microRNA tuning of gregarious versus antisocial behavior in juveniles

microRNA 调节青少年群居与反社会行为

基本信息

批准号：
10839665
负责人：
Lauren A O'Connell
金额：
$ 39.73万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10839665
关键词：
Acute Address Adolescent Adult Aggressive behavior Amygdaloid structure Animals Behavior Behavioral Behavioral Paradigm Brain Brain region COVID-19 pandemic Cells Child Childhood Chronic Communities DNA Sequence Data Development Down-Regulation Emotional Endorphins Exhibits Gene Expression Genes Goals Human Individual Laboratory Animals Lead Link Loneliness Mammals Messenger RNA MicroRNAs Molecular Mus Nervous System Neurons Opioid Receptor Organism Output Pathology Phenotype Poison Predisposition Prisons Probability Proteins Public Health Rana Recovery Regulation Research Rodent Role Signal Transduction Social Behavior Social Environment Social Responsibility Social isolation Societies Study models Tadpoles Testing Therapeutic Time Vertebrates Violence Visualization Withdrawal Work antisocial behavior behavioral phenotyping behavioral response cell type cognitive development experimental study follow-up inhibitor insight knock-down locust male member motor behavior neural neural circuit neurobiological mechanism neurogenetics neuromechanism novel peer programs pup resilience single cell sequencing social social organization tool translational approach

项目摘要

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.

项目概要儿童的健康行为发展依赖于社会孤立和孤独。童年可能会导致有害的行为表型，并持续到成年期，例如对他人的攻击然而，青少年攻击行为的基本原理尚不清楚，部分原因是传统的。实验动物不表现出攻击性，因为青少年和人类儿童的功能研究仍然存在为了解决这一缺陷，本研究旨在揭示基本的神经生物学机制。社会孤立会导致幼年蝌蚪的攻击行为，可能会出现暴力攻击行为或社交群居行为基于社会教养条件，我们将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可以探究社会隔离引起的攻击行为的神经元基础。我们将这项研究重点放在 microRNA 上，因为 microRNA 负责跨群体的社交性转换。广泛的分类单元，通过应用 microRNA 模拟物或抑制剂具有广阔的治疗潜力我们实验室的最新数据显示，它可以在不改变 DNA 序列的情况下改变基因表达程序。蝌蚪的攻击行为与杏仁核、内啡肽信号传导和叉头盒蛋白 2 (FOXP2) 表达减少，该基因与许多类群的社会行为相关。根据这些可靠的初步数据，我们建议检验 microRNA 改变 FOXP2 表达的假设内啡肽敏感神经元诱导易受社会孤立的青少年的攻击行为。首先使用单细胞确定社会隔离如何改变青少年大脑的 microRNA 景观测序并测试 FOXP2 和内啡肽敏感神经元中 microRNA 表达的变化。我们将研究杏仁核中的 microRNA 如何根据社交调节青少年的行为反应最后，由于攻击性人类的杏仁核连通性降低，我们将功能测试 miR-9 在改变杏仁核连接性和促进蝌蚪群居中的作用总之，所提出的实验将最终剖析其机制。一项研究中 microRNA 调节 FOXP2 和 µ 阿片受体来调节青少年的社交性和攻击性具有其他研究难以实现的实验易处理性和强大行为输出的生物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行为的普遍原则。需要这项研究，因为目前还没有建立模型来研究神经机制这项工作对公共卫生很重要，因为新冠肺炎 (COVID-19) 疫情使儿童与世隔绝。来自同龄人的攻击性行为增加，这种行为可以持续到成年并预测时间需要对监狱中的青少年攻击行为进行更多研究，以更好地进行研究。了解我们社会最年轻成员的这些病症。