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级别的人际关系的基础 父母与孩子之间的关系，浪漫的伴侣与同龄人和团体隶属关系。中断 依恋在精神疾病的范围内发生，严重的神经精神疾病经常表现出来 随着社会依恋和认知的巨大崩溃。尽管社会依恋的关键作用，但几乎没有 有关附着的神经和遗传机制的已知。小鼠和其他遗传模型 生物不会表现出持久的社会依恋，排除对这些行为的遗传分析。 草原田鼠是伴侣之间表现出社交一夫一妻制或成对纽带的小啮齿动物。配对键 形成导致许多其他先天社会行为发生巨大变化。因此，草原田鼠从事富人 社会行为的曲目恰好反映了人类中的依恋。开创性工作确定了肽 激素加压素（AVP）和催产素（OXT），作为田鼠和社会认知的伴侣键合的关键介体 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 保持保存，并且确实启发了寻求使用这些激素改善干扰的临床试验 由于神经精神疾病而引起的社会认知。然而，这些途径和其他基因如何 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，我们一直无法理解OXTR和V1AR如何控制神经模式 响应伴侣或陌生人的活动。我们已经在Oxttr中产生了带有突变的草原田鼠， V1AR完全消除了这些受体的功能，并开发了光学记录的方法 在草原田鼠的行为和基因表达的行为和基因表达分析过程中自由移动的动物的神经活动。使用 这个功能强大的系统，我们现在可以检验OXTR和V1AR控制不同方面1）对的假设 纽带和成人社会依恋行为，2）在 社交互动过程中沃尔大脑的特定区域，以及3）社会基因表达的变化 这些神经种群的依恋。我们的初步工作表明不需要OXTR信号 在大草原田鼠中的偶发上，遗传上的键合，因此，对神经和 社会依恋基础的分子途径可能会为介导的途径提供新的见解 形成如此长期的社会记忆和隶属关系。这些研究将阐明 OXTR和V1AR促进附着，并最终告知整个频谱的新治疗方法 精神疾病。