Identification of bacterial products required for brain development

越来越多的证据表明，肠道微生物区系在正常神经系统中起着重要作用。 发展，尽管潜在的分子机制通常是未知的。我们建议 调查肠道微生物区系在已鉴定的浅表性肺炎种群发育中的作用 斑马鱼视觉顶盖中的中间神经元(SIN)，是视觉引导的猎物捕获行为所必需的。 先前的工作表明，在含有罪恶基因的幼虫中，捕获猎物的能力显著受损 消融了。我们发现，微生物区系是SINS区分其GABA能表型所必需的，并且 因此，仔鱼饲养无菌(GF)，在没有细菌的情况下，捕食者捕食不足 罪孽已被去除的幼虫。我们假设与斑马鱼相关的微生物群的成员 正常情况下会产生促进SIN分化的分子产物。我们将使用一个 无偏筛选以确定影响SIN分化的细菌产物。首先，我们将使用诺维菌素 用特定的斑马鱼细菌分离物定植斑马鱼，以了解哪些细菌种类是必需的 正常的罪恶发展和猎物捕获行为。然后我们将利用我们建立的管道 它利用细菌遗传学、生物信息学和生化方法来了解 细菌产品。发现寄主相关细菌促进的分子机制 正常的神经系统发育将为一个基本的过程提供重要的新见解 很好地理解，揭示这个过程如何在肠道生物失调期间出错，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，并提供 开发靶向治疗的新可能性。

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.