Systematic characterization of social attachment behaviors and their underlying molecular substrates

社会依恋行为及其潜在分子基础的系统表征

• 批准号: 10599761
• 负责人: Devanand Sadanand Manoli
• 金额: $ 13.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599761
• 关键词: Address; Adult; Alleles; Amygdaloid structure; Animal Model; Animals; Behavior; Biological Assay; Brain; Brain region; CRISPR/Cas technology; Cells; Child; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Fiber; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genetic; Group Affiliation; Hormone use; Hormones; Human; Lateral; Medial; Mediating; Mediator of activation protein; Memory; Mental disorders; Microtus; Molecular; Molecular Profiling; Mutation; Neurons; Nucleus Accumbens; Optics; Other Genetics; Oxytocin; Oxytocin Receptor; Pair Bond; Parents; Partner in relationship; Pathway interactions; Pattern; Peer Group; Photometry; Population; Receptor Signaling; Rodent; Role; Siblings; Signal Pathway; Signal Transduction; Social Behavior; Social Controls; Social Interaction; Stimulus; System; Testing; Vasopressins; Work; base; behavior change; gene function; genetic analysis; in vivo; insight; loss of function mutation; mouse genetics; mutant; neural patterning; neuropsychiatric disorder; neuropsychiatry; neuroregulation; novel therapeutic intervention; peptide hormone; prairie vole; receptor; receptor function; relating to nervous system; response; sex; social; social attachment; social cognition; social organization; social relationships; transcriptome sequencing

PROJECT SUMMARY Social attachments form the basis of human relationships at every level of social organization, from relationships between parents and children, romantic partners, to peers and group affiliation. Disruptions in attachment occur across the spectrum of mental illness, and severe neuropsychiatric disorders often manifest with a dramatic collapse of social attachment and cognition. Despite this critical role of social attachment, little is known regarding the neural and genetic mechanisms underlying attachment. Mice and other genetic model organisms do not exhibit enduring social attachments, precluding genetic analysis of these behaviors. Prairie voles are small rodents that display social monogamy, or pair bonds, between mates. Pair bond formation results in dramatic changes to many other innate social behaviors. Thus, prairie voles engage in a rich repertoire of social behaviors that strikingly mirror attachment in humans. Pioneering work identified the peptide hormones vasopressin (Avp) and oxytocin (Oxt), as critical mediators of pair bonding in voles and social cognition and behaviors in humans. These findings suggest that the genetics and neural control of social attachment may be conserved, and indeed, have inspired clinical trials seeking to use these hormones to ameliorate disruptions in social cognition due to neuropsychiatric conditions. Nevertheless, how these pathways and other genes function to control specific aspects of complex social behaviors remains unknown. Until now, we have been unable to understand how OxtR and V1aR function to control patterns of neural activity in response to partners or strangers. We have generated prairie voles bearing mutations in OxtR and V1aR that completely eliminate the function of these receptors, and developed approaches for optical recording of neural activity in freely moving animals during behavior and profiling of gene expression in prairie voles. Using this powerful system, we can now test the hypothesis that OxtR and V1aR control distinct aspects of 1) pair bonding and adult social attachment behaviors, 2) partner- or stranger-specific patterns of neural activity in specific regions of the vole brain during social interactions, and 3) changes in gene expression underlying social attachment in these neural populations. Our preliminary work suggests that OxtR signaling is not required genetically for pair bonding in prairie voles, and, thus, that a more refined understanding of the neural and molecular pathways underlying social attachment may provide new insights into the pathways that mediate the formation of such long term social memory and affiliation. These studies will elucidate the mechanisms by which OxtR and V1aR facilitate attachment and, eventually, inform new therapeutic approaches across the spectrum of mental illness.

项目概要 社会依恋构成了社会组织各个层面的人际关系的基础，从 父母与孩子、浪漫伴侣、同龄人和团体之间的关系。中断 依恋发生在各种精神疾病中，严重的神经精神疾病常常表现出来 社会依恋和认知的急剧崩溃。尽管社会依恋发挥着至关重要的作用，但几乎没有什么作用 已知依恋背后的神经和遗传机制。小鼠和其他遗传模型 生物体不表现出持久的社会依恋，排除了对这些行为的遗传分析。 草原田鼠是小型啮齿动物，在配偶之间表现出社会一夫一妻制或配对关系。配对债券 形成会导致许多其他先天社会行为的巨大变化。因此，草原田鼠从事丰富的 一系列社会行为惊人地反映了人类的依恋。开创性工作确定了肽 激素加压素 (Avp) 和催产素 (Oxt)，作为田鼠配对和社会认知的关键介质 以及人类的行为。这些发现表明，社会依恋的遗传学和神经控制可能 被保存下来，并且确实激发了寻求使用这些激素来改善干扰的临床试验 由于神经精神疾病导致的社会认知能力下降。然而，这些途径和其他基因如何 控制复杂社会行为特定方面的功能仍然未知。 到目前为止，我们还无法理解 OxtR 和 V1aR 如何发挥作用来控制神经模式 对伙伴或陌生人做出反应的活动。我们已经培育出携带 OxtR 突变的草原田鼠 V1aR完全消除了这些受体的功能，并开发了光学记录方法 自由活动的动物在行为过程中的神经活动以及草原田鼠基因表达的分析。使用 这个强大的系统，我们现在可以测试 OxtR 和 V1aR 控制 1) 对的不同方面的假设 结合和成人社会依恋行为，2）伴侣或陌生人特定的神经活动模式 社交互动期间田鼠大脑的特定区域，以及3）社交背后的基因表达的变化 这些神经群体的依恋。我们的初步工作表明不需要 OxtR 信号传导 从基因上讲，草原田鼠的配对结合，因此可以更深入地了解神经和 社会依恋背后的分子途径可能为介导社会依恋的途径提供新的见解 形成这种长期的社会记忆和归属感。这些研究将阐明其机制 OxtR 和 V1aR 促进依附，并最终为整个谱系提供新的治疗方法 的精神疾病。