Neurobiology of sociability in a mouse model system relevant to autism

点击翻译按钮获取中文摘要

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.