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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.

描述（由申请人提供）：社会依恋在人类互动的大多数（如果不是全部）层面上发挥着核心作用，从亲子依恋、兄弟情谊和亲属关系、友谊和社会归属，到与伴侣的持久伙伴关系。社会依恋行为在临床上也非常相关，因为自闭症谱系障碍和精神分裂症等几种破坏性病症常常表现为人际互动的急剧崩溃。由于灵长类动物研究的局限性，这些令人着迷的行为传统上对遗传和神经生物学方法产生了抵制。小鼠是迄今为止唯一一种基因可控的哺乳动物模型，它似乎没有表现出成年社会依恋行为。该提案旨在建立草原田鼠（Microtus ochrogaster）作为模型系统，以检查因与精神疾病相关的基因突变而导致的社会依恋行为缺陷。草原田鼠是一种像老鼠一样的小型啮齿动物，它们表现出强烈的社会依恋行为，因此配偶通常会形成持久的配对关系。结对关系会导致其他社会行为发生巨大变化。这些发现表明，田鼠具有丰富的社会依恋行为，这些行为与人类观察到的许多社会行为惊人相似。草原田鼠的开创性工作已确定加压素 (Avp) 和催产素 (Oxt)、神经肽和激素是配对结合的关键介质。引人注目的是，AVP 和 OXT 信号传导也与人类的社会依恋类型行为有关。鉴于人类和其他真兽类哺乳动物（包括草原田鼠）之间在进化上具有深刻的相似性，这些发现表明，社会依恋的遗传和神经控制在人类和草原田鼠之间也可能是保守的。因此，草原田鼠的发现可能会直接影响我们对人类依恋行为的理解。因此，我们建议通过生成携带神经精神疾病相关基因突变的草原田鼠，在这个理想的社会依恋行为模型系统中模拟精神疾病中表现的社会缺陷。虽然没有一个模型系统可能能够概括人类精神疾病中发生的所有复杂症状，但该模型系统将首次允许用于了解这些疾病中深刻的社会缺陷背后的神经生物学。自闭症谱系障碍 (ASD) 和精神分裂症通常会导致明显的社交缺陷，表现为社会支持和关系显着有限、难以维持就业以及社交技能的总体缺陷。我们建议 1) 为与自闭症、SH3 和多个锚蛋白重复结构域 3 (SHANK3) 以及精神分裂症、Disks 大同源物 2 (DLG2) 相关的基因生成草原田鼠突变体，2) 检查因这些基因功能丧失而导致的社会依恋行为缺陷模式，以及 3) 确定与依恋相关缺陷相关的神经元激活模式的变化行为。