Impact of Amygdala Lateralization on Processing and Modulation of Bladder Pain

项目总结 泌尿系慢性盆腔疼痛综合征(UCPPS)是最常见的慢性内脏疼痛类型 无序。尽管来自内脏的外周输入的调节失调可能解释了许多 症状UCPPS，未能了解和治疗中枢神经系统(CNS)变化可能会阻止 使受影响的患者完全康复。我们实验室的长期目标是了解 大脑中负责发展和维持持续性疼痛和伴随疼痛的区域 存在于泌尿系统疾病中的情感障碍。最近的证据表明，中央银行 中枢神经系统的杏仁核可能是内脏疼痛和焦虑相互作用的重要部位， 可能成为UCPPS等慢性病的驱动因素。通过确定杏仁核在脑内的作用 对于膀胱疼痛的动物模型，将提供对人类状况的潜在生理学的洞察力。 来自人类和动物模型的证据表明，左侧和右侧杏仁核可能存在差异 调节疼痛。人类语言很好地描述了左半球和右半球激活的差异 生产、视觉处理和复杂的计划任务。情感中存在功能偏侧化 大脑的处理区域，包括杏仁核，跨越多个分类，其中右脑充当 对压力和伤害的反应中心。这一守恒表明边缘回路的偏侧化是一种 进化上重要的现象。偏侧化中的失调可能也会对 在疾病中的作用是一个具有临床意义的新概念。UCPPS患者表现出偏侧性改变 杏仁核灰质和杏仁核与中枢神经其他区域的功能连接。我们最近 确定了一个关键的分子介质，通过杏仁核的偏侧化调节膀胱痛。 在小鼠身上，这种神经肽的应用方向取决于大脑的一侧。这样做的目的是 建议解剖这种神经肽在急性膀胱疼痛向持续性膀胱疼痛转变过程中的作用。 一种包括探索杏仁核介导脑诱发的传出回路的啮齿动物模型 膀胱疼痛的止痛或痛觉过敏。这一目标将通过三个截然不同但相辅相成的方式实现 明确的目标。在目标1中，我们将确定持续性膀胱疼痛的发展改变的程度。 左侧杏仁核与右侧杏仁核偏侧。在目标2中，我们将处理来自 杏仁核识别独特的止痛剂和痛觉过敏通路。在目标3中，我们将结合新的和 现有的生理学数据来开发一个现实的杏仁核三维计算模型，它可以 用于预测实验室结果，以推进膀胱疼痛的研究和治疗。总体而言，这项提议将 帮助确定痛性膀胱刺激期间杏仁核激活的程度和机制 如UCPPS中所见，过度活跃的杏仁核可能导致膀胱疼痛的机制。

PROJECT SUMMARY Urologic chronic pelvic pain syndrome (UCPPS) represents the most common type of chronic visceral pain disorder. Although dysregulation of peripheral inputs from the viscera likely account for a number of the symptoms UCPPS, a failure to understand and treat central nervous system (CNS) changes likely prevents complete recovery for affected patients. The long-term goal of our lab is to understand the extent to which areas in the brain are responsible for the development and maintenance of persistent pain and accompanying affective disturbances that exist within urologic conditions. Recent evidence has suggested that the central amygdala in the CNS may be an important locus for the interaction between visceral pain and anxiety, potentially serving as a driver for chronic conditions like UCPPS. By determining the role of the amygdala in animal models of bladder pain, insight will be provided into the underlying physiology of the human condition. Evidence from human and animal models has shown that the left and right amygdala may differentially regulate pain. Variances in left and right hemisphere activation are well described in human language production, visual processing, and complex planning tasks. Functional lateralization exists in emotional processing areas of the brain, including the amygdala, across multiple taxa where the right brain serves as a reactive center to stress and injury. This conservation suggests that lateralization of limbic circuits is an evolutionarily important phenomenon. The idea that dysregulation in lateralization might also play a significant role in disease is a novel concept with clinical relevance. UCPPS patients show lateralized changes in amygdala gray matter and lateralized amygdala functional connectivity to other areas in the CNS. We recently identified a key molecular mediator through which lateralization of the amygdala modulates bladder pain bi- directionally in mice depending on the side of the brain this neuropeptide is applied. The objective of this proposal is to dissect the impact of this neuropeptide during the transition of acute to persistent bladder pain in a rodent model including exploring the efferent circuits from the amygdala that mediate brain-induced analgesia or hyperalgesia for bladder pain. This objective will be met through three distinct but complementary specific aims. In Aim 1, we will determine the extent to which the development of persistent bladder pain alters left versus right amygdala lateralization. In Aim 2, we will manipulate specific efferent outputs from the amygdala to identify the unique analgesic versus hyperalgesic pathways. In Aim 3, we will incorporate new and existing physiology data to develop a realistic 3-dimensional computational model of the amygdala that can be used to predict laboratory results to progress bladder pain studies and therapies. Overall, this proposal will help determine the extent and mechanisms of amygdala activation during painful bladder stimulation and the mechanisms by which an overactive amygdala may contribute to bladder pain as seen in UCPPS.