Neurobiology of sociability in a mouse model system relevant to autism

描述（由申请人提供）：社会神经科学的中心目标是阐明社交性（寻求社会互动的倾向）的神经生物学。自闭症谱系障碍的特点是社交能力严重下降，这在儿童时期最为明显。在少数几个自闭症的神经解剖学表型中，复制良好的有：1)大脑异常增大（在儿童时期最为明显）；2)胼胝体发育不全。这些解剖表型被假设为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行为和大脑内表型之间关系的假设提供了机会，并确定遗传和环境因素对表型的影响。来自Brodkin实验室和其他小组的数据表明，与C57BL/6J自交系相比，BALB/cJ自交系小鼠表现出普遍的低社交模式；异常大的脑容量；以及胼胝体发育不全或缺失（40%的BALB/cJ小鼠）。在小鼠模型中，社会行为和大脑发育的发育变异研究相对不足，但考虑到自闭症发育变异的重要性，这样的研究是必要的。我们建议利用BALB/c和C57BL/6J菌株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进行详细分析。我们还将评估社会行为和大脑发育与自闭症相关的内表型之间可能存在的联系。具体目标：1；社会行为的发展分析。我们将验证这样的假设，即相对于C57BL/6J小鼠，BALB/cJ小鼠在青春期前表现出更低的社交能力。社交能力和焦虑相关行为之间的关系将被测试。2. 脑大小和胼胝体大小与社会行为关系的发育分析。我们将测试这样一个假设，即相对于C57BL/6J小鼠，BALB/cJ小鼠在青春期前（社交能力最弱的时候）的大脑发育最为明显，其模式与自闭症相似。我们还将测试在BALB/cJ菌株中胼胝体大小与社交能力正相关的假设。3. 遗传和环境因素对社会行为和脑表型的影响。在BALB/cJ和C57BL/6J小鼠的F1和F2群体中，将测量社会行为、胼胝体大小和脑大小的遗传力。将测量行为和大脑表型之间的遗传相关性。环境对性状的影响将在交叉培养实验中测量。通过对社会行为与自闭症相关脑表型之间关系的检验，这些研究可能为未来自闭症社交障碍的临床和基础研究指明有希望的方向。

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.