Regulation of enteric motor neurocircuits by enteric glia in health and disease

健康和疾病中肠神经胶质细胞对肠运动神经回路的调节

• 批准号: 10213012
• 负责人: BRIAN D. GULBRANSEN
• 金额: $ 34.51万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10213012
• 关键词: Acute; Address; Affect; Biological Assay; Cells; Chronic; Colitis; Complex; Cues; Data; Development; Disease; Enteral; Enteric Nervous System; Feedback; Functional disorder; Funding; Gastrointestinal Diseases; Gastrointestinal Motility; Glial Fibrillary Acidic Protein; Goals; Health; Human; Image; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Motility; Intestinal Pseudo-Obstruction; Intestines; Irritable Bowel Syndrome; Knockout Mice; Mediator of activation protein; Modeling; Motor; Motor Pathways; Mus; Muscle; Mutant Strains Mice; Neural Pathways; Neuroglia; Neuronal Plasticity; Neurons; Neurotransmitters; Nitrergic Neurons; Peristalsis; Pharmaceutical Preparations; Phase; Recruitment Activity; Reflex action; Regulation; Role; Signal Transduction; Specificity; Synapses; System; Testing; Tissues; Transgenic Mice; calcium indicator; cell motility; excitatory neuron; experimental study; gastrointestinal; glial activation; inhibitory neuron; insight; motility disorder; motor behavior; mouse model; neural circuit; neural network; neuroinflammation; neuron loss; neuronal excitability; neuroregulation; neurotransmission; novel; novel strategies; novel therapeutics; recruit; therapeutic development

PROJECT SUMMARY Reflexive motor behaviors of the intestine including peristalsis are controlled by the enteric nervous system (ENS); a complex neural network embedded in the gut wall. Perturbations within the ENS contribute to the development of dysmotility in irritable bowel syndrome, inflammatory bowel disease, and severe motility disorders such as chronic intestinal pseudo-obstruction, but the mechanisms responsible for persistent changes in enteric neural circuitry are unknown. Recent data show that enteric glia, non-neuronal cells that surround enteric neurons, regulate neuronal excitability and contribute to neuroinflammation. The overall goal of this proposal is to define how specialized interactions between enteric glia and neurons regulate motility and how alterations in those mechanisms contribute to disease. This proposal tests the central hypothesis that enteric glia are specialized to potentiate the activity of ascending excitatory neural pathways involved in normal contractile motility, and that disruption of this regulatory system by inflammation contributes to neuronal hyperexcitability. This dual hypothesis will be tested in two specific aims that utilize genetically encoded calcium indicators to study neuron-glia interactions, glial chemogenetic actuators to study how glia modulate specific types of enteric neurons, and a post-inflammatory model of enteric neuroplasticity to study how glia contribute to neuronal hyperexcitability following inflammation. Aim 1 will test the hypothesis that enteric glia are specialized to sense excitatory neurons and potentiate ascending neural pathways involved in the contractile phase of motility. Aim 1.1 will use genetically encoded calcium indicators to study glial recruitment by polarized neural pathways in motility reflexes. Aim 1.2 will combine the chemogenetic activation of enteric glia with neuronal and glial imaging using genetically encoded calcium indicators to test the hypothesis that glia differentially affect subsets of enteric neurons. Aim 2 will test the hypothesis that glia contribute to neuronal hyperexcitability following colitis by increasing positive feedback to excitatory neurons and by reducing inhibitory feedback from inhibitory neurons. Aim 2.1 will study how altered interactions between glia and excitatory neurons contribute to neuronal hyperexcitability following colitis. Aim 2.2 will use mutant mice and selective drugs to study how glia contribute to neuronal hyperexcitability through interactions with inhibitory neurons. The results of this study will provide novel insight into glial mechanisms that regulate the excitability of enteric neural circuits. A better understanding of the glial mechanisms that regulate motility will facilitate the development of therapeutics for dysmotility by revealing novel targets to modify gastrointestinal reflexes.

项目摘要 包括蠕动在内的肠道的反射运动行为由肠神经系统控制 （ENS）;嵌入肠壁中的复杂神经网络。 ENS内部的扰动有助于 肠易激综合症，炎症性肠病和严重运动的发育不良发育 诸如慢性肠道伪腹结构之类的疾病，但负责持续的机制 肠神经回路的变化尚不清楚。最近的数据表明，肠神经胶质细胞，非神经元细胞 围绕肠神经元，调节神经元兴奋性并有助于神经炎症。总体目标 该建议的是定义肠神经元与神经元之间的专业相互作用如何调节运动性和 这些机制的改变如何促进疾病。该提案检验了一个中心假设，即 肠神经胶质的专门用于增强与正常相关的上升兴奋性神经途径的活性 收缩的运动性以及这种调节系统的破坏会导致神经元 过度兴奋。该双重假设将以两个利用遗传编码的特定目的进行测试 钙指标研究神经元相互作用，神经胶质化学发生执行剂，以研究神经胶质如何调节 特定类型的肠神经元，以及肠神经塑性的炎后模型，以研究神经胶质 炎症后有助于神经元过度刺激性。 AIM 1将检验肠神经胶质的假设 专门用于感知兴奋性神经元和增强涉及的上升神经途径 动力的收缩阶段。 AIM 1.1将使用遗传编码的钙指标研究神经胶质募集 通过运动反射的极化神经通路。 AIM 1.2将结合肠的化学发生激活 使用遗传编码的钙指标，具有神经元和神经胶质成像的神经胶质 差异影响肠神经元的子集。 AIM 2将检验神经胶质有助于神经元的假设 结肠炎后过度兴奋，通过增加对兴奋性神经元的积极反馈并减少 抑制性神经元的抑制反馈。 AIM 2.1将研究神经胶质与之间的相互作用改变 兴奋性神经元在结肠炎后有助于神经元过度兴奋。 AIM 2.2将使用突变小鼠，并且 选择性药物研究神经胶质如何通过与抑制性的相互作用来促进神经元过度兴奋性 神经元。这项研究的结果将为调节兴奋性的神经胶质机制提供新的见解 肠神经回路。更好地了解调节运动性的神经胶质机制将有助于 通过揭示新的靶标改变胃肠道反射，开发用于运动障碍的治疗疗法。