Dysfunction of distinct amygdala circuits in a 16p11.2 model of autism

16p11.2 自闭症模型中不同杏仁核回路的功能障碍

基本信息

批准号：
9372984
负责人：
Bo LI
金额：
$ 28.8万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-11 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9372984
关键词：
16p11.2 Alleles Amygdaloid structure Anxiety Anxiety Disorders Autistic Disorder Behavior Behavior Disorders Behavioral Biological Assay Brain Characteristics Clinical Comorbidity Corpus striatum structure Data Development Electrophysiology (science)Emotional Employee Strikes Etiology Excitatory Synapse Exhibits Extinction (Psychology)Female Fright Functional disorder Gender Genetic Models Genetic Variation Goals Habits High Prevalence Human Human Chromosomes Hyperactive behavior Impairment Lateral Link Measurement Measures Modeling Molecular Genetics Mus Names Neurons Outcome Pathogenesis Pathway interactions Patients Phenotype Play Population Protein Kinase C Publishing Research Ritual compulsion Role Somatostatin Stereotyped Behavior Structure Structure of terminal stria nuclei of preoptic region Substantia nigra structure Symptoms Synapses Synaptic Transmission Techniques Testing anxiety-related behavior associated symptom autism spectrum disorder base conditioned fear experimental study insight male microdeletion neuromechanism novel pars compacta programs repetitive behavior tool

项目摘要

Dysfunction of distinct amygdala circuits in a 16p11.2 model of autism The overall goal of this project is to investigate the brain mechanisms underlying the abnormal repetitive behaviors and emotional processing in a genetic model of autism spectrum disorders (ASD), which was developed in mice to mimic a microdeletion on human chromosome 16p11.2, one of the most common genetic variations found in ASD. Besides other symptoms, patients with this deletion show severe repetitive behaviors and anxiety, two frequently comorbid symptoms in ASD. Despite intensive study, the mechanisms underlying the repetitive behaviors in ASD and the high prevalence of comorbidity between ASD and anxiety disorders remain largely unknown. In the proposed study, we plan to approach these questions by investigating the role of distinct amygdala circuits in abnormal habitual behaviors and fear processing in mice heterozygous for a deficiency allele of the region corresponding to the human 16p11.2, named as the 16p11.2 df/+ mice. We will test the hypothesis that dysfunction of distinct amygdala circuits in the 16p11.2 df/+ mice causes abnormal habitual behaviors and impairment in fear processing characteristic of ASD. In order to test this hypothesis, we have devised an integrated strategy that combines molecular genetic tools together with electrophysiological, chemogenetic, and behavioral techniques. Findings from this research program will provide novel insight into the synaptic, cellular, and circuit mechanisms by which dysfunction of distinct amygdala circuits contributes to abnormal behaviors related to ASD.

16p11.2自闭症模型中不同杏仁核电路的功能障碍该项目的总体目标是调查异常重复性的脑机制自闭症谱系疾病遗传模型（ASD）中的行为和情感处理（ASD）在小鼠中开发以模仿人类染色体16p11.2的微缺失，这是最常见的遗传之一在ASD中发现的变化。除其他症状外，此缺失的患者还显示出严重的重复行为和焦虑，两种经常在ASD中合并症状。尽管进行了深入研究，但其基础机制 ASD的重复行为以及ASD和焦虑症之间合并症的高流行率在很大程度上未知。在拟议的研究中，我们计划通过研究不同的杏仁核的作用来解决这些问题异常习惯行为的电路和恐惧处理的杂合子的恐惧处理缺乏等位基因与人16p11.2相对应的区域，称为16p11.2 df/+小鼠。我们将检验以下假设 16p11.2 df/+小鼠中不同杏仁核电路功能障碍会导致异常习惯行为和恐惧处理特征的损害。为了检验这一假设，我们设计了一个将分子遗传工具与电生理学，化学发生的综合策略相结合和行为技术。该研究计划的发现将提供有关突触，细胞和电路机制，通过不同的杏仁核电路功能障碍有助于异常与ASD有关的行为。