Cellular mechanism of Arid1b haploinsufficiency-associated social deficit

Arid1b单倍体不足相关的社会缺陷的细胞机制

基本信息

批准号：
10736386
负责人：
Woo-Yang Kim
金额：
$ 55.71万
依托单位：
KENT STATE 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：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736386
关键词：
ARID Domain ARID1A gene ATP Synthesis Pathway Animal Model Area Axon Behavior Behavior Control Behavior Disorders Behavioral Biochemical Biogenesis Biological Assay Brain Cells Child Complement Complex Data Defect Development Dopamine Electron Transport Electrophysiology (science)FOS gene Foundations Fragile X Syndrome Functional disorder Gene Expression Alteration Genes Genetic Genetic study Glutathione Goals Human Impairment Individual Intellectual functioning disability Investigation Label Link Mediating Messenger RNA Midbrain structure Mitochondria Modeling Molecular Mus Neurodevelopmental Disorder Neurons Neuropathogenesis Nucleus Accumbens Oxidative Stress Oxygen Consumption Pathogenicity Pathologic Pathway interactions Patients Phenotype Physiology Play Prevention Prevention strategy Production Reactive Oxygen Species Reporting Rewards RiboTag Role Sampling Severities Social Behavior Social Interaction Synapses Testing Transcription Elongation Transcriptional Regulation Ventral Tegmental Area Virus autism spectrum disorder autistic children behavioral impairment cell type data modeling dopaminergic neuron human model improved induced pluripotent stem cell insight mitochondrial dysfunction mouse genetics mouse model nerve supply neurodevelopment neuropathology novel optogenetics overexpression pharmacologic preference promoter repetitive behavior respiratory enzyme response single-cell RNA sequencing social social communication social deficits therapeutic development tool transcription factor treatment strategy

项目摘要

Project Summary Autism spectrum disorder (ASD) is characterized by impaired social interaction and communication as well as repetitive behavior. While ASD behaviors are well described, the pathological mechanism underlying this developmental condition remains unknown. There are no pharmacological and/or genetic preventions or cures for ASD. Development of therapeutic tools requires identification of causative factors and their cellular mechanisms in the brain. Recent genetic studies have shown that haploinsufficiency of the AT-rich interactive domain 1B (ARID1B) gene causes ASD and intellectual disability, suggesting that ARID1B may play a critical role in social behavior control. Although ARID1B haploinsufficiency reportedly causes ASD, nothing was known about how ARID1B dysfunction leads to abnormal social behavior in ASD. In response to this challenge, we generated a mouse model of ARID1B haploinsufficiency and found that this mouse displays social deficits recapitulating human ASD phenotypes. Our goal is to identify the cellular mechanism of ARID1B haploinsufficiency-induced social deficits. Prior studies show that the brain circuit between the ventral tagmental area (VTA) and nucleus accumbens (NAc) regulates social behavior. They also present a strong link between ASD and mitochondrial defects. Furthermore, studies suggest an association of Arid1b haploinsufficiency with mitochondrial dysfunction. In our preliminary investigation, we found that the VTA-to-NAc connection was reduced in Arid1b haploinsufficient mice compared to wild-type controls. Additionally, we observed functional alterations of mitochondria and overproduction of reactive oxygen species in the Arid1b mouse model of ASD. Mitochondria-associated genes were downregulated in the Arid1b model. Based on our preliminary findings combined with previous studies, we hypothesize that disturbance in the VTA-NAc circuit plays a key role in social deficits in Arid1b haploinsufficient mice and that mitochondrial defects underlie the social alteration. Using a combination of mouse genetics, virus-mediated circuit manipulation, electrophysiological assessment, human iPSC investigation, and molecular/biochemical approaches, we will test these ideas in mouse and human models by examining the following related aims: Aim 1) Examine the role of the mesolimbic circuit in social behavior in Arid1b haploinsufficient mice; Aim 2) Examine mitochondrial dysfunction as a cellular mechanism of Arid1b haploinsufficiency-induced mesolimbic abnormality; Aim 3) Identify the molecular mechanism underlying mitochondrial dysfunction in Arid1b haploinsufficiency. Our study may provide novel mechanistic insights into social deficits in ASD related to brain circuit alteration and mitochondrial dysfunction.

项目概要自闭症谱系障碍 (ASD) 的特点是社交互动和沟通受损以及重复的行为。虽然 ASD 行为已得到很好的描述，但其背后的病理机制发育状况仍未知。没有药物和/或遗传预防或治疗方法对于自闭症谱系障碍。治疗工具的开发需要识别致病因素及其细胞大脑中的机制。最近的遗传学研究表明，富含 AT 的相互作用的单倍体不足结构域 1B (ARID1B) 基因导致 ASD 和智力障碍，表明 ARID1B 可能发挥关键作用在社会行为控制中的作用。尽管据报道 ARID1B 单倍体不足会导致自闭症谱系障碍 (ASD)，但我们对此一无所知关于 ARID1B 功能障碍如何导致自闭症谱系障碍 (ASD) 患者的异常社会行为。为了应对这一挑战，我们建立了 ARID1B 单倍体不足的小鼠模型，并发现这只小鼠表现出社交缺陷概括人类 ASD 表型。我们的目标是确定 ARID1B 的细胞机制单倍体不足引起的社会缺陷。先前的研究表明，腹侧标签之间的大脑回路区（VTA）和伏隔核（NAc）调节社会行为。它们还呈现出之间的紧密联系 ASD 和线粒体缺陷。此外，研究表明 Arid1b 单倍体不足与线粒体功能障碍。在我们的初步调查中，我们发现 VTA 到 NAc 的连接是与野生型对照相比，Arid1b 单倍体不足的小鼠中的减少。此外，我们观察到功能 Arid1b 小鼠自闭症谱系障碍模型中线粒体的改变和活性氧的过量产生。线粒体相关基因在 Arid1b 模型中下调。根据我们的初步调查结果结合之前的研究，我们假设 VTA-NAc 回路中的干扰在 Arid1b 单倍体不足的小鼠存在社交缺陷，线粒体缺陷是社交改变的基础。结合小鼠遗传学、病毒介导的电路操作、电生理评估、人类 iPSC 研究和分子/生化方法，我们将在小鼠和通过检查以下相关目标的人体模型：目标 1) 检查中脑边缘回路在 Arid1b 单倍体不足小鼠的社会行为；目标 2) 检查线粒体功能障碍作为细胞 Arid1b单倍体不足引起中脑边缘异常的机制；目标 3) 识别分子 Arid1b 单倍体不足导致线粒体功能障碍的机制。我们的研究可能会提供新颖的对自闭症谱系障碍中与脑回路改变和线粒体功能障碍相关的社会缺陷的机制见解。