microRNA tuning of gregarious versus antisocial behavior in juveniles

项目摘要 儿童健康的行为发展依赖于社会联系。社会孤独感与孤独 童年可导致有害的行为表型，并持续到成年，如攻击性 自己和其他人。然而，青少年攻击性的基本原理是未知的，部分原因是传统的 实验动物在青少年时期没有表现出攻击性，人类儿童的功能研究仍在继续 很有挑战性。为了解决这一缺陷，这项研究旨在揭示 社交孤立会导致青少年对蝌蚪的攻击，这种攻击可能是暴力的，也可能是社交的 基于社会养育条件。我们将这一新颖的研究机构和行为范式与 先进的神经遗传学工具，以询问由社会隔离引起的攻击的神经元底物。 我们将这项研究集中在microRNAs上，因为microRNAs负责 广泛的分类群，并通过应用microRNA模拟物或抑制剂具有良好的治疗潜力 可以在不改变DNA序列的情况下改变基因表达程序。我们实验室的最新数据显示 这种蝌蚪攻击性与杏仁核中活动增加、内啡肽信号和 叉头盒蛋白2(FOXP2)表达减少，这是一个与许多分类群中的社会行为有关的基因。基座 在这个稳健的初步数据基础上，我们建议检验以下假设：microRNAs改变FOXP2在 内啡肽敏感神经元在易受社会孤立的青少年中诱导攻击行为。我们会 首先确定社会隔离如何利用单个细胞改变青少年大脑的microRNA图景 测序和测试FOXP2和内啡肽敏感神经元中microRNA的表达如何变化。然后, 我们将研究杏仁核中的microRNAs是如何调整青少年的行为反应的 养育条件。最后，随着攻击性人类杏仁核的连通性降低，我们将 从功能上测试miR-9在改变杏仁核连接和使蝌蚪群居方面的作用 或者咄咄逼人。总之，拟议中的实验将系统地剖析 一项研究中，microRNAs调节FOXP2和阿片受体以调节青少年的社交和攻击性 具有实验驯化能力和健壮的行为输出的生物体，这在其他研究中是难以实现的 有机体。由于社会运动行为的分子因素和整体大脑组织是保守的 在脊椎动物中，这项研究将确定青少年攻击性的一般原则。有一项紧迫的任务 需要进行这项研究，因为目前还没有建立起研究神经机制的模型 青少年攻击性的表现。这项工作对公共卫生很重要，因为新冠肺炎大流行隔离了儿童 并导致攻击性行为的增加，这种行为可以持续到成年，并预测时间 在监狱里度过。需要对青少年社交孤立和孤独的攻击行为进行更多的研究，以便更好地 理解我们社会中最年轻的成员的这些病态。

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.