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

• 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
• 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

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.

项目摘要 自闭症谱系障碍(ASD)的特征是社交和沟通能力受损以及 重复的行为。虽然ASD的行为得到了很好的描述，但其背后的病理机制 发育状况尚不清楚。没有药物和/或遗传上的预防或治愈方法 对于ASD。治疗工具的发展需要确定致病因素及其细胞 大脑中的机制。最近的遗传学研究表明，富含AT的单倍体不足是相互作用的 ARID1B区(ARID1B)基因导致ASD和智能障碍，提示ARID1B可能在ASD和智能障碍中起关键作用 在社会行为控制中的作用。尽管据报道ARID1B单倍体功能不全会导致ASD，但目前尚不清楚 关于ARID1B功能障碍如何导致自闭症患者的异常社会行为。为了应对这一挑战，我们 建立了ARID1B单倍体功能不全的小鼠模型，发现该小鼠表现出社交缺陷 重述人类ASD的表型。我们的目标是确定ARID1B的细胞机制 单倍体不足导致的社会赤字。先前的研究表明，腹侧标记脑区之间的大脑回路 伏隔核区(VTA)和伏隔核(NAC)调节社会行为。它们之间也有很强的联系 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单倍体缺陷小鼠的表达减少。此外，我们观察到功能 Arid1b小鼠ASD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 结合前人的研究，我们假设VTA-NAC电路中的干扰在 Arid1b单倍体缺陷小鼠的社会缺陷和线粒体缺陷是社会改变的基础。 利用小鼠遗传学、病毒介导的电路操作、电生理评估、 人类IPSC研究，以及分子/生化方法，我们将在小鼠和 通过检查以下相关目的来建立人体模型：目的1)检查中脑边缘环路在 Arid1b单倍体缺陷小鼠的社会行为；目的2)检测线粒体功能障碍作为细胞 Arid1b单倍体功能不全致中脑边缘异常的机制 Arid1b单倍体功能不全线粒体功能障碍的机制。我们的研究可能会为我们提供新的 对ASD中与脑回路改变和线粒体功能障碍相关的社会缺陷的机械论见解。