UCSF

Social relationships are the basis of all civilization, and vital to an individual’s role in society and well-being. In particular, the complex behaviors that comprise social attachment are necessary to maintain successful bonds with other individuals throughout life. Deficits in adult social attachment behaviors and disruptions in social relationships are observed across many psychiatric diseases, and are fundamental diagnostic criteria for Autism Spectrum Disorders (ASD). ASD is a clinically heterogenous disorder with a complex and highly variable etiology, with studies indicating both genetic and environmental contributions to risk. The underlying neurobiology of ASD is not well understood, and thus there exists a lack of biologically based diagnosis and treatments for social attachment deficits. Further research into the neural mechanisms of social attachment deficits has been restricted by the lack of model organisms which display ethologically relevant social bonding behaviors analogous to humans.In this dissertation I report on experiments describing genetic and environmental manipulations on social attachment behaviors in a socially monogamous rodent, the prairie vole (Microtus ochrogaster). Prairie voles form enduring and selective social attachments between mates, defined as a pair bond, which can be robustly and reliably measured in the laboratory. Varied mutations in Shank3 in humans have been identified as contributing high risk to ASD symptomology. I used CRISPR-mediated mutagenesis to generate two vole lines bearing unique mutations in Shank3, which alter specific isoforms of Shank3 protein. I identified a female- and mutation- specific behavioral phenotype of diminished social attachment to a bonded male partner in heterozygous Shank3 mutants. These studies establish a clinically relevant prairie vole model for the social deficits observed in ASD, and provide novel results which begin to isolate which functional domains of Shank3 protein are implicated in social attachment deficits. Secondly, I show an environmental contribution to social attachment behaviors by demonstrating that early life social isolation impairs adult social attachment, in female prairie voles. Early life stress has been attributed to increased adult vulnerability to psychiatric disease. Specifically, early life social isolation can cause an increase in disinhibited attachment, defined by lack of selectivity in social relationships, as well as autistic-like features, such as impaired social relationships. I report that 4 weeks of juvenile isolation is sufficient to extinguish social attachment behaviors typical in female prairie voles. Taken together, these results (1) establish the prairie vole as a model of adult social attachment deficits in psychiatric disease, (2) describe the contribution of a specific and clinically relevant gene mutation to adult social attachment deficits, and (3) provide an example of an environmental basis of adult social attachment deficits. Beyond social attachment, these investigations highlight the use of species specific innate behaviors to calibrate a research question, and establishes several molecular genetic, histological, and behavioral techniques for use in the prairie vole.