Dissecting gut microbiota-based effects on aging-associated cognitive deficits

剖析肠道微生物群对衰老相关认知缺陷的影响

• 批准号: 10022087
• 负责人: Christine Olson
• 金额: $ 3.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022087
• 关键词: Ablation; Adult; Affect; Aging; Alzheimer' s disease patient; American; Animal Model; Antibiotic Therapy; Anxiety; Attention; Behavior; Behavioral; Brain; Carbohydrates; Centers for Disease Control and Prevention (U.S.); Clinical; Cognition; Cognitive; Cognitive deficits; Communities; Consumption; Data; Development; Diet; Disease; Electrophysiology (science); Emotional; Environmental Risk Factor; Equilibrium; Exposure to; Fatty acid glycerol esters; Future; Genetic Predisposition to Disease; Germ-Free; Gnotobiotic; Health; High Fat Diet; Hippocampus (Brain); Hypoxia; Impaired cognition; Impairment; Infection; Investigation; Learning; Lipofuscin; Long-Term Potentiation; Mediating; Memory; Memory impairment; Metabolic syndrome; Microbe; Molecular; Mus; Nerve; Physical Exercise; Play; Prevention; Prevention strategy; Probability; Public Health; Research; Resistance; Risk; Risk Factors; Rodent; Role; Sensory; Short-Term Memory; Signal Pathway; Signal Transduction; Stress; Symptoms; Taxonomy; Testing; Vagus nerve structure; afferent nerve; aged; aging population; base; behavior test; behavioral outcome; brain behavior; clinically relevant; cognitive performance; economic impact; effective therapy; gut bacteria; gut microbes; gut microbiome; gut microbiota; improved; ketogenic diet; microbial; microbiome; microbiota; microbiota-gut-brain axis; morris water maze; neurotransmission; novel; novel therapeutics; object recognition; response; social; spatial memory; tau Proteins; tau-1; therapeutic target; treatment strategy

PROJECT SUMMARY Cognitive impairment, defined by reduced attention, diminished learning and memory, and impaired reasoning, is a common and pressing public health concern, afflicting 16 million Americans and increasing globally (CDC 2011). Aging constitutes the greatest risk factor for cognitive impairment, and the American aging population is expected to increase to 88.5 million people by 2050. There is a pressing public health need to identify clinically tractable targets for prevention and/or treatment of cognitive impairment arising from both the lack of current treatment options and the rising aging population. Environmental factors including hypoxic insult and dietary consumption contribute to cognitive impairment probability, but precise mechanisms for how environmental factors interact with impairment risk remains poorly understood. The gut microbiota mediates environmental contributions to host health and disease and causally modulates cognitive behavior in the novel object recognition, Barnes maze, and Morris water maze tasks. Together, this evidence warrants investigation into whether the gut microbiota modulates cognition during adulthood and aging. Our preliminary data support our central hypothesis that the gut microbiota is important for mediating detrimental effects of hypoxia (Hyp) murine hippocampal-dependent cognitive performance under ketogenic diet (KD) consumption. Given the similarities between molecular mechanisms for Hyp-induced and aging-induced cognitive impairment, we further hypothesize that select microbes modify aging-induced cognitive deficits. Our rationale is that identification of gut microbes contributing to cognition through changes in hippocampal and/or vagal nerve signaling pathways will offer new therapeutic opportunities for aging-induced cognitive impairment. Our specific aims test the following hypotheses: Aim 1: Identify specific microbial taxa that mediate effects of the ketogenic diet (KD) and hypoxia (Hyp) on cognitive behavior and test whether treatment with select microbes modifies cognitive deficits due to aging; Aim 2: Determine roles for the gut microbiota in modulating hippocampal activity relevant to cognitive behavior; Aim 3: Assess the contribution of vagal nerve signaling to microbiota- dependent modulation of cognitive behavior. Upon conclusion, we will gain better understanding of how the gut microbiota modulates cognitive behavioral outcomes. This contribution is significant since it represents a mechanistic approach towards identifying microbiota manipulations that could serve as clinically tractable therapeutic targets to aid cognition. Future studies will analyze the role microbiota-gut-brain circuits play in microbial modulation of host cognition and focus on identifying precise microbial molecules responsible for cognitive behavioral changes.

项目摘要 认知障碍，定义为注意力下降、学习和记忆力下降以及推理能力受损， 是一个普遍而紧迫的公共卫生问题，困扰着1600万美国人，并在全球范围内不断增加（CDC 2011年）。老龄化构成认知障碍的最大危险因素，美国老龄化人口是 预计到2050年将增加到8850万人。有一个紧迫的公共卫生需要确定临床 用于预防和/或治疗由缺乏电流和/或电流刺激引起的认知损害的易处理的靶点。 治疗选择和日益老龄化的人口。环境因素，包括缺氧损伤和饮食 消费有助于认知障碍的可能性，但环境如何的精确机制 与损害风险相互作用的因素仍然知之甚少。肠道微生物群介导环境 对宿主健康和疾病的贡献，并因果地调节新对象的认知行为 识别、巴恩斯迷宫和莫里斯水迷宫任务。总之，这些证据值得调查 肠道微生物群是否调节成年和衰老期间的认知。 我们的初步数据支持我们的中心假设，即肠道微生物群对于介导有害的 缺氧（Hyp）对生酮饮食（KD）下小鼠大脑皮层依赖性认知能力的影响 消费鉴于Hyp-induced和aging-induced的分子机制之间的相似性， 认知障碍，我们进一步假设，选择微生物修改老化引起的认知缺陷。我们 基本原理是通过海马和/或海马神经元的变化来鉴定有助于认知的肠道微生物， 迷走神经信号通路将为衰老引起的认知障碍提供新的治疗机会。 我们的具体目标是测试以下假设：目标1：鉴定介导微生物作用的特定微生物类群。 生酮饮食（KD）和缺氧（Hyp）对认知行为的影响，并测试是否用选择的微生物治疗 改善衰老引起的认知缺陷;目的2：确定肠道微生物群在调节海马神经元中的作用 与认知行为相关的活动;目的3：评估迷走神经信号传导对微生物群的贡献- 认知行为的依赖性调节。在结论中，我们将更好地了解肠道如何 微生物群调节认知行为结果。这一贡献意义重大，因为它代表了一个 确定微生物群操作的机械方法， 治疗目标来帮助认知。 未来的研究将分析微生物-肠道-大脑回路在微生物调节宿主认知中的作用 并专注于识别负责认知行为变化的精确微生物分子。