Neuroplasticity of the gut-brain axis in functional dyspepsia

描述(申请人提供)：最近的临床证据表明，脑-肠轴是双向的，心理困扰会加剧功能性胃肠功能障碍，进而产生心理异常。然而，对后者负责的机制仍不清楚。我们已经建立了一种胃刺激(功能性消化不良)的大鼠模型，并表明与对照组相比，在新生期暴露于一过性胃刺激的大鼠表现出持续的抑郁和焦虑样行为。使用这个模型，我们将检验这样一个假设，即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的高反应。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功能性消化不良中维持胃传入神经(迷走神经和脊髓)的高反应性和疼痛行为中的作用。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)和野外测试(针对焦虑)等测试来评估行为。神经活动的变化将使用电生理学进行记录。在目标3中，我们将通过使用药理学药物和RNAi技术来描述应激肽的作用，来研究功能性消化不良患者下丘脑神经内分泌变化与疼痛和心理异常的原因和后果。在目标4中，我们将研究与疼痛有关的下丘脑炎症的原因和后果，以及功能性消化不良的神经内分泌和心理异常。将通过免疫荧光和显微镜来评估脑部炎症，并将评估特定细胞因子的贡献。我们的发现将对肠道干扰如何导致慢性影响提供深入的见解，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。这项建议具有很高的创新性，并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.