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极大地影响了我们对发育和神经疾病的神经基础的理解。然而，尽管最近取得了进展，但自闭症患者的解剖成像通常显示的病理证据很少，除了有证据表明大脑大小短暂增加以及胼胝体和小脑大小的一些证据。这些解剖特征和一些功能磁共振成像研究假设自闭症大脑中存在一种连接中断的状态，这可能是自闭症中观察到的行为特征的原因。为了验证这一假设，并更好地理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弥散张量成像（DTI）技术作为更好地诊断该疾病的替代方法。虽然DTI已广泛应用于人类受试者，但将这种方法应用于啮齿类动物将非常有用，因为小鼠是在良好控制的环境中探索大脑结构与社会/行为模式之间关系的绝佳模型，并为组织学证实提供了组织。然而，一个真正的自闭症动物模型可能是不可能实现的，近亲繁殖的小鼠和具有特定基因突变的小鼠都被认为表现出一些在自闭症患者中观察到的内表型行为，这表明它们作为研究自闭症谱系障碍的相关模型的效用。我们将研究近交系（BALB/cJ）和突变型（神经胶质素-3）小鼠的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，包括社交能力下降和胼胝体发育不足。我们将在小鼠模型中检验DTI参数的纵向变化可以检测自闭症相关行为表型基础上的特定解剖破坏的总体假设。目的1：确定DTI作为评估BALB/cJ小鼠大脑连通性和社会行为模式的发育变化（从青春期前到成年早期）的替代标记物的效用。目的2：确定Nl-3基因敲入小鼠DTI特征与社会行为的相关性及其在青春期的纵向变化。纵向体内DTI研究（从青春期前到成年早期）将使用基于体素的分析来测量大脑DTI指标的变化。DTI指标与社交能力之间的相关性将在每个小组中进行测试。每次体内实验结束后，将处死部分小鼠，分离其大脑，进行高分辨率的离体DTI研究，并与组织学测量相关联。DTI技术在小鼠体内的成功实施，不仅有助于理解自闭症谱系障碍的生物学和生理学基础，也将有利于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：在本提案中，将开发小鼠大脑的高分辨率弥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，而且还将有益于其他发育和精神脑疾病（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.