Genetic analysis of intrinsic sensory neuron function in the enteric neural circuits

摘要 胃肠道(GI)是唯一具有自身肠道神经系统进化的腹部器官。 (ENS)完全包含在肠壁内，也被称为肠道中的“第二脑”。我们的长期目标是 了解ENS中的固有初级感觉神经元(IPAN)如何检测和响应物理 以及肠腔中的化学信号和控制结肠中内容物的推进。 尽管已经知道了大约25年，iPAN仍然是神经内窥镜中最神秘的神经元的一个子集。 因为它们如何参与协调的肌肉运动(运动)，调节免疫细胞功能 (免疫)和维持肠道屏障的完整性尚不完全清楚。同样神秘的是 智能人工神经网络能否发挥“模式生成器”的功能，控制生物周期的节律性？ 沿着结肠传播收缩。这在很大程度上是因为缺乏可用于有选择地 操纵特定种类的肠神经细胞的兴奋性，以及尝试过的任何药物 刺激或阻断IPAN中的活动可能会作用于许多其他类型的神经元(或非神经细胞)， 使结果的解释变得不清楚。 在试点研究中，我们生成了关键资源，使我们能够确定并选择性地针对β- 表达降钙素基因相关肽(β-cGRP+)的IPANs。通过使用这些独特的资源，我们将能够提出重要的 关于β-CGRP+IPAN在ENS中的作用的问题：β-CGRP+IPAN在ENS中有什么作用 神经活动沿着肠道的传播？这些IPAN是由机械和化学信号激活的吗 在肠腔里？这些IPAN能作为不同微生物区系衍生代谢物的细胞传感器吗？ 这项提议代表着一项重大的技术进步，它使用了尖端的神经遗传学方法， 使从基因上定位并确定β-CGRP+IPAN在ENS和ENS中的功能成为可能 提供了关于β-cGRP+选择性激活和抑制的第一个见解 ENS中的IPAN影响胃肠动力。这些信息将促进我们对 ENS为运动性GI治疗的新策略的开发提供了新的见解 通过瞄准ENS中的IPAN来扰乱秩序。

SUMMARY The gastrointestinal (GI) tract is the only abdominal organ that has evolved with its own enteric nervous system (ENS) fully contained within the gut wall, also known as the “second brain” in the gut. Our long-term goal is to understand how the intrinsic primary sensory neurons (IPANs) in the ENS detect and respond to both physical and chemical cues in the gut lumen and control propulsion of content in the colon. Although known for about 25 years, the IPANs are still a subset of the most mysterious neurons in the ENS because how they participate in coordinated muscle movements (motility), regulate immune cell function (immunity) and maintain integrity of intestinal barrier is not completely understood. Equally as mysterious is whether the IPANs can fulfil the function as a “pattern generator” and can control the rhythmicity of cyclical propagating contractions along the colon. This is largely due to a lack of tools that can be used to selectively manipulate the excitability of specific classes of enteric neurons and any drugs that have been tried to stimulate or block activity in IPANs will likely act on many other types of neurons (or non-neuronal cells), making interpretation of the results unclear. In pilot studies, we have generated critical resources enabling us to identify and selectively targeting the β- CGRP-expressing (β-CGRP+) IPANs. By using these unique resources, we will be able to ask important questions regarding the roles of the β-CGRP+ IPANs in the ENS: What role the β-CGRP+ IPANs have in the propagation of neural activity along the gut? Are these IPANs activated by both mechanical and chemical cues in the gut lumen? Can these IPANs serve as cellular sensors for distinct microbiota-derived metabolites? This proposal represents a major technical advance by using cutting-edge neurogenetic approaches which make it possible to genetically target and determine the functionality of the β-CGRP+ IPANs in the ENS both ex vivo and in vivo, providing the first insights into how selective activation and inhibition of the β-CGRP+ IPANs in the ENS affects GI-motility. This information will advance our understanding of the inner workings of the ENS and shed new insights on the development of novel strategies for the treatment of motility-related GI disorders by targeting the IPANs in the ENS.