Encoding of inflammatory mediators by vagal sensory neurons

项目摘要 神经系统和免疫系统相互沟通以对感染作出反应 并保持免疫平衡。过去二十年的研究表明，迷走神经 神经是神经免疫传递运动信号下行的关键途径 到身体，除了感觉信号上升到大脑。这些路径包括 神经免疫反射回路中的两个弧形称为炎症反射，其中神经活动 在迷走神经上调节脾中细胞因子的产生。虽然功能性和 脾的下行运动通路的分子机制在 这种反射，目前还不清楚迷走感觉神经元是如何检测和代表 原位炎症。这一未知的机制是人类上升感觉弧线的关键部分。 炎症反射。因此，拟议研究的目标是使用大规模的钙 成像以发现迷走感觉神经元如何编码和表示特定的信息 炎症介质。通过监测迷走感觉神经元当它们被呈现时 先天免疫反应的炎性介质(例如促炎和抗炎 细胞因子、阻尼剂、PAMP)，我们的目标是在种群水平和在 单个感觉神经元的水平。这一新的理解将提供至关重要的机制 对免疫信号的神经系统表现的洞察是一个普遍的原则，它 可以用来了解一系列炎症性疾病的问题所在 免疫失调。 拥有一支经验丰富的科学家团队，他们是免疫神经调节方面的专家，我们 将使用感觉神经科学的技术和方法来确定迷走神经 感觉神经元编码有关炎症介质的信息。这一新的基本原理 对神经免疫通讯的理解可能会提供新的机制洞察力 关于免疫动态平衡紊乱。它还可能导致识别新的 基于迷走神经的神经调节治疗多种炎症性疾病的靶点和策略 精神错乱。

Project Summary The nervous system and immune system communicate with each other to respond to infections and maintain immune homeostasis. Work over the last two decades has shown that the vagus nerve is a critical pathway for neuro-immune communication carrying motor signals descending to the body, in addition to sensory signals ascending to the brain. These pathways comprise the two arcs in the neuro-immune reflex circuit termed the inflammatory reflex, in which neural activity on the vagus nerve regulates cytokine production in the spleen. While the functional and molecular mechanisms of the descending motor pathway to the spleen are well-established in this reflex, it is unclear how vagal sensory neurons detect and represent information about inflammation in situ. This unknown mechanism is a critical piece of the ascending sensory arc of the inflammatory reflex. Therefore, the goal of the proposed studies is to use large-scale calcium imaging to discover how vagal sensory neurons encode and represent information about specific inflammatory mediators. By monitoring vagal sensory neurons while they are presented with inflammatory mediators of the innate immune response (e.g. pro- and anti-inflammatory cytokines, DAMPs, PAMPs), we aim to uncover a neural code both at the population-level and at the level of individual sensory neurons. This new understanding will provide crucial mechanistic insights into the nervous system representation of immune signals as a general principle, which can be used to understand what goes wrong in a host of inflammatory disorders that involve immune dysregulation. With a team of experienced scientists who are experts in the neural regulation of immunity, we will use techniques and approaches adapted from sensory neuroscience to determine how vagal sensory neurons encode information about inflammatory mediators. This new fundamental understanding of neuro-immune communication will potentially provide new mechanistic insights about disorders of disrupted immune homeostasis. It may also lead to the identification of new targets and strategies for vagus nerve-based neuromodulation to treat a host of inflammatory disorders.