CNS Mechanisms of IC/BPS

摘要 间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种病因不明的严重疼痛疾病 影响了美国3 - 6%的女性IC/BPS的主要临床症状为膀胱疼痛 充盈和尿急和尿频增加。大多数IC/BPS患者（90%）还患有 共病焦虑和/或抑郁，导致生活质量差。高比例的情感共病 IC/BPS患者的疾病表明，共同的脊髓上神经回路可能是导致这两种疾病的原因。 IC/BPS患者的疼痛和负面影响增加。基于大量的工作， 在神经科学中，我们假设杏仁核中央核（CeA）是神经元的重要枢纽， 调节膀胱疼痛和负面情绪的活动。在这个项目中，我们提出了一系列的研究， 该研究旨在确定脑内CeA中神经元亚群的必要性和充分性， 在模型中诱导排尿功能障碍、疼痛敏感化和共病焦虑和抑郁 膀胱炎该回路的激活是否仅导致对刺激的超敏反应，或者这对于 持续性或自发性疼痛？是否同一群神经元既介导疼痛敏感化， 受伤后的焦虑增加？这些神经元的关键输入和投射是什么 膀胱炎导致的衰弱后果我们采用多学科的方法，包括病毒 解剖束追踪，光遗传学，化学遗传学，以及清醒，自由 来解决这些问题。这些研究将提供新的见解的关键作用， 膀胱疼痛综合征背景下膀胱疼痛和共病情感障碍中的CeA，并提供 未来研究的基础是建立在此基础上，以深入了解电路，细胞和突触机制， 排尿功能障碍、慢性疼痛和共病焦虑和抑郁。

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.