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

项目总结 认知障碍，定义为注意力减退、学习和记忆减退以及推理能力减退。 是一种常见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)。老龄化是认知障碍的最大风险因素，而美国老龄化人口 预计到2050年将增加到8850万人。公共卫生迫切需要在临床上识别 预防和/或治疗因缺乏电流而引起的认知障碍的易于处理的目标 治疗选择和不断增长的老龄化人口。环境因素包括缺氧性侮辱和饮食 消费有助于认知障碍的概率，但环境如何影响的精确机制 与减值风险相互作用的因素仍然知之甚少。肠道微生物区系调节环境 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。总而言之，这一证据值得调查 肠道微生物区系是否在成年期和衰老过程中调节认知。 我们的初步数据支持我们的中心假设，即肠道微生物区系对于调节有害的 生酮饮食对低氧(Hyp)小鼠海马区依赖认知功能的影响 消费。鉴于Hyp诱导和衰老诱导的分子机制的相似性 关于认知障碍，我们进一步假设，选择微生物可以改变衰老诱导的认知障碍。我们的 基本原理是确定肠道微生物通过海马体和/或改变对认知起作用 迷走神经信号通路将为增龄性认知障碍提供新的治疗机会。 我们的具体目标验证了以下假设：目标1：确定介导 生酮饮食(KD)和低氧(Hyp)对认知行为的影响并测试是否用选定的微生物治疗 改善衰老引起的认知缺陷；目标2：确定肠道微生物区系在调节海马体中的作用 与认知行为相关的活动；目标3：评估迷走神经信号对微生物区系的贡献 认知行为的依赖调节。在得出结论后，我们将更好地了解肠道是如何 微生物区系调节认知行为结果。这一贡献意义重大，因为它代表着 用于识别可作为临床易处理的微生物区系操作的机械性方法 帮助认知的治疗靶点。 未来的研究将分析微生物区系-肠道-大脑回路在微生物调节宿主认知中所起的作用 并专注于识别导致认知行为变化的精确微生物分子。

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.