Identification of bacterial products required for brain development

鉴定大脑发育所需的细菌产物

• 批准号: 9807763
• 负责人: JUDITH S EISEN
• 金额: $ 22.13万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807763
• 关键词: Ablation; Affect; Alzheimer' s Disease; Animals; Anxiety; Bacteria; Bacterial Proteins; Behavior; Behavioral; Biochemical; Bioinformatics; Biological Assay; Brain; Brain region; Development; Diagnostic; Disease; Failure; Gene Expression; Genetic; Germ-Free; Gnotobiotic; Homologous Gene; Human; Impairment; Individual; Interneurons; Intestines; Investigation; Knowledge; Larva; Lead; Learning; Link; Mental Depression; Modeling; Molecular; Morphology; Motor Activity; Nature; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Outcome; Parkinson Disease; Phenocopy; Phenotype; Play; Population; Process; Protein Analysis; Reporting; Research; Role; Schizophrenia; Surface; Testing; Therapeutic; Visual system structure; Work; Zebrafish; autism spectrum disorder; bacterial community; bacterial genetics; base; developmental disease; dysbiosis; gut microbiota; insight; member; microbiome; microbiota; mouse model; nervous system development; neurodevelopment; neuronal circuitry; normal microbiota; novel; offspring; preference; social; superior colliculus Corpora quadrigemina; targeted treatment; vision development

There is mounting evidence that the intestinal microbiota play an important role in normal nervous system development, although the underlying molecular mechanisms are generally unknown. We propose to investigate the role of the intestinal microbiota in development of an identified population of superficial interneurons (SINs) in the zebrafish optic tectum that are required for visually-guided prey capture behavior. Previous work showed that prey capture is significantly impaired in larvae in which SINs are genetically ablated. We find that the microbiota are necessary for SINs to differentiate their GABAergic phenotype, and consequently larvae reared germ free (GF), in the absence of bacteria, phenocopy the prey capture deficit of larvae in which SINs have been ablated. We hypothesize that members of the zebrafish-associated microbiota normally produce molecular products that promote SIN differentiation. We will test this hypothesis using an unbiased screen to identify bacterial products that affect SIN differentiation. First we will use gnotobiotic zebrafish colonized with specific zebrafish bacterial isolates to learn which bacterial species are required for normal SIN development and prey capture behavior. We will then take advantage of a pipeline we established that utilizes bacterial genetics, bioinformatics, and biochemical approaches, to learn the molecular nature of the bacterial products. Discovering the molecular mechanisms by which host-associated bacteria promote normal nervous system development will provide important new insights into a fundamental process that is not well understood, reveal how this process can go awry during intestinal dysbiosis, an imbalance that has been linked to neurodevelopmental conditions such as autism spectrum disorder and schizophrenia, and provide new possibilities for developing targeted therapies.

越来越多的证据表明肠道菌群在正常神经系统中起着重要作用 发展，虽然潜在的分子机制通常是未知的。我们建议 研究肠道微生物群在确定的浅表性 中间神经元（SIN）在斑马鱼的视顶盖所需的视觉引导猎物捕获行为。 先前的工作表明，在基因上具有SINs的幼虫中，猎物捕获显着受损 消融。我们发现微生物群是SIN分化其GABA能表型所必需的， 因此，幼虫饲养无菌（GF），在没有细菌的情况下， 其中SIN已被消融的幼虫。我们假设与斑马鱼相关的微生物群成员 通常产生促进SIN分化的分子产物。我们将使用一个 无偏筛选以鉴定影响SIN分化的细菌产物。首先，我们将使用gnotobiotic 用特定的斑马鱼细菌分离物定殖斑马鱼，以了解需要哪些细菌物种 正常的SIN发育和猎物捕获行为。然后我们将利用我们建立的管道 利用细菌遗传学，生物信息学和生物化学方法，了解细菌的分子性质。 细菌产品。发现宿主相关细菌促进 正常的神经系统发育将提供重要的新的见解，一个基本的过程， 很好地理解，揭示了这个过程如何在肠道生态失调期间出错，这种失衡一直是 与自闭症谱系障碍和精神分裂症等神经发育状况有关， 开发靶向治疗的新可能性。