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.

项目摘要 社会依恋构成了社会组织各个层面的人际关系的基础， 父母和孩子之间的关系，浪漫的合作伙伴，同龄人和团体归属。中断 依恋发生在精神疾病的各个方面，严重的神经精神障碍往往表现为 社会依附和认知的急剧崩溃。尽管社会依恋起着关键作用， 关于依恋背后的神经和遗传机制的研究小鼠和其他遗传模型 生物体不会表现出持久的社会依恋，这就排除了对这些行为进行遗传分析的可能性。 草原田鼠是一种小型啮齿类动物，在配偶之间表现出社会性的一夫一妻制，或称成对关系。对键 形成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 这些社会行为的一系列特征与人类的依恋有着惊人的相似。开创性的工作确定了这种肽 后叶加压素（Avp）和催产素（Oxt）是田鼠配对和社会认知的关键调节因子 和人类的行为。这些发现表明，社会依恋的遗传和神经控制可能 事实上，它已经激发了寻求使用这些激素来改善干扰的临床试验。 在社会认知方面的影响然而，这些途径和其他基因 控制复杂社会行为的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是如何控制神经细胞的模式的。 对伴侣或陌生人的反应。我们已经产生了携带OxtR突变的草原田鼠， V1 aR完全消除了这些受体的功能，并开发了光学记录的方法 自由活动的动物在行为过程中的神经活动，以及草原田鼠的基因表达谱。使用 这个强大的系统，我们现在可以测试假设，OxtR和V1aR控制不同方面的1）对 结合和成人社会依恋行为，2）合作伙伴或陌生人的神经活动的具体模式， 在社会互动过程中，田鼠大脑的特定区域，以及3）社会互动背后的基因表达变化 这些神经群体中的依恋。我们的初步工作表明，OxtR信号转导不是必需的， 遗传学上对草原田鼠的配对结合，因此，更精确地理解神经和 社会依恋的分子途径可能为介导这种关系的途径提供新的见解。 这种长期的社会记忆和联系的形成。这些研究将阐明 OxtR和V1aR促进附着，并最终为整个范围内的新治疗方法提供信息 精神疾病