Comorbid mood and urogenital disorders in mice following neonatal maternal separation

描述(申请人提供)：估计有11%的女性和5%的男性患有与间质性膀胱炎/痛性膀胱综合症(IC/PBS)相关的症状，在美国，这种症状每年至少产生200亿美元的直接医疗费用。大约17%-40%的IC/PBS患者表现出继发性慢性盆腔疼痛障碍的症状，多达一半的患者患有抑郁和/或恐慌障碍。综合征的共病与下丘脑-垂体-肾上腺(HPA)轴的功能改变有关，HPA轴调节应激反应并影响疼痛感知。促肾上腺皮质激素释放因子(CRF)是应激反应的主要始发者，与相关的尿皮炎(UCN)一起，介导下游的应激反应，并影响对HPA轴的正反馈和负反馈。CRF也是外周肥大细胞脱颗粒的有力刺激因素，其功能是一种神经肽，参与调节中枢排尿反射。早期的生活压力或创伤是HPA轴中断的重要危险因素，并显著增加了青春期或成年期发生慢性盆腔疼痛和情绪障碍的可能性。新生儿应激的啮齿动物模型表现出对HPA轴的适当反馈中断，导致快感丧失、焦虑样行为、痛觉过敏和盆腔内脏的神经源性炎症。自愿锻炼已被证明可以逆转许多与早期生活压力有关的异常，包括与慢性疼痛和情绪障碍有关的症状。目前这项提议的目标是了解操纵边缘调节和HPA轴的下游输出如何影响暴露在早期生活应激下的小鼠的行为和泌尿生殖系统敏感性。我们的中心假设是，NMS小鼠并发的泌尿生殖系统疼痛综合征和情绪障碍源于HPA轴输出的增加，这是由于来自海马体的负调节输入减少，并可以通过外周和中枢调节的干预措施而不同地减弱。我们设计了三个特定的目标(SA)来检验这一假设。SA1将决定NMS如何改变CRF反应脑区的表达模式和下游外周影响。SA2将确定肥大细胞激活对NMS小鼠的泌尿生殖系统敏感性和排尿的影响。SA3将确定自愿运动对改善NMS小鼠HPA轴上的海马体调节性输入的影响。在这个项目完成后，我们将对早期生活压力后并发盆腔疼痛和情绪障碍的潜在机制有了新的见解。我们还将获得临床前证据，证明锻炼是一种易于翻译的干预措施，作为这些衰弱障碍的潜在治疗策略。

DESCRIPTION (provided by applicant): An estimated 11% of women and 5% of men suffer from symptoms related to interstitial cystitis/painful bladder syndrome (IC/PBS), which generates a minimum $20 billion in direct medical costs annually in the United States. Approximately 17-40% of IC/PBS patients exhibit symptoms of a secondary chronic pelvic pain disorder and up to half suffer from depression and/or panic disorder. Comorbidity of syndromes has been associated with altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response and influences the perception of pain. Corticotropin-releasing factor (CRF) is the principal initiator of the stress response and, along with the related urocortis (Ucn), mediates downstream stress responses, as well as influences both positive and negative feedback onto the HPA axis. CRF is also a potent stimulator of peripheral mast cell degranulation and functions as a neuropeptide involved in regulating the central micturition reflex. Early life stress or trauma is a significant risk factor for HPA axis disruption and significantly increases the likelihood of developing chronic pelvic pain and mood disorders during adolescence or adulthood. Rodent models of neonatal stress display disruption of proper feedback onto the HPA axis, resulting in anhedonia, anxiety-like behaviors, and hyperalgesia and neurogenic inflammation in the pelvic viscera. Voluntary exercise has been shown to reverse many abnormalities associated with early life stress, including symptoms associated with chronic pain and mood disorders. The goal of the current proposal is to understand how manipulation of the limbic regulation and downstream output of the HPA axis affects both behavior and urogenital sensitivity in mice that were exposed to early life stress. Our central hypothesis is that comorbid urogenital pain syndromes and mood disorders in NMS mice arise from increased output of the HPA axis, due to diminished negative regulatory input from the hippocampus, and can be differentially attenuated by peripherally- and centrally-mediated interventions. We have designed three specific aims (SAs) to test this hypothesis. SA1 will determine how NMS alters the expression patterns and downstream peripheral influences of CRF-responsive brain regions. SA2 will determine the impact of mast cell activation on urogenital sensitivity and micturition in NMS mice. SA3 will determine the impact of voluntary exercise on improving hippocampal regulatory input onto the HPA axis in NMS mice. At the completion of this project, we will have gained novel insight on the mechanisms underlying comorbid pelvic pain and mood disorders following early life stress. We will also have obtained preclinical evidence on the efficacy of exercise, an easily translatable intervention, as a potentil treatment strategy for these debilitating disorders.