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）：社会神经科学的核心目标是阐明社交性神经生物学（寻求社会互动的趋势）。自闭症谱系障碍的特征是社交性的严重降低，这在童年时期最为惊人。在很少的自闭症中，自闭症中良好复制的神经解剖表型是1）异常肿大的大脑（在儿童时期最为明显），而2）call体的发育不足。这些解剖表型已被认为会导致大脑的功能不足，这可能是自闭症行为症状的基础。社会行为和大脑发育中的近交小鼠菌株之间的变化为测试与自闭症相关的行为和脑内跨表型之间的关系的假设，并确定遗传和环境因素对表型的影响。来自Brodkin实验室和其他组的数据表明，与C57BL/6J近交菌株相比，BALB/CJ近交小鼠菌株显示出低社交性的普遍模式。大脑大小异常大；以及call体的欠发达或缺失（在40％的BALB/CJ小鼠中）。在小鼠模型中，社会行为和大脑增长的发展变化已经相对研究，但是鉴于自闭症发育差异的重要性，需要进行此类研究。我们在这里建议使用BALB/C和C57BL/6J菌株对社会行为进行发展研究，包括对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展内表型之间的可能联系。具体目的：1。社会行为的发展分析。我们将检验以下假设：相对于C57BL/6J小鼠，BALB/CJ小鼠显示出降低的社交能力，这在预次启动中尤为明显。社交和与焦虑有关的行为之间的关系将进行测试。 2。与社会行为有关的大脑大小和call体大小的发展分析。我们将检验以下假设：相对于C57BL/6J小鼠，BALB/CJ小鼠显示出与自闭症相似的模式，在预孵化中最明显的大脑增大（在社交性最低时）。我们还将检验以下假设：call体大小与BALB/CJ菌株中的社交性呈正相关。 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C57BL/6J小鼠的F1和F2种群中，将测量社交行为，call体大小和大脑大小的遗传力。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训实验中测量。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，这些研究可能会确定对自闭症社交障碍的未来临床和基础研究的有希望的方向。