Microbial modulation of forebrain development and social behavior

前脑发育和社会行为的微生物调节

• 批准号: 9760850
• 负责人: Joseph James Bruckner
• 金额: $ 2.97万
• 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: 2019-02-08 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760850
• 关键词: Address; Adolescent; Adult; Aggressive behavior; Alzheimer' s Disease; Animal Model; Animals; Antibiotics; Bacteria; Behavior; Behavior Disorders; Behavioral; Biological Assay; Brain; Brain region; Characteristics; Complex; Derivation procedure; Development; Disease; Environment; Exhibits; Forebrain Development; Future; Genetic; Germ-Free; Gnotobiotic; Goals; Intervention; Intestines; Larva; Link; Mammals; Measures; Mediating; Mental Depression; Microscopy; Modeling; Monitor; Morphology; Multiple Sclerosis; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Organ; Parkinson Disease; Pathway interactions; Phenotype; Probiotics; Program Development; Prosencephalon; Resolution; Role; Series; Social Behavior; Social Development; Social Interaction; Telencephalon; Testing; Therapeutic; Time; Tissues; Vertebrates; Work; Zebrafish; anxiety-related behavior; autism spectrum disorder; body system; critical period; experimental study; genetic manipulation; gut microbiota; host-associated microbial communities; improved; in vivo imaging; insight; microbial; microbial colonization; microbiota; nervous system disorder; neurodevelopment; neuron component; neuron development; preference; programs; social; trait

PROJECT SUMMARY In addition to intrinsic genetic programs, the development and function of multiple tissues is influenced by extrinsic factors including host-associated microbes. Similarly, host-associated microbes have been linked to neurological disorders including autism-spectrum disorder, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. To develop successful therapeutics for these disorders we must understand the roles of extrinsic factors such as the intestinal microbiota in influencing neurodevelopment. Increasing evidence in animal models suggests that the intestinal microbiota modulates social behavior. However, it is still unclear how neuronal characteristics might be influenced by specific microbial strains and products. In initial work, we have demonstrated that the intestinal microbiota is required for social behavior in zebrafish. Additional preliminary results have led us to hypothesize that microbial modulation of social behavior centers on neuronal development in the zebrafish forebrain. The goal of the proposed work is to use the advantages of our gnotobiotic zebrafish model to identify the specific pathways by which microbial strains and products modulate social behavior. With the ability to manipulate and monitor both the intestinal microbiota and host genetics in large numbers of intact adult and juvenile zebrafish, we have a unique opportunity to reveal mechanistic insights that current models of microbial influence in the brain lack. In Aim 1, I will measure social behavior during a developmental time series to determine the critical period during which the intestinal microbiota influences zebrafish behavior. In Aim 2 I will use high resolution microscopy in intact zebrafish to test whether the intestinal microbiota is required for development of neuronal features that influence network function, including neuronal morphology and activity. Finally, in Aim 3 I will use our established gnotobiotic pipeline to identify the particular bacterial strains and their products that mediate microbial influence on social behavior. Insights from these experiments will suggest new avenues for probiotic and antibiotic interventions in multiple neurological disorders by revealing the specific mechanisms that link the intestinal microbiota and development of social behavior.

项目总结 除了固有的遗传程序外，多种组织的发育和功能还受到 外在因素，包括与宿主相关的微生物。同样，与宿主相关的微生物也与 神经系统疾病，包括自闭症谱系障碍、多发性硬化症、阿尔茨海默病和 帕金森氏症。为了开发成功的治疗这些疾病的方法，我们必须了解 影响神经发育的外在因素，如肠道微生物区系。越来越多的证据表明 动物模型表明，肠道微生物区系调节社会行为。然而，目前仍不清楚 神经元特征可能如何受到特定微生物菌株和产物的影响。在最初的工作中，我们 已经证明，斑马鱼的社会行为需要肠道微生物群。其他内容 初步结果使我们假设微生物对社会行为的调节以神经元为中心 斑马鱼前脑的发育。拟议工作的目标是利用我们的优势 识别微生物菌株和产品的特定途径的共生斑马鱼模型 调节社会行为。 有能力操纵和监测肠道微生物区系和宿主遗传学在大量 完整的成年斑马鱼和幼斑马鱼，我们有一个独特的机会来揭示当前 关于微生物对大脑影响的模型还很缺乏。在目标1中，我将测量发育过程中的社会行为 时间序列，以确定肠道微生物区系影响斑马鱼行为的关键时期。 在目标2中，我将使用高分辨率显微镜在完整的斑马鱼身上测试肠道微生物区系是否 发展影响网络功能的神经元功能所必需的，包括神经元形态 和活动。最后，在目标3中，我将使用我们建立的灵知生菌管道来鉴定特定的细菌 调节微生物对社会行为产生影响的菌株及其产品。从这些实验中获得的见解 将为益生菌和抗生素干预多种神经疾病提供新的途径 揭示了将肠道微生物区系和社会行为发展联系起来的具体机制。