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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要总结