Neurobiology of sociability in a mouse model system relevant to autism

与自闭症相关的小鼠模型系统社交能力的神经生物学

• 批准号: 7290850
• 负责人: EDWARD S BRODKIN
• 金额: $ 35.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290850
• 关键词: Age; Anxiety; Autistic Disorder; BALB/cJ Mouse; Basic Science; Behavior; Behavioral; Behavioral Symptoms; Biological Models; Brain; Childhood; Clinical; Corpus Callosum; Crossbreeding; Data; Development; Employee Strikes; Environmental Risk Factor; Fostering; Future; Genetic; Goals; Growth; Heritability; Home environment; Hybrids; Impairment; Inbred BALB C Mice; Inbred Strain; Inbred Strains Mice; Individual; Lead; Link; Magnetic Resonance Imaging; Measures; Memory; Mus; Neurobiology; Pattern; Phenotype; Population; Puberty; Relative (related person); Resources; Social Behavior; Social Interaction; Staging; Testing; Time; Variant; Weight; autism spectrum disorder; behavior test; brain size; brain volume; endophenotype; mouse model; postnatal; research study; size; social; social neuroscience; trait

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.

描述（由申请人提供）：社会神经科学的一个中心目标是阐明社会性的神经生物学（寻求社会互动的倾向）。自闭症谱系障碍的特征是社交能力严重下降，这在儿童时期最为明显。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）异常增大的大脑（在儿童时期最明显）; 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。近交系小鼠品系之间的社会行为和大脑发育的变化提供了一个机会，以测试这些行为和大脑内表型相关的自闭症之间的关系的假设，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C57 BL/6 J近交系小鼠相比，BALB/cJ近交系小鼠表现出普遍的低社交性模式;异常大的大脑尺寸;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相对来说研究得不够，但是考虑到自闭症发育变异的重要性，这样的研究是必要的。我们建议使用BALB/c和C57 BL/6 J品系进行社会行为的发展研究，包括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在表型之间的可能联系。具体目标：1。社会行为的发展分析。我们将测试的假设，相对于C57 BL/6 J小鼠，BALB/cJ小鼠表现出减少的社会性，尤其是在青春期前明显。将测试社交能力和焦虑相关行为之间的关系。2.大脑大小和胼胝体大小与社会行为关系的发育分析。我们将测试的假设，相对于C57 BL/6 J小鼠，BALB/cJ小鼠表现出最明显的大脑在青春期前（在最减少的社交时间），在一个模式类似于自闭症中看到的扩大。我们还将测试的假设，胼胝体的大小是呈正相关的BALB/cJ株内的社交能力。3.遗传和环境因素对社会行为和大脑表型的影响。在来自BALB/cJ和C57 BL/6 J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率。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。通过测试自闭症相关的社会行为和大脑表型之间的关系，这些研究可能会为未来自闭症社交障碍的临床和基础研究确定有前途的方向。