Neuroplasticity of the gut-brain axis in functional dyspepsia

描述（由申请人提供）：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重，进而产生心理异常。然而，导致后者的机制仍不清楚。我们已经建立了一个胃刺激大鼠模型（功能性消化不良），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。使用这个模型，我们将检验功能性消化不良的主要表现，包括感觉和心理障碍，都起源于胃，驱动迷走神经和脊髓传入神经的高反应性的假设。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异常，从而导致抑郁和焦虑。在Aim 1中，我们将研究胃肥大细胞在维持胃传入神经（迷走神经和脊髓神经）的高反应性和功能性消化不良疼痛行为中的作用。在Aim 2中，我们将研究迷走神经在功能性消化不良患者疼痛行为和心理异常中的作用。行为将通过诸如蔗糖偏好测试（抑郁）和开放场地测试（焦虑）等测试进行评估。神经活动的变化将用电生理学记录下来。在Aim 3中，我们将通过使用药物和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患者疼痛和心理异常的原因和后果。在Aim 4中，我们将研究下丘脑炎症与功能性消化不良患者疼痛、神经内分泌和心理异常的原因和后果。脑炎症将通过免疫荧光和显微镜进行评估，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绪紊乱，并提供一个令人满意的统一解释，将这两种现象联系在一起。这一建议极具创新性，解决了一个具有重大意义的临床问题。

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.