CNS Mechanisms of IC/BPS

摘要 间质性膀胱炎/膀胱痛综合征(IC/BPS)是一种原因不明的严重疼痛症状 这影响了美国3%-6%的女性。IC/BPS的主要临床症状是膀胱痛 充盈，尿液紧迫感和尿频增加。大多数IC/BPS患者(90%)也患有 焦虑和/或抑郁并存，导致生活质量不佳。情感并存的高比率 IC/BPS患者的疾病提示共同的脊髓上神经回路可能对两者都有作用 IC/BPS患者的疼痛和负性情绪增加。基于大量的工作 神经科学，我们假设杏仁中央核(CEA)是神经元的重要中枢 调节膀胱疼痛和负性情绪的活动。在这个项目中，我们提出了一系列研究 旨在确定CEA中神经元亚群的必要性和充分性 诱导大鼠排尿功能障碍、疼痛敏感化、焦虑和抑郁共病 膀胱炎。这个回路的激活是否只导致对刺激的高敏感性，或者这也是对 持续性疼痛还是自发性疼痛？同样数量的神经元是否同时调节疼痛敏感化和 受伤后焦虑增加了吗？这些神经元的关键输入和投射是什么 对膀胱炎的这些令人衰弱的后果？我们采用了包括病毒在内的多学科方法 清醒时神经活动的解剖轨迹追踪、光遗传学、化学遗传学和活体成像 移动老鼠来解决这些问题。这些研究将提供新的洞察力，让人们了解 CEA在膀胱痛和膀胱痛综合征背景下的共病情感障碍中的作用，并提供 以此为基础的未来研究的基础是深入了解脑电、细胞和突触的机制 排尿功能障碍，慢性疼痛以及焦虑和抑郁的共病。

Abstract Interstitial cystitis/Bladder Pain Syndrome (IC/BPS) is a serious and painful condition of unknown etiology that affects 3-6% of women in the United States. The major clinical symptoms of IC/BPS are pain on bladder filling and increased urinary urgency and frequency. The majority of IC/BPS patients (90%) also suffer from comorbid anxiety and/or depression, contributing to a poor quality of life. The high rate of comorbid affective disorders in IC/BPS patients suggests that a common supraspinal neural circuit may be responsible for both enhanced pain and negative affect in patients with IC/BPS. Based on a large body of work in the neurosciences, we hypothesize that the central nucleus of the amygdala (CeA) is a crucial hub of neuronal activity that regulates both bladder pain and negative affect. In this project, we propose a series of studies that seeks to determine the necessity and sufficiency of neuronal subpopulations in the CeA in the induction of voiding dysfunction, pain sensitization, and comorbid anxiety and depression in models of cystitis. Does activation of this circuit lead only to hypersensitivity to stimulation, or is this also critical for ongoing or spontaneous pain? Does the same population of neurons mediate both pain sensitization and increased anxiety following injury? What are the critical inputs and projections from these neurons that lead to these debilitating consequences of cystitis? We employ a multidisciplinary approach including viral anatomical tract tracing, optogenetics, chemogenetics, and in vivo imaging of neural activity in awake, freely moving mice to address these questions. These studies will provide new insights into the critical role of the CeA in bladder pain and comorbid affective disorders in the context of bladder pain syndrome, and provide the basis for future studies building on this to gain insights into circuit, cellular and synaptic mechanisms of voiding dysfunction, chronic pain and comorbid anxiety and depression.