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（由应用程序提供）：社会依恋在大多数（如果不是全部（如果不是全部））的层次中起着核心作用。社会依恋行为在临床上也非常相关，因为几种毁灭性的疾病，例如自闭症谱系障碍和精神分裂症通常会出现人际关系互动的剧烈崩溃。传统上，这些迷人的行为对遗传和神经生物学方法具有抵抗力，因为在私人方面施加的局限性。小鼠是迄今为止唯一可以遗传处理的哺乳动物模型，似乎并未显示成人的社会依恋行为。该提案旨在建立草原vole（Microtus ochrogaster）作为模型系统，以检查社会依恋行为的缺陷，这些不足是由与精神病草原田径相关的基因突变导致的，是小鼠样啮齿动物，这些啮齿动物是小鼠样啮齿动物，它们表现出强大的社会依恋行为，这些行为表现出强大的社会依恋行为，这些行为通常形成持久的成对键。配对结合导致其他社会行为发生巨大变化。这些发现表明，田鼠参与了社会依恋行为的丰富曲目，与人类观察到的许多社会行为具有显着相似之处。草原vole的开创性工作已确定加压素（AVP）和催产素（OXT），神经肽和恐怖症，是成对键合的关键介体。令人惊讶的是，在人类的社会依恋类型行为中也暗示了AVP和OXT信号传导。鉴于人类与其他欧地哺乳动物（包括草原田鼠）之间的深厚进化相似性，这些发现表明，社会依恋的遗传学和神经元控制也可以在人类和草原田鼠之间得到保存。这就是草原田鼠中的发现可以直接告知我们对人类依恋行为的理解。因此，我们建议通过在神经精神疾病中隐含的基因中产生突变的大草原田鼠，以在这种理想的社会依恋行为模型系统中模拟精神疾病中表现出的社会缺陷。尽管没有单一模型系统可能会概括人类精神病中发生的整个复杂症状的整个频谱，但该模型系统将首次允许用来了解这些疾病中深远的社会缺陷的神经生物学。自闭症谱系障碍（ASD）和精神分裂症通常会导致明显的社会缺陷，这表现出显着有限的社会支持和关系，难以维持就业以及社交技能的整体缺陷。我们建议1）生成在自闭症，SH3和多个Ankyrin重复域3（shank3）和精神分裂症的基因中生成草原vols突变体，磁盘大型同源物2（DLG2），2）检查社会依恋行为中的定义模式，这些定义与这些基因的丧失相关的定义，以及这些基因丧失的定义，并确定了这些基因的变化。行为。