Systematic characterization of social attachment behaviors and their underlying molecular substrates

项目总结 社会依恋构成了社会组织各个层面上人际关系的基础，从 父母和孩子之间的关系，恋人之间的关系，与同龄人和团体的关系。中途中断 依恋发生在各种精神疾病中，严重的神经精神障碍常常表现出来。 伴随着社会依恋和认知的戏剧性崩溃。尽管社交依恋起着至关重要的作用，但几乎没有 已知依恋背后的神经和遗传机制。小鼠和其他遗传模型 生物体不会表现出持久的社会依恋，这排除了对这些行为的遗传分析。 草原田鼠是一种小型啮齿动物，在配偶之间表现出社会一夫一妻制或结对纽带。配对键合 形成导致了许多其他与生俱来的社会行为的戏剧性变化。因此，草原田鼠从事着一种富有的 这些社会行为惊人地反映了人类的依恋。开创性的工作鉴定了这种多肽 荷尔蒙加压素(AVP)和催产素(OXT)作为田鼠配对结合和社会认知的关键媒介 以及人类的行为。这些发现表明，社会依恋的遗传和神经控制可能 保守，而且确实启发了寻求使用这些激素来改善干扰的临床试验 由于神经精神疾病造成的社会认知障碍。然而，这些途径和其他基因是如何 控制复杂社会行为的特定方面的功能仍不清楚。 到目前为止，我们还不能理解OXTR和V1aR是如何控制神经模式的 回应伴侣或陌生人的活动。我们已经产生了携带OXTR和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。vbl.使用 这个强大的系统，我们现在可以检验OXTR和V1aR控制1)对的不同方面的假设 联系和成人社交依恋行为，2)伴侣或陌生人特有的神经活动模式 在社会互动过程中，田鼠大脑的特定区域，以及3)潜在社会互动的基因表达的变化 在这些神经群体中的依恋。我们的初步工作表明，OXTR信令不是必需的 从基因上讲，草原田鼠的配对结合，因此，对神经和 潜在的社会依恋的分子途径可能提供新的见解，以调节 形成这种长期的社会记忆和联系。这些研究将阐明 OXTR和V1aR促进了依恋，并最终形成了各种新的治疗方法 精神疾病。

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.