Elucidating neural substrates that mediate autism-like behaviors

阐明介导自闭症样行为的神经基质

• 批准号: 10215438
• 负责人: Gloria Choi
• 金额: $ 51.44万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 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/10215438
• 关键词: ASD patient; Adult; Affect; Anatomy; Animal Model; Animals; Appearance; Area; Atlases; Automobile Driving; Behavior; Behavioral; Blocking Antibodies; Brain; Brain region; Cells; Coin; Cortical Malformation; Development; Double-Stranded RNA; Embryo; Exhibits; Exposure to; FOS gene; Fetal Development; Genetic; Helper-Inducer T-Lymphocyte; IL17 gene; Immediate-Early Genes; Immune; Immunologics; In Vitro; Individual; Inflammation; Inflammatory; Knock-out; Lead; Location; Maps; Mediating; Modeling; Mothers; Neurologic; Pathologic; Pathway interactions; Phenotype; Pregnant Women; Risk Factors; Rodent; Role; Signal Transduction; Stress; Structural defect; Structure; Surveys; Symptoms; Testing; Therapeutic; Translating; Uterus; Virus Diseases; autism spectrum disorder; behavioral phenotyping; cell type; cytokine; fetal; immune activation; in utero; individuals with autism spectrum disorder; mouse model; mutant; neural circuit; offspring; optogenetics; pregnant; receptor; relating to nervous system; repetitive behavior; voltage clamp

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 在母体子宫中发育的胎儿可能会暴露在环境压力下，这可能会导致 长期的神经和行为变化。不受控 子宫内的炎症及其对后代行为的影响已被建模 在啮齿类动物中，随后被称为母体免疫激活（MIA）。但是依然 尚不清楚发生在怀孕母鼠中的免疫激活是如何转化为 神经和行为的变化。 使用缺乏特定促炎免疫细胞亚群的遗传突变体和 阻断针对其活性的抗体，我们最近发现，促炎性T细胞 母亲中表达白细胞介素-17 α（IL-17 α）的辅助细胞（Th 17细胞）诱导MIA依赖性 行为变化和异常的皮质表型。我们还观察到， IL-17 a受体（IL-17 Ra）在胎儿脑中表达，其表达在胎儿期增加。 大脑皮质板的位置这些观察结果表明， 在胎儿脑中表达的IL-17 Ra的不受控制的激活诱导 异常的皮质斑块和这些结构异常最终导致MIA- 相关行为表型。因此，在本申请中，我们提出1）确定是否 皮质异常可以预测MIA后代的行为表型，2）表征 成年MIA后代的皮质异常，以及3）功能性地确定皮质是否 表型是MIA行为异常的根本原因。

项目成果

IL-17a promotes sociability in mouse models of neurodevelopmental disorders.

• DOI: 10.1038/s41586-019-1843-6
• 发表时间: 2020-01
• 期刊: Nature
• 影响因子: 64.8
• 作者: Reed MD;Yim YS;Wimmer RD;Kim H;Ryu C;Welch GM;Andina M;King HO;Waisman A;Halassa MM;Huh JR;Choi GB
• 通讯作者: Choi GB