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Genetic models for social attachment deficits in psychiatric illness

精神疾病社会依恋缺陷的遗传模型

基本信息

批准号：
9241444
负责人：
Devanand Sadanand Manoli
金额：
$ 18.41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241444
关键词：
Adult Animal Model Ankyrin Repeat Autistic Disorder Basic Science Behavior Biological Models Brain Cells Child Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Development Disease Drosophila genus Embryo Embryo Transfer Employee Strikes Employment Exhibits Female Friendships Gene Targeting Generations Genes Genetic Genetic Models Harvest Health Heritability Hormones Human Individual Injectable Injection of therapeutic agent Interpersonal Relations Mammals Mediator of activation protein Mental disorders Messenger RNA Microinjections Microtus Modeling Molecular Molecular Genetics Mood Disorders Moods Mus Mutation Neurobiology Neurons Neuropeptides OXT gene Other Genetics Oxytocin Pair Bond Palmitoylated Membrane Protein 2 Parents Partner in relationship Patients Pattern Personality Disorders Phosphorylation Play Primates Protocols documentation Research Resistance Ribosomes Rodent Role Rupture Schizophrenia Separation Anxiety Signal Transduction Social Behavior Social Controls Social support Symptoms Techniques Technology Testing Therapeutic Time Ursidae Family Vasopressins Work Zebrafish autism spectrum disorder blastocyst clinically relevant embryo culture embryonic stem cell endophenotype fascinate gene function genetic analysis genetic approach insight knockout gene loss of function mutant neural circuit neuromechanism neuronal patterning neuropsychiatric disorder neuroregulation offspring prairie vole public health relevance reverse genetics social social attachment social organization social skills tool zygote

项目摘要

DESCRIPTION (provided by applicant): Social attachments play a central role in most, if not all, levels of human interaction, from parent-child attachment, fraternity and kinship, friendship and social affiliation, to enduring partnerships with mates. Social attachment behaviors are also clinically very relevant, as several devastating conditions such as autism spectrum disorders and schizophrenia often manifest with a dramatic collapse of inter-personal interactions. These fascinating behaviors have traditionally been resistant to genetic and neurobiological approaches because of the limitations imposed by working on primates. Mice, the only genetically tractable mammalian model to date, appear not to display adult social attachment behaviors. This proposal seeks to establish the prairie vole (Microtus ochrogaster) as a model system to examine the deficits in social attachment behaviors that result from mutations in genes associated with psychiatric illnesses. Prairie voles are small mouse-like rodents that display strong social attachment behaviors such that mates typically form an enduring pair bond. Pair bonding results in dramatic changes in other social behaviors. These findings suggest that voles engage in a rich repertoire of social attachment behaviors that bear a striking resemblance to many of the social behaviors observed in humans. Pioneering work in the prairie vole has identified vasopressin (Avp) and oxytocin (Oxt), neuropeptides and hormones, as critical mediators of pair bonding. Strikingly, AVP and OXT signaling have also been implicated in social attachment type behaviors in humans. Given the deep evolutionary similarity between humans and other eutherian mammals, including prairie voles, these findings indicate that the genetics and neural control of social attachment may also be conserved between humans and prairie voles. Thus, findings in the prairie voles may directly inform our understanding of human attachment behaviors. We therefore propose to model the social deficits that manifest in psychiatric illness in this ideal model system for social attachment behaviors by generating prairie voles bearing mutations in genes implicated in neuropsychiatric disorders. While no single model system is likely to recapitulate the entire spectrum of complex symptoms that occur in human psychiatric illness, this model system will, for the first time, allow use to understand the neurobiology underlying the profound social deficits in these disorders. Autism spectrum disorders (ASD) and schizophrenia often result in marked social deficits, which manifest as significantly limited social supports and relationships, difficulty maintaining employment, and overall deficits in social skills. We propose 1) to generate prairie voles mutant for genes implicated in autism, SH3 and multiple ankyrin repeat domains 3 (SHANK3), and schizophrenia, Disks large homolog 2 (DLG2), 2) examine the pattern of deficits in social attachment behaviors that result from the loss of function of these genes, and 3) determine the change in patterns of neuronal activation that correlate with deficits in attachment related behaviors.