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Elucidating neural substrates that mediate autism-like behaviors

阐明介导自闭症样行为的神经基质

基本信息

批准号：
9423335
负责人：
Gloria Choi
金额：
$ 54.15万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2017-09-12 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9423335
关键词：
Adult Affect Anatomy Animal Model Animals Appearance Area Atlases Autistic Disorder Automobile Driving Behavior Behavioral Blocking Antibodies Brain Brain region CD4 Positive T Lymphocytes Cells Coin Cortical Malformation Development Double-Stranded RNA Embryo Exhibits FOS gene Fetus Genetic Helper-Inducer T-Lymphocyte IL17 gene Immediate-Early Genes Immune Immunologics In Vitro Individual Inflammation Inflammatory Injectable Knock-out Lead Location Maps Mediating Modeling Mothers Neurologic Pathologic Pathway interactions Patients Phenotype Risk Factors Rodent Role Signal Transduction Stress Structural defect Surveys Symptoms Testing Therapeutic Translating Uterus Virus Diseases autism spectrum disorder cell type cytokine fetal immune activation in utero mouse model mutant neural circuit offspring optogenetics pregnant receptor relating to nervous system repetitive behavior voltage clamp

项目摘要

ABSTRACT Developing fetus in maternal womb can be exposed to environmental stress, and this may lead to the development of long-lasting neurological and behavioral changes. Uncontrolled Inflammation encountered in utero and its effects on behaviors of offspring have been modeled in rodents and subsequently coined as maternal immune activation (MIA). However, it is still unknown how the immune activation, which takes place in pregnant dams, is translated into neurological and behavioral changes in offspring. Using both genetic mutants lacking a particular subset of pro-inflammatory immune cells and blocking antibodies targeting their activities, we have recently found that pro-inflammatory T helper cells (Th17 cells) expressing intereukin-17a (IL-17a) in mothers induce MIA-dependent behavioral changes and abnormal cortical phenotypes in offspring. We also observed that the receptor for IL-17a (IL-17Ra) is expressed in the fetal brain and its expression is increased in the cortical plate upon MIA. These observations taken together suggest an exciting hypothesis that uncontrolled activation of IL-17Ra expressed in fetal brain induces abnormal cortical patches and these structural abnormalities eventually lead to the MIA- associated behavioral phenotypes. Thus, in this application, we propose 1) to determine if cortical abnormalities could predict behavioral phenotypes in MIA offspring, 2) to characterize cortical abnormalities in adult MIA offspring, and 3) functionally determine if the cortical phenotype is the underlying cause of the MIA behavioral abnormalities.

摘要