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: 8627830
• 负责人: Aditi Bhargava
• 金额: $ 54.74万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627830
• 关键词: Abdomen; Address; Adrenal Glands; Adult; Affect; Anxiety; Automobile Driving; Behavior; Brain; CRF receptor type 1; Characteristics; Chronic; Clinical; Corticotropin-Releasing Hormone; Data; Depressed mood; Development; Disease; Dyspepsia; Electrophysiology (science); Etiology; Face; Gastrointestinal Diseases; Hypersensitivity; Hypothalamic structure; Immunofluorescence Microscopy; Inflammation; Intestines; Laboratories; Link; 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; Process; Quality of life; RNA Interference; Rattus; Recurrent pain; Research; Role; Sensory; Solid; Spinal; Stomach; Stress; Sucrose; Syndrome; Techniques; Testing; Vagus nerve structure; Visceral; afferent nerve; base; cytokine; disturbance in affect; feeding; gastrointestinal; hypothalamic pituitary axis; hypothalamic-pituitary-adrenal axis; improved; innovation; insight; irritation; life time cost; mast cell; novel; pain behavior; preference; psychologic; psychological distress; public health relevance

ABSTRACT SUMMARY 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 the 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.

抽象概括 最近的临床证据表明，脑-肠轴是双向的， 心理困扰会加剧这些障碍，进而产生心理异常。 然而，负责后者的机制仍不清楚。我们建立了大鼠胃粘膜损伤模型， 刺激（功能性消化不良），并显示，大鼠暴露于短暂的胃刺激，在新生儿 与对照组相比，周期显示持续的抑郁样和焦虑样行为。利用这个模型， 我们将检验这一假设，即功能性消化不良的主要表现，包括感觉和 心理障碍，有他们的起源在胃，驱动高反应性迷走神经和 脊髓传入神经迷走神经活动反过来导致中枢神经系统炎症和神经内分泌 导致抑郁和焦虑的异常。在目的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）的高反应性和疼痛行为， 功能性消化不良在目标2中，我们将研究迷走神经在疼痛行为和心理中的作用。 功能性消化不良的异常。将使用蔗糖偏好测试等测试评估行为 (for抑郁症）和旷场测试（焦虑症）。神经元活动的变化将使用 电生理学在目标3中，我们将研究下丘脑神经内分泌的原因和后果 功能性消化不良患者疼痛和心理异常的变化 试剂和RNAi技术来描绘应激肽的作用。在目标4中，我们将研究原因， 下丘脑炎症的后果与疼痛和神经内分泌和心理 功能性消化不良的异常。脑中的炎症将通过免疫荧光和 将评价显微镜检查和特异性细胞因子的作用。我们的研究结果将提供洞察如何 肠道紊乱可引起慢性情感紊乱， 把这两种现象联系在一起。该提案具有高度创新性，并解决了临床 具有重大意义的问题。