Project 1: Sato

项目1：佐藤

• 批准号: 10556542
• 负责人: Takashi Sato
• 金额: $ 22.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556542
• 关键词: Affect; Applications Grants; Behavioral Assay; Bioinformatics; Biometry; Brain; Brain imaging; Cell Nucleus; Cells; Centers of Research Excellence; Collaborations; Complement; Data; Data Set; Databases; Development; Disease; Equilibrium; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profile; Genomics; Heterozygote; Impairment; Inhibitory Synapse; Interneuron function; Interneurons; Link; Mediating; Mentors; Mentorship; Molecular Genetics; Monitor; Mus; Mutant Strains Mice; Neurons; Parvalbumins; Pattern; Prefrontal Cortex; Prosencephalon; Research; Research Personnel; Role; Social Behavior; Social Development; Social Interaction; Somatostatin; Symptoms; Testing; Tissue-Specific Gene Expression; Tissues; Training; United States National Institutes of Health; Virus; Visualization; Wild Type Mouse; autism spectrum disorder; behavioral phenotyping; calcium indicator; career development; cell type; excitatory neuron; hippocampal pyramidal neuron; in vivo; in vivo calcium imaging; in vivo imaging; information processing; inhibitory neuron; innovation; insight; mouse model; multidisciplinary; myocyte-specific enhancer-binding-factor 2C; neurodevelopment; novel strategies; optogenetics; preference; programs; repetitive behavior; risk variant; single-cell RNA sequencing; social; social deficits; tool; transcriptome sequencing; transcriptomics

PROJECT 1 – PROJECT SUMMARY Impairment in social behaviors is a core symptom in autism spectrum disorder (ASD), yet the underlying mechanisms of this dysfunction are not known. The current project aims to provide a mechanistic link between a highly penetrant, syndromic ASD risk gene, MEF2C, and the development of social deficits. Our preliminary data show that the reduction of Mef2c in inhibitory interneurons, rather than excitatory neurons, is critical for establishing social deficits. We will extend these preliminary data to test the hypothesis that a specific subtype of interneuron (parvalbumin-positive interneurons or PV-INs) is a critical circuit component that links Mef2c to neurotypical social behavior. In Aim 1, we will employ in vivo calcium imaging to monitor changes in the activity of PV-INs and other major neuron classes in the prefrontal cortex to better understand altered circuit activity patterns that link to social deficits in Mef2c mutant mice. In Aim 2, we will determine altered gene expression patterns in PV-INs and other types of neurons in Mef2c mutant mice, including a novel approach to tag neurons that were active during social interaction. Together, our study will clarify how excitatory and inhibitory circuits for social information processing are affected in an ASD mouse model. The project will benefit from the CNDD cores for behavioral assays, in vivo imaging, bioinformatics approaches, and advanced biostatistical consulting. The career development and mentorship will help the PI obtain future NIH R01 funding to facilitate the transition to an established investigator in the field of neurodevelopment and its disorders.

项目1 -项目概要 社交行为障碍是自闭症谱系障碍（ASD）的核心症状，但其潜在的 这种功能障碍的机制尚不清楚。目前的项目旨在提供一个机械的联系， 一个高度外显的、综合征性ASD风险基因MEF 2C与社会缺陷的发展。我们的初步 数据显示，抑制性中间神经元而不是兴奋性神经元中Mef 2c的减少对于 造成社会赤字。我们将扩展这些初步数据，以检验一种特定亚型 中间神经元（小白蛋白阳性中间神经元或PV-IN）是连接Mef 2c与 典型的社会行为在目标1中，我们将采用体内钙成像来监测活性的变化， PV-IN和前额叶皮层中的其他主要神经元类别，以更好地了解改变的回路活动 与Mef 2c突变小鼠的社会缺陷有关的模式。在目标2中，我们将确定改变的基因表达 Mef 2c突变小鼠中PV-IN和其他类型神经元的模式，包括标记神经元的新方法 在社交活动中很活跃总之，我们的研究将阐明兴奋性和抑制性回路是如何 社交信息处理在ASD小鼠模型中受到影响。该项目将受益于CNDD核心 用于行为分析、体内成像、生物信息学方法和高级生物统计咨询。的 职业发展和指导将帮助PI获得未来的NIH R 01资金，以促进向 神经发育及其障碍领域的公认研究者。