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

项目总结 世界卫生组织认为，神经性疾病是最大的威胁之一。 公共卫生。“据估计，帕金森氏症(PD)在全球范围内折磨着近1000万人， 其中100万人居住在美国。最近的证据表明，微生物区系在促进 帕金森病动物模型的运动行为异常和α-突触核蛋白病理，但准确的 调节这些影响的机制仍然难以捉摸。此外，迷走神经广泛存在于 推测在淀粉样病变从肠神经系统向中枢扩散的过程中起作用 神经系统在帕金森病的发展过程中，但到目前为止还没有人询问其后果 微生物组诱导的迷走神经活动改变对帕金森病症状的发展。这些基本原则 围绕微生物组如何调节帕金森病症状的知识空白激发了我的研究 在帕金森病小鼠模型中揭示微生物与迷走神经活动之间的相互作用。我假设那个迷路的人 微生物调节代谢物的化学感觉有助于帕金森病相关症状的发展。 这项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的任务相一致，以“寻求关于大脑和 神经系统可以减轻神经系统疾病的负担。 我的初步数据支持这样一个中心假设，即微生物群在体内调节迷走神经纤维的活动， 而迷走神经活动的改变是由于短时间内对细菌刺激的主动感觉造成的 比例。此外，我的实验结果表明，在帕金森病小鼠模型中，迷走神经纤维活动增强， 支持迷走神经过度活动是导致帕金森病相关行为发展的一个因素。在……里面 根据这些数据，我推测迷走神经传入信号的功能改变是由 肠腔内微生物信号的失调以及微生物群诱导的迷走神经过度活动 有助于帕金森病症状的发展。我建议通过以下几点来检验这些假设 目标。目的1：确定调节迷走神经活动的微生物介导的代谢产物；目标2： 确定迷走神经活动中微生物群驱动的改变在帕金森病相关疾病发展中的作用 症状。这些目标的发现将揭示对分子和细胞信号传递的新见解 帕金森病内稳和进展过程中微生物区系-肠道-脑通讯的机制 症状。

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.