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。 影响了美国6%的女性。IC/BPS的主要临床症状是膀胱充盈疼痛和 尿急和尿频增加。大多数IC/BPS患者(90%)也同时患有 焦虑和/或抑郁，导致生活质量不佳。目前可用于IC/BPS的治疗方法有 很大程度上无效，只提供轻微的症状缓解。鉴于这种令人衰弱的疾病的流行 由于缺乏有效的治疗方法，还需要进一步的研究来更好地了解 贡献IC/BPS和那些调节高发病率焦虑和抑郁的因素。我们之前 报道称，IC/BPS患者表现为腹痛过敏症，是中枢敏感化的明显征象。在 在之前的资助期间，我们使用了单核RNA测序、空间转录和原位杂交 杂交和鉴定了在膀胱炎中被激活并似乎发挥作用的两组CEA神经元 在膀胱疼痛的调节中扮演相反的角色。在这里，我们将在系统中应用最先进的方法 神经科学揭示CEA中这些独特的神经元亚群在相互作用中的潜在作用 疼痛、排尿功能障碍和负面情感行为的调节(IC/BPS样条件)。什么是 这两种人群在膀胱痛中各自扮演的角色？是明显的促痛和反伤害性作用 Pde1c和Cartpt群体分别局限于参照超敏反应，或者它们也是相互作用的 控制持续的疼痛？这些群体在排尿行为的调节中是否扮演着不同的角色？ 消极的情感行为？这些神经元的关键输入和投射是什么？做这些事吧 人群在膀胱炎的诱发和维持中经历了不同的可塑性？动力学是如何 随着膀胱炎的消退，这个回路的变化？在这里，我们建议通过一系列研究来回答这些问题 检验中心假设，即这些独特的CEA神经元亚群中的非适应性可塑性调节 膀胱炎模型中的排尿功能障碍、疼痛敏感化和共病的负面影响。这些研究将 为CEA中促伤害性和抗伤害性神经元在膀胱痛和膀胱痛中的关键作用提供新的见解 与膀胱痛综合征相关的共病情感障碍。如果成功，这些研究将指出 确定药物方法以恢复这些神经元周围正常的电路功能的方法提供 缓解IC/BPS患者的膀胱疼痛、排尿功能障碍以及共存的焦虑和抑郁。

Abstract Interstitial cystitis/Bladder Pain Syndrome (IC/BPS) is a serious and painful condition of unknown etiology that affects 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. Current available treatments for IC/BPS are largely ineffective, providing only mild symptomatic relief. Given the prevalence of this debilitating disease and the lack of effective treatments, further studies are needed to better understand the underlying mechanisms that contribute IC/BPS and those that mediate the high incidence of comorbid anxiety and depression. We previously reported that IC/BPS patients show referred abdominal hyperalgesia, a clear sign of central sensitization. In the previous funding period, we used the single nucleus RNA sequencing, spatial transcriptomics and in situ hybridization and identified two populations of CeA neurons that are activated in cystitis and appear to play opposing roles in the regulation of bladder pain. Here we will apply state of the art approaches in systems neuroscience to unravel the potential role of these unique neuronal subpopulations in the CeA in the reciprocal regulation of pain, voiding dysfunction, and negative affective behaviors (IC/BPS-like conditions). What are the respective roles of the two populations in bladder pain? Are the apparent pro- and anti-nociceptive actions of the Pde1c and Cartpt populations, respectively, restricted to referred hypersensitivity, or do they also reciprocally regulate ongoing pain? Do these populations play differential roles in the regulation of voiding behavior and negative affective behaviors? What are the critical inputs to and projections from these neurons? Do these populations undergo plasticity differentially in the induction and maintenance of cystitis? How do the dynamics of this circuit change as cystitis resolves? Here we propose to answer these questions in a series of studies that test the central hypothesis that maladaptive plasticity in these unique subpopulations of CeA neurons regulates voiding dysfunction, pain sensitization, and comorbid negative affect in models of cystitis. These studies will provide new insights into the critical role of the pro- and anti-nociceptive neurons in the CeA in bladder pain and comorbid affective disorders in the context of bladder pain syndrome. If successful, these studies will point the way to identifying pharmacological approaches to restore normal circuit function around these neurons to provide relief from bladder pain, voiding dysfunction, and comorbid anxiety and depression in patients with IC/BPS.