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）的特征是社会互动和沟通受损 重复行为。虽然ASD行为得到了很好的描述，但此基础的病理机制 发展状况仍然未知。没有药理和/或遗传预防或治疗方法 对于ASD。治疗工具的开发需要确定因果因素及其细胞 大脑中的机制。最近的遗传研究表明，富含富含互动的单倍度不足 域1B（ariD1b）基因导致ASD和智力障碍，这表明ARID1B可能起关键 在社会行为控制中的作用。尽管据报道ARID1B单倍弥补导致ASD，但尚未知道 关于ARID1B功能障碍如何导致ASD中的社会行为异常。为了应对这一挑战，我们 生成了ARID1B单倍弥补的鼠标模型，发现该鼠标显示社会缺陷 概括人ASD表型。我们的目标是确定ARID1B的细胞机制 单倍弥补引起的社会缺陷。先前的研究表明，腹侧标记之间的大脑电路 区域（VTA）和伏隔核（NAC）调节社会行为。他们还提出了牢固的联系 ASD和线粒体缺陷。此外，研究表明ARID1B单倍宽度与 线粒体功能障碍。在我们的初步调查中，我们发现VTA到NAC连接是 与野生型对照相比，ARID1B单倍型小鼠的小鼠降低。此外，我们观察到功能 在ASD的ARID1B小鼠模型中，线粒体的改变和活性氧的过量生产。 线粒体相关基因在ARID1B模型中下调。根据我们的初步发现 结合以前的研究，我们假设VTA-NAC电路中的干扰在 ARID1B单倍弹性小鼠的社会缺陷和线粒体缺陷是社会改变的基础。 结合小鼠遗传学，病毒介导的电路操作，电生理评估， 人类IPSC调查以及分子/生化方法，我们将在小鼠和 通过检查以下相关目的：目标1）检查中边缘电路在 ARID1B单倍弹性小鼠的社会行为；目标2）检查线粒体功能障碍作为细胞 ARID1B单倍度弥补引起的中唇异常的机制；目标3）识别分子 ARID1B单倍度不足的线粒体功能障碍的机制。我们的研究可能提供新颖 与脑电路改变和线粒体功能障碍有关的ASD社会缺陷的机械洞察力。