Neurobiology of sociability in a mouse model system relevant to autism

描述(申请人提供)：社会神经科学的一个中心目标是阐明社会性(寻求社会互动的倾向)的神经生物学。自闭症谱系障碍的特征是严重丧失社交能力，这在儿童时期最为显著。在极少数的自闭症患者中，复制良好的神经解剖学表型包括：1)大脑异常增大(最明显的是在儿童时期)，以及2)胼胝体发育不良。这些解剖表型被假设导致大脑功能连接不足，这可能是自闭症行为症状的基础。近交系小鼠在社会行为和大脑发育方面的差异为检验与自闭症相关的这些行为和大脑内表型之间的关系的假设提供了机会，并确定了遗传和环境因素对表型的影响。来自Brodkin实验室和其他研究小组的数据表明，与C57BL/6J近交系小鼠相比，BALB/CJ近交系小鼠表现出一种普遍的模式，即低社交能力；异常大的大脑；以及未发育或缺乏胼胝体(在40%的BALB/CJ小鼠中)。在小鼠模型中，对社会行为和大脑发育的发育变异研究相对较少，但鉴于自闭症发育变异的重要性，这样的研究是必要的。我们在这里建议使用BALB/c和C57BL/6J菌株来开展社会行为的发育研究，包括对与自闭症相关的社会行为的详细分析。我们还将评估与自闭症相关的社会行为和大脑发育内表型之间的可能联系。具体目标：1。社会行为发展分析。我们将检验这一假设，即相对于C57BL/6J小鼠，BALB/CJ小鼠表现出社交能力降低，尤其是在青春期前。我们将测试社交能力和焦虑相关行为之间的关系。2.脑大小和穹隆大小与社会行为关系的发育分析。我们将检验这一假设，即相对于C57BL/6J小鼠，BALB/CJ小鼠在青春期前(社交能力最差的时候)表现出最明显的脑肿大，其模式类似于自闭症。在BALB/CJ品系中，我们还将检验这样一种假设，即胼胝体大小与社交能力呈正相关。3.遗传和环境因素对社会行为和脑表型的影响。在来自BALB/CJ和C57BL/6J小鼠的F1和F2群体中，将测量社会行为的遗传力、胼胝体大小和脑大小。将测量行为和大脑表型之间的遗传相关性。环境对这些性状的影响将在交叉培养实验中进行测量。通过测试与自闭症相关的社会行为和大脑表型之间的关系，这些研究可能为未来关于自闭症社交能力障碍的临床和基础研究确定有希望的方向。

DESCRIPTION (provided by applicant): A central goal of social neuroscience is to elucidate the neurobiology of sociability (the tendency to seek social interaction). Autism spectrum disorders are characterized by a profoundly disabling reduction in sociability, which is most striking in childhood. Among the very few, well-replicated neuroanatomical phenotypes in autism are 1) abnormally enlarged brains (most pronounced in childhood), and 2) underdevelopment of the corpus callosum. These anatomical phenotypes have been hypothesized to lead to functional underconnectivity of the brain that may underlie the behavioral symptoms of autism. Variation between inbred mouse strains in social behaviors and brain development provides an opportunity to test hypotheses about relationships among these behavioral and brain endophenotypes relevant to autism, and to identify the impact of genetic and environmental factors on the phenotypes. Data from the Brodkin lab and other groups indicate that, in contrast to the C57BL/6J inbred strain, the BALB/cJ inbred mouse strain shows a pervasive pattern of low sociability; unusually large brain size; and underdevelopment or absence of the corpus callosum (in 40 percent of BALB/cJ mice). Developmental variations in social behaviors and brain growth have been relatively understudied in mouse models, but such studies are needed, given the importance of developmental variations in autism. We propose here to use the BALB/c and C57BL/6J strains to carry out developmental studies of social behaviors, including detailed analyses of social behaviors that are relevant to autism. We will also evaluate possible links among social behavior and brain development endophenotypes relevant to autism. Specific Aims: 1. Developmental analysis of social behaviors. We will test the hypothesis that, relative to C57BL/6J mice, BALB/cJ mice show reduced sociability that is especially pronounced in prepubescence. The relationship between sociability and anxiety-related behaviors will be tested. 2. Developmental analysis of brain size and corpus callosum size in relation to social behaviors. We will test the hypothesis that, relative to C57BL/6J mice, BALB/cJ mice show the most pronounced enlargement of brain in prepubescence (at the time of most reduced sociability), in a pattern similar to that seen in autism. We will also test the hypothesis that corpus callosum size is positively correlated with sociability within the BALB/cJ strain. 3. The effects of genetic and environmental factors on social behaviors and brain phenotypes. In an F1 and F2 population derived from BALB/cJ and C57BL/6J mice, the heritability of social behaviors, corpus callosum size, and brain size will be measured. Genetic correlations among the behavioral and brain phenotypes will be measured. Environmental influences on the traits will be measured in a cross-fostering experiment. By testing the relationships among social behavior and brain phenotypes relevant to autism, these studies may identify promising directions for future clinical and basic research on sociability impairments in autism.