Neuroplasticity of the gut-brain axis in functional dyspepsia

功能性消化不良中肠脑轴的神经可塑性

• 批准号: 9058052
• 负责人: Aditi Bhargava
• 金额: $ 55.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058052
• 关键词: Abdomen; Address; Adrenal Glands; Adult; Affect; Anxiety; Automobile Driving; Behavior; Brain; CRF receptor type 1; Cells; Characteristics; Chronic; Clinical; Corticotropin-Releasing Hormone; Data; Depressed mood; Development; Disease; Dyspepsia; Electrophysiology (science); Etiology; Face; Gastrointestinal Diseases; Health; Hypersensitivity; Hypothalamic structure; Immunofluorescence Microscopy; Inflammation; Intestines; Laboratories; Link; Literature; Mechanics; Mediating; Mental Depression; Modeling; Molecular; Motor; Neonatal; Neuraxis; Neurogenic Inflammation; Neuronal Plasticity; Neurons; Neurosecretory Systems; Nociception; Pain; Pathogenesis; Patient observation; Patients; Peptides; Persistent pain; Phenotype; Pituitary Gland; Population; Process; Quality of life; RNA Interference; Rattus; Recurrent pain; Research; Role; Sensory; Solid; Spinal; Spine pain; Stomach; Stress; Sucrose; Syndrome; Techniques; Testing; Vagus nerve structure; Visceral; afferent nerve; anxiety-like behavior; anxious; base; cytokine; disturbance in affect; feeding; field study; gastrointestinal; hypothalamic pituitary axis; hypothalamic-pituitary-adrenal axis; improved; innovation; insight; irritation; life time cost; novel; pain behavior; patient subsets; preference; psychologic; psychological distress

DESCRIPTION (provided by applicant): Recent clinical evidence suggests that the brain-gut axis is bidirectional, whereby functional gastrointestinal disturbances are aggravated by psychological distress and in turn, produce psychological abnormalities. However, the mechanisms responsible for the latter remain unclear. We have developed a rat model of gastric irritation (functional dyspepsia) and shown that rats exposed to a transient gastric irritation in he neonatal period display persistent depression-like and anxiety-like behaviors as compared to controls. Using this model, we will test the hypothesis that the primary manifestations of functional dyspepsia, including both sensory and psychological disturbances, have their origins in the stomach, driving hyper-responsiveness of both vagal and spinal afferents. Vagal activity in turn results in central nervous system inflammation and neuroendocrine abnormalities that cause depression and anxiety. In Aim 1, we will examine the role of gastric mast cells in maintaining the hyper-responsiveness of gastric afferent nerves (vagal and spinal) and pain behavior in functional dyspepsia. In Aim 2, we will examine the role of the vagus nerve in pain behavior and psychological abnormalities in functional dyspepsia. Behavior will be assessed using tests such as sucrose preference test (for depression) and open field test (for anxiety). Change in neuronal activity will be recorded using electrophysiology. In Aim 3, we will examine the cause and consequences of hypothalamic neuroendocrine changes with respect to pain and psychological abnormalities in functional dyspepsia by using pharmacological agents and RNAi techniques to delineate the role of stress peptides. In Aim 4, we will examine the cause and consequences of hypothalamic inflammation with respect to pain and the neuroendocrine and psychological abnormalities in functional dyspepsia. Inflammation in brain will be evaluated by immunofluorescence and microscopy and contribution of specific cytokines will be evaluated. Our findings will provide insight into how disturbances in the gut can cause chronic disturbances in affect and provide a satisfactory and unifying explanation to tie these two phenomena together. This proposal is highly innovative and addresses a clinical problem of major significance.

描述（申请人提供）：最近的临床证据表明，脑肠轴是双向的，功能性胃肠道紊乱会因心理困扰而加剧，进而产生心理异常。然而，造成后者的机制仍不清楚。我们开发了胃刺激（功能性消化不良）的大鼠模型，并表明与对照组相比，在新生儿期暴露于短暂胃刺激的大鼠表现出持续的抑郁样和焦虑样行为。使用该模型，我们将检验以下假设：功能性消化不良的主要表现（包括感觉和心理障碍）起源于胃，导致迷走神经和脊髓传入神经的高反应性。迷走神经活动反过来会导致中枢神经系统炎症和神经内分泌异常，从而导致抑郁和焦虑。在目标 1 中，我们将研究胃肥大细胞在维持胃传入神经（迷走神经和脊髓）的高反应性以及功能性消化不良的疼痛行为中的作用。在目标 2 中，我们将研究迷走神经在功能性消化不良的疼痛行为和心理异常中的作用。将使用蔗糖偏好测试（针对抑郁症）和旷场测试（针对焦虑症）等测试来评估行为。将使用电生理学记录神经元活动的变化。在目标 3 中，我们将通过使用药物制剂和 RNAi 技术来描述应激肽的作用，研究下丘脑神经内分泌变化与功能性消化不良中的疼痛和心理异常相关的原因和后果。在目标 4 中，我们将研究下丘脑炎症与疼痛以及功能性消化不良的神经内分泌和心理异常相关的原因和后果。将通过免疫荧光和显微镜评估脑部炎症，并评估特定细胞因子的贡献。我们的研究结果将深入了解肠道紊乱如何导致慢性情感紊乱，并为将这两种现象联系在一起提供令人满意且统一的解释。该提案具有高度创新性，解决了具有重大意义的临床问题。