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Identification of bacterial products required for brain development

鉴定大脑发育所需的细菌产物

基本信息

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
项目类别：
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&apos 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

项目摘要

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，肠道微生物群在正常神经系统中起着重要作用