Impact of Amygdala Lateralization on Processing and Modulation of Bladder Pain

项目摘要 泌尿系慢性盆腔疼痛（UCPP）综合征，通常诊断为间质性膀胱炎/膀胱疼痛 综合征（IC/BPS）或慢性前列腺炎/慢性骨盆疼痛综合征（CP/CPPS）， 一种常见的慢性内脏疼痛疾病。虽然内脏的外周输入失调 可能解释了一些疾病的症状，未能理解和治疗中枢神经系统 中枢神经系统（CNS）的变化可能会阻止受影响患者的完全恢复。我们实验室的长期目标是 了解大脑中负责发育和维持的区域的程度， 泌尿系统疾病中存在的持续性疼痛和伴随的情感障碍。我们的目标是 发现和开发针对这种疾病的新型CNS治疗范例，以补充针对 膀胱最近的证据表明，中枢杏仁核可能是一个重要的位点 内脏疼痛和焦虑之间的相互作用，可能是慢性疾病的驱动因素， UCPP。通过确定扁桃体在膀胱疼痛动物模型中的作用，将为以下方面提供见解： 人类状况的潜在生理学来自人类和动物模型的证据表明， 左杏仁核和右杏仁核可以不同地调节疼痛。左右半球激活的差异 在人类语言产生、视觉处理和复杂的规划任务中得到了很好的描述。[职能 偏侧化存在于大脑的情绪处理区域，包括杏仁核，跨越多个分类群 包括鸟类和哺乳动物，它们的右脑是压力和伤害的反应中心。这 保守性表明边缘回路的偏侧化可能是进化上的重要现象。 偏侧化失调也可能在疾病中起重要作用的想法是一个新概念， 重要的临床意义。UCPP患者表现出杏仁核灰质的偏侧性变化， 杏仁核与CNS其他区域的功能连接。负责传入的分子介质 左杏仁核与右杏仁核的信息仍然未知。本提案的目的是确定 膀胱疼痛在左右中央杏仁核之间的偏侧化程度和分子水平 造成这种现象的机制。这一目标将通过两个不同但 互补的具体目标。在本建议的目标1中，我们将确定左侧和右侧杏仁核的范围 刺激控制或致敏膀胱后的激活，同时也探测大脑区域 伤害性信息的传播途径在目标2中，我们将操纵特定的脑干投射到 杏仁核，以确定哪些细胞是足够的和必要的偏侧疼痛样输出在两个控制 和敏化条件。总的来说，这一建议将有助于确定杏仁核的程度和机制， 疼痛性膀胱刺激期间的激活以及过度活跃的杏仁核可能 导致膀胱疼痛，如在UCPP中所见。

PROJECT SUMMARY Urologic chronic pelvic pain (UCPP) syndromes, commonly diagnosed as interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), represent the most common type of chronic visceral pain disorders. Although dysregulation of peripheral inputs from the viscera likely account for a number of the symptoms of the diseases, 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. We aim to discover and develop novel CNS treatment paradigms for this disease to complement approaches directed at the bladder. 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 UCPP. 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 including birds and mammals where the right brain serves as a reactive center to stress and injury. This conservation suggests that lateralization of limbic circuits is likely an evolutionarily important phenomenon.] The idea that dysregulation in lateralization might also play a significant role in disease is a novel concept with important clinical relevance. UCPP patients show lateralized changes in amygdala gray matter and lateralized amygdala functional connectivity to other areas in the CNS. The molecular mediators responsible for incoming information to the left versus right amygdala remain unknown. The objective of this proposal is to determine the extent of bladder pain lateralization between the left and right central amygdalae and the molecular mechanisms responsible for this phenomenon. This objective will be met through two distinct but complementary specific aims. In Aim 1 of this proposal, we will determine the extent of left and right amygdala activation following stimulation of control or sensitized bladders, while also probing the areas of the brain through which nociceptive information travels. In Aim 2, we will manipulate specific brainstem projections to the amygdala to determine which cells are sufficient and necessary for lateralized pain-like output in both control and sensitized conditions. 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 UCPP.