基础，而且还将有助于对其他发育和精神性脑疾病模型的研究，如精神分裂症。

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.