microRNA tuning of gregarious versus antisocial behavior in juveniles

项目摘要 儿童的健康行为发展依赖于社会联系。社会隔离和孤独 儿童期可能导致有害的行为表型，这些表型持续到成年期，例如对 自己和他人。然而，青少年攻击的基本原则是未知的，部分原因是传统的 实验室动物在青少年时期没有表现出攻击性， 挑战性为了解决这一缺陷，这项研究旨在揭示基本的神经生物学机制， 社会隔离导致蝌蚪的青少年攻击性，可能是暴力攻击性或社会群居性 基于社会抚养条件。我们将联合收割机这种新颖的研究有机体和行为范式与 先进的神经遗传学工具来询问由社会隔离引起的攻击性的神经基质。 我们把这项研究的重点放在microRNA上，因为microRNA负责跨细胞的社会性开关。 通过应用microRNA模拟物或抑制剂， 可以改变基因表达程序而不改变DNA序列。我们实验室的最新数据显示 蝌蚪的攻击性与杏仁核、内啡肽信号和 叉头盒蛋白2（FOXP2）表达减少，FOXP2是许多分类群中与社会行为相关的基因。基于 基于这一可靠的初步数据，我们建议检验microRNA改变FOXP2表达的假设， 内啡肽敏感的神经元诱导攻击行为的青少年容易社会隔离。我们将 首先确定社会隔离如何改变青少年大脑的microRNA景观使用单细胞 测序和测试FOXP2和内啡肽敏感神经元中microRNA表达的变化。然后， 我们将研究杏仁核中的microRNA如何根据社会因素调节青少年的行为反应， 饲养条件。最后，由于人类杏仁核的连通性在具有攻击性的人类中减少，我们将 功能测试miR-9在改变杏仁核连接和诱发蝌蚪群居中的作用 或者攻击性总之，拟议的实验将系统地剖析机制， 在一项研究中，microRNA调节FOXP2和μ阿片受体来调节青少年的社会性和攻击性。 具有实验易驾驭性和其他研究难以实现的强大行为输出的生物体 有机体由于社会运动行为的分子因素和整体脑组织是保守的 在脊椎动物中，这项研究将确定青少年攻击的普遍原则。当前迫切 需要这项研究，因为目前还没有建立模型来研究神经机制 青少年的侵略性。这项工作对公共卫生很重要，因为COVID-19大流行隔离了儿童 从他们的同龄人，并导致增加的攻击性行为，这可以持续到成年，并预测时间 在监狱里度过需要更多关于青少年社交孤立和孤独攻击的研究，以更好地 了解我们社会中最年轻成员的这些病理。

Project Summary Healthy behavioral development in children relies on social connectedness. Social isolation and loneliness during childhood can lead deleterious behavioral phenotypes that continue into adulthood, such as aggression towards oneself and others. However, the basic principles of juvenile aggression are unknown, in part, because traditional laboratory animals do not show aggression as juveniles and functional studies in human children remain challenging. To address this deficit, this research aims to uncover basic neurobiological mechanisms of how social isolation leads to juvenile aggression in tadpoles that can be violently aggressive or socially gregarious based on social rearing conditions. We combine this novel research organism and behavioral paradigm with advanced neurogenetic tools to interrogate the neuronal substrates of aggression induced by social isolation. We focus this research on microRNAs because microRNAs are responsible for the sociality switches across a wide range of taxa and have promising therapeutic potential through application of microRNA mimics or inhibitors that can change gene expression programs without altering DNA sequences. Recent data from our lab shows that tadpole aggression is associated with increased activity in the amygdala, endorphin signaling, and a decrease in forkhead box protein 2 (FOXP2) expression, a gene linked to social behavior in many taxa. Based on this robust preliminary data, we propose to test the hypothesis that microRNAs alter FOXP2 expression in endorphin-sensitive neurons to induce aggressive behavior in juveniles susceptible to social isolation. We will first determine how social isolation shifts the microRNA landscape of the juvenile brain using single cell sequencing and testing how microRNA expression changes in FOXP2- and endorphin-sensitive neurons. Then, we will examine how microRNAs in the amygdala tune the behavioral responses of juveniles based on social rearing conditions. Finally, as connectivity of the human amygdala is reduced in aggressive humans, we will functionally test the role of miR-9 in altering amygdala connectivity and predisposing tadpoles to be gregarious or aggressive. Together, the proposed experiments will systematically dissect the mechanisms by which microRNAs regulate FOXP2 and the µ opioid receptor to regulate juvenile sociality and aggression in a research organism with experimental tractability and a robust behavioral output that is difficult to achieve in other research organisms. As the molecular factors and overall brain organization of social-motor behaviors are conserved across vertebrates, this research will identify generalizable principles of juvenile aggression. There is a pressing need for this research because there are currently no established models for studying the neural mechanisms of juvenile aggression. This work is important to public health because the COVID-19 pandemic isolated children from their peers and led to an increase in aggressive behaviors, which can last into adulthood and predicts time spent in prison. More research on juvenile aggression from social isolation and loneliness is needed to better understand these pathologies in the youngest members of our society.