Impact of amygdala lateralization on processing and modulation of bladder pain

项目总结 尿路慢性盆腔疼痛(UCPP)综合征，通常诊断为间质性膀胱炎/膀胱痛 综合征(IC/BPS)或慢性前列腺炎/慢性盆腔疼痛综合征(CP/CPPS)是最常见的 常见类型的慢性内脏疼痛障碍。尽管来自内脏的外周输入调节失调 很可能是一些疾病的症状，未能了解和治疗中枢神经 系统(中枢神经系统)的改变可能会阻碍受影响患者的完全康复。我们实验室的长期目标是 为了了解大脑中负责发育和维持的区域的程度 存在于泌尿系疾病中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的中枢神经系统治疗范例，以补充针对 膀胱。最近的证据表明，中枢神经系统的中央杏仁核可能是一个重要的部位。 对于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，如 UCPP。通过确定杏仁核在膀胱痛动物模型中的作用，我们将深入了解 人类状况的基本生理学。来自人类和动物模型的证据表明 左右杏仁核可能不同地调节疼痛。左半球和右半球激活的差异 在人类语言产生、视觉处理和复杂的计划任务中都有很好的描述。[功能 偏侧化存在于大脑的情绪处理区域，包括杏仁核，跨越多个类群 包括鸟类和哺乳动物，在这些动物中，右脑是压力和伤害的反应中心。这 守恒表明，边缘回路的偏侧化可能是一种进化上的重要现象。] 偏侧调节失调也可能在疾病中发挥重要作用的想法是一个新的概念，与 重要的临床意义。UCPP患者表现为杏仁核灰质偏侧改变和偏侧 杏仁核与中枢神经系统其他区域的功能连接。负责传入的分子介体 左侧杏仁核与右侧杏仁核的信息仍不清楚。这项建议的目标是确定 左侧和右侧杏仁中央区膀胱疼痛的偏侧化程度及其分子 造成这一现象的机制。这一目标将通过两个不同但 互补的具体目标。在本提案的目标1中，我们将确定左侧和右侧杏仁核的范围 刺激控制性或敏感型膀胱后的激活，同时也探测大脑区域 伤害性信息通过它传播。在目标2中，我们将操作特定的脑干投影到 杏仁核，以确定在两个对照组中，哪些细胞是偏侧痛样输出的充分和必要的 和敏化条件。总体而言，这一建议将有助于确定杏仁核的范围和机制 痛性膀胱刺激时的激活和杏仁核过度活动的机制 如UCPP中所见，会导致膀胱疼痛。

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.