Project 1: Sato

项目1：佐藤

基本信息

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
项目类别：
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

项目摘要

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 – 项目摘要社交行为障碍是自闭症谱系障碍 (ASD) 的核心症状，但其根本原因是这种功能障碍的机制尚不清楚，当前项目旨在提供两者之间的机械联系。高度渗透性自闭症谱系障碍风险基因 MEF2C 与社会缺陷的发展。数据表明，抑制性中间神经元中的 Mef2c 减少，而不是兴奋性神经元中的 Mef2c 的减少，对于我们将扩展这些初步数据来检验特定亚型的假设。中间神经元（小清蛋白阳性中间神经元或 PV-IN）的关键电路组件将 Mef2c 连接到在目标 1 中，我们将采用体内钙成像来监测活动的变化。前额皮质中的 PV-IN 和其他主要神经元类别，以更好地了解改变的电路活动与 Mef2c 突变小鼠的社交缺陷相关的模式在目标 2 中，我们将确定改变的基因表达。 Mef2c 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我们的研究将共同阐明兴奋性和抑制性回路是如何发挥作用的。 ASD 小鼠模型中的社交信息处理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。职业发展和指导将帮助 PI 未来获得 NIH R01 资助，以促进向神经发育及其疾病领域的知名研究者。