Impact of Amygdala Lateralization on Processing and Modulation of Bladder Pain

项目摘要 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 disorder.虽然来自内脏的外周输入的失调可能解释了许多 症状UCPPS，未能理解和治疗中枢神经系统（CNS）的变化可能会阻止 使受影响的患者完全康复。我们实验室的长期目标是了解 大脑中的区域负责持续性疼痛的发展和维持， 存在于泌尿系统疾病中的情感障碍。最近的证据表明，中央 中枢神经系统中的杏仁核可能是内脏疼痛和焦虑之间相互作用的重要部位， 潜在地作为慢性疾病如UCPPS的驱动因素。通过确定杏仁核在 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。 来自人类和动物模型的证据表明，左杏仁核和右杏仁核可能存在差异， 调节疼痛。左右半球激活的差异在人类语言中得到了很好的描述 生产、视觉处理和复杂的规划任务。情感神经元存在功能偏侧化 大脑的处理区域，包括杏仁核，在多个分类群中，右脑充当一个 对压力和伤害的反应中心。这种保守性表明，边缘回路的偏侧化是一种 重要的进化现象。偏侧化的失调也可能对大脑皮层的形成起重要作用， 在疾病中的作用是一个具有临床意义的新概念。UCPPS患者在以下方面表现出偏侧性变化： 杏仁核灰质和偏侧杏仁核与CNS中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，通过它杏仁核的偏侧化调节膀胱疼痛， 在小鼠中根据脑的一侧定向地施用该神经肽。的目的 这项研究的目的是分析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， 啮齿动物模型，包括探索杏仁核的传出回路，其介导脑诱导的 用于膀胱疼痛的镇痛或痛觉过敏。这一目标将通过三个不同但互补的途径来实现 具体目标。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， 杏仁核左右侧化。在目标2中，我们将操纵特定的传出输出， 杏仁核，以确定独特的镇痛与痛觉过敏的途径。在目标3中，我们将纳入新的和 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， 用于预测实验室结果，以推进膀胱疼痛研究和治疗。总的来说，这项建议将 有助于确定疼痛膀胱刺激期间杏仁核激活的程度和机制， 杏仁核过度活跃可能导致膀胱疼痛的机制，如在UCPPS中所见。

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.