Neuronal Excitability and Motility in Colitis

结肠炎中的神经元兴奋性和运动性

• 批准号: 7918602
• 负责人: Gary M Mawe
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918602
• 关键词: Action Potentials; Affect; Afferent Neurons; Animals; Biological Assay; Budgets; Calcium-Activated Potassium Channel; Cations; Cells; Colitis; Colon; Comprehension; Diagnostic Procedure; Digestion; Disease; Disease remission; Down-Regulation; Electron Microscopy; Electrophysiology (science); Elements; Excitatory Postsynaptic Potentials; Exhibits; Exposure to; Fire - disasters; Functional disorder; Genus Cola; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Interstitial Cell of Cajal; Intestines; Investigation; Irritable Bowel Syndrome; Lead; Maps; Mediating; Messenger RNA; Molecular; Motor; Myenteric Plexus; Nerve; Neuronal Plasticity; Neurons; Neurotransmitters; Normal tissue morphology; Nutrient; Pattern; Peristalsis; Polymerase Chain Reaction; Presynaptic Terminals; Process; Recovery; Reflex action; Research Personnel; Resolution; Rest; Serotonin; Signal Transduction; Site; Smooth Muscle; Stimulus; Symptoms; Synapses; Synaptic Potentials; Synaptic Transmission; Techniques; Testing; Time; Tissues; Up-Regulation; absorption; cell motility; density; design; experience; gastrointestinal symptom; hyperpolarization-activated cation channel; improved; motility disorder; neural circuit; neuromuscular; neuronal excitability; neurotransmission; neurotransmitter release; postsynaptic; presynaptic; programs; relating to nervous system; research study; response; spatiotemporal; voltage; wasting

Neurons in the wall of the intestine control how the gut reacts to an ingested meal; they also regulate the processes of digestion, nutrient absorption, and waste elimination. In inflammatory bowel disease (IBD), various features of gut function, including motility, secretion and sensitivity are altered. As nerve cells of the bowel regulate all of these functions, it is likely that changes in these neurons cause the symptoms that lead to the suffering experienced by afflicted individuals. In the past 3 years, we have evaluated inflammation- induced changes along the circuitry of the colon in a step-wise fashion, and we have identified fundamental changes at three sites in particular: (1) increased serotonin availability in the mucosal layer; (2) intrinsic sensory neuron hyperexcitability; and (3) facilitation of synaptic signals between neurons. The proposed experiments are designed to elucidate the mechanisms that underlie these changes, how these changes affect colonic motility, and what changes persist following recovery from inflammation. In specific aim 1, we will use electrophysiology and molecular approaches to test the hypothesis that intrinsic sensory neuron hyperexcitability involves down-regulation of intermediate conductance, Ca2+-activated K* channels and an up-regulation of hyperpolarization-activated cation channels. In specific aim 2, we will use electrophysiology and electron microscopy to investigate the mechanisms of synaptic facilitation by testing for changes in presynaptic neurotransmitter release, postsynaptic sensitivity and nerve terminal density in the myenteric plexus. In specific aim 3, we will study colonic peristalsis, spatiotemporal motility patterns and neuromuscular responses to determine which inflammation-induced changes in the reflex circuitry contribute to altered colonic motility and how this occurs. In specific aim 4, we will test whether inflammation-induced neuroplasticity and related changes in motility persist beyond recovery from inflammation. Such changes would be undetectable by standard diagnostic procedures, and could underlie altered gut function during remission from inflammatory bowel disease and in post-inflammatory irritable bowel syndrome (IBS). An array of techniques will be used, including intracellular voltage and current recordings, real time quantitative polymerase chain reaction, electron microscopy, and digitally enhanced motility assays. In this way, we will provide a unique, integrated/translational view of neurotransmission in the inflamed colon. The findings of these investigations, all of which are highly feasible, will enhance our understanding of the pathophysiology of the inflamed colon, and they will improve our comprehension of IBS.

肠壁上的神经元控制肠道对摄入食物的反应；他们还监管