Investigating the effects of the microbiota on vagal afferent sensory neuronal activity in an animal model of Parkinson’s disease

研究微生物群对帕金森病动物模型迷走神经传入感觉神经元活动的影响

• 批准号: 10221619
• 负责人: Kelly Jameson
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221619
• 关键词: Age-Years; Animal Model; Antibiotics; Behavior; Brain; Calcium; Cell Death; Characteristics; Clinical Research; Data; Development; Disease; Disease Progression; Early Diagnosis; Early Intervention; Early treatment; Electrophysiology (science); Enteric Nervous System; Esthesia; Fiber; Genetic; Germ-Free; Gnotobiotic; Homeostasis; Hyperactivity; Image; Intestinal Content; Intestines; Knowledge; Ligands; Light; Mass Spectrum Analysis; Mediating; Microbe; Mission; Molecular; Motor; Mus; National Institute of Neurological Disorders and Stroke; Nerve; Neuraxis; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Perfusion; Phase; Play; Population; Public Health; Recombinant DNA; Regulation; Research; Role; Sensory; Signal Pathway; Signal Transduction; Small Intestines; Stimulus; Substantia nigra structure; Symptoms; Testing; Time; United States; Vagotomy; Vagus nerve structure; Viral; World Health Organization; alpha synuclein; amyloid pathology; amyloidogenesis; base; behavioral impairment; brain behavior; designer receptors exclusively activated by designer drugs; dopaminergic neuron; experience; experimental study; frontier; gastrointestinal; germ free condition; gut microbiome; gut microbiota; gut-brain axis; in vivo; insight; metabolomics; microbial; microbiome; microbiome alteration; microbiota; microbiota transplantation; motor behavior; motor deficit; motor disorder; motor symptom; mouse model; nervous system disorder; new therapeutic target; novel; overexpression; receptor; response; stem; tool

PROJECT SUMMARY Neurological disorders are recognized by the World Health Organization as “one of the greatest threats to public health.” Parkinson's disease (PD) in particular is estimated to afflict nearly 10 million people worldwide, 1 million of whom reside in the US. Recent evidence suggests a causal role for the microbiota in promoting motor behaviorial abnormalities and alpha-synuclein pathology in animal models of PD, but the precise mechanisms that mediate these effects remain elusive. In addition, the vagus nerve has been extensively hypothesized to play a role in the spread of amyloid pathology from the enteric nervous system to the central nervous system during development of PD, but there has been no interrogation to date into the consequences of microbiome-induced alterations in vagal activity on the development of PD symptoms. These fundamental gaps in knowledge surrounding precisely how the microbiome modulates PD symptoms motivates my research on uncovering interactions between microbes and vagal activity in a PD mouse model. I hypothesize that vagal chemosensation of microbially-modulated metabolites contributes to the development of PD-related symptoms. The proposed research has the potential to inform novel therapeutic targets for early intervention or diagnosis of PD, and aligns directly with the NINDS mission to “seek fundamental knowledge about the brain and nervous system to reduce the burden of neurological disease.” My preliminary data support the central hypothesis that the microbiome modulates vagal fiber activity in vivo, and that alterations in vagal activity result from active sensation of bacterial stimuli occurring on short time scales. Further, results from my experiments indicate that vagal fiber activity is elevated in a PD mouse model, supporting a role for vagal hyperactivity as a contributing factor to the development of PD-related behaviors. In light of these data, I hypothesize that functional alterations in vagal afferent signaling to the CNS arise from dysregulated microbial signals in the intestinal lumen and that microbiome-induced vagal hyperactivity contributes to the development of PD symptoms. I propose to test these hypotheses through the following aims. Aim 1: Identify select microbially-mediated metabolites that regulate vagal neuronal activity; Aim 2: Determine the role of mcirobiota-driven alterations in vagal activity in the development of PD-related symptoms. Findings from these aims will reveal novel insights into the molecular and cellular signaling mechanisms underlying microbiota-gut-brain communication at homeostasis and during the progression of PD symptoms.

项目摘要 神经系统疾病被世界卫生组织认为是“对人类健康的最大威胁之一”。 公共卫生”。特别是帕金森氏病（PD）估计在全世界折磨近1000万人， 其中100万人居住在美国。最近的证据表明，微生物群在促进 运动行为异常和α-突触核蛋白病理，但精确的 介导这些效应的机制仍然难以捉摸。此外，迷走神经已经广泛地 假设其在淀粉样病变从肠神经系统向中枢神经系统的传播中起作用， 神经系统在发展过程中的PD，但一直没有审问到目前为止的后果 微生物群诱导的迷走神经活动变化对PD症状发展的影响。这些基本 围绕微生物组如何精确调节PD症状的知识空白激发了我的研究 揭示PD小鼠模型中微生物和迷走神经活动之间的相互作用。我假设迷走神经 微生物调节的代谢物的化学感觉有助于PD相关症状的发展。 拟议的研究有可能为早期干预或诊断提供新的治疗靶点 并直接与NINDS的使命“寻求关于大脑的基本知识， 神经系统以减轻神经系统疾病的负担。” 我的初步数据支持微生物组在体内调节迷走神经纤维活动的中心假设， 迷走神经活动的改变是由短时间内对细菌刺激的主动感觉引起的 鳞片此外，我的实验结果表明，迷走神经纤维活动在PD小鼠模型中升高， 支持迷走神经活动过度作为PD相关行为发展的促成因素的作用。在 根据这些数据，我假设中枢神经系统迷走神经传入信号的功能改变是由以下因素引起的： 肠腔内微生物信号失调，微生物群诱导的迷走神经功能亢进 有助于PD症状的发展。我建议通过以下方式来检验这些假设 目标。目的1：鉴定调节迷走神经元活动的微生物介导的代谢物;目的2： 确定微生物群驱动的迷走神经活动改变在PD相关性 症状这些目标的发现将揭示分子和细胞信号转导的新见解 在PD进展过程中和稳态时微生物群-肠-脑通讯的潜在机制 症状

项目成果

Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia.

• DOI: 10.1016/j.chom.2021.07.004
• 发表时间: 2021-09-08
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Olson CA;Iñiguez AJ;Yang GE;Fang P;Pronovost GN;Jameson KG;Rendon TK;Paramo J;Barlow JT;Ismagilov RF;Hsiao EY
• 通讯作者: Hsiao EY