Comorbid mood and urogenital disorders in mice following neonatal maternal separation

新生儿母亲分离后小鼠的共病情绪和泌尿生殖系统疾病

基本信息

批准号：
9118993
负责人：
Julie A Carlsten Christianson
金额：
$ 33.98万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-23 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118993
关键词：
Abdomen Adolescence Adult Adverse effects Adverse event Affect Afferent Neurons Affinity Age Anhedonia Anxiety Attenuated Behavior Binding Binding Proteins Bladder Brain region Calcium Cell Nucleus Cell physiology Childhood Chronic Prostatitis Comorbidity Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Disease Effectiveness Event Exercise Exhibits Feedback Frequencies Gene Expression Genitourinary system Glucocorticoid Receptor Goals Growth and Development function Health Hippocampus (Brain)Housing Hyperalgesia Hypersensitivity Hypothalamic structure Image Infiltration Inflammation Inflammatory Interstitial Cystitis Intervention Irritable Bowel Syndrome Label Life Life Stress Ligands Long-Term Effects Mast Cell Stabilizer Measures Mediating Medical Mental Depression Micturition Reflex Modeling Mood Disorders Moods Mus Neonatal Nervous system structure Neurogenic Inflammation Neurons Neuropeptides Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 2 Organ Output PAR-2 Receptor Pain Pain Disorder Panic Disorder Patients Pattern Pelvic Pain Pelvis Perception Peripheral Pontine structure Process Regulation Reporting Risk Factors Rodent Model Running Sensory Stress Sucrose Symptoms Syndrome Testing Time Trauma Treatment Efficacy Tryptase United States Urination Vagina Viscera Vulvodynia Weaning Woman anxiety-like behavior associated symptom biological adaptation to stress chronic pain chronic pelvic pain cost design gastrointestinal system hypothalamic-pituitary-adrenal axis improved insight mast cell maternal separation men neglect nerve supply novel patient subsets postnatal pre-clinical preference prevent protein expression psychological stressor receptor expression research study therapeutic target treatment strategy

项目摘要

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.

描述（由申请人提供）：估计 11% 的女性和 5% 的男性患有间质性膀胱炎/膀胱疼痛综合征 (IC/PBS) 相关症状，在美国每年产生至少 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病症的症状，并且多达一半患有抑郁症和/或恐慌症。综合征的合并症与下丘脑-垂体-肾上腺 (HPA) 轴的功能改变有关，该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) 是应激反应的主要引发剂，与相关的尿皮质 (Ucn) 一起介导下游应激反应，并影响 HPA 轴的正反馈和负反馈。 CRF 也是外周肥大细胞脱颗粒的有效刺激剂，并作为参与调节中枢排尿反射的神经肽发挥作用。早年生活压力或创伤是 HPA 轴破坏的重要危险因素，并显着增加青春期或成年期间患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显示 HPA 轴的正确反馈受到破坏，导致快感缺乏、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相关的异常现象，包括与慢性疼痛和情绪障碍相关的症状。当前提案的目标是了解边缘调节和 HPA 轴下游输出的操纵如何影响早期生活压力小鼠的行为和泌尿生殖敏感性。我们的中心假设是，NMS 小鼠的共病泌尿生殖疼痛综合征和情绪障碍是由于海马负调节输入减少而导致 HPA 轴输出增加引起的，并且可以通过外周和中枢介导的干预措施不同程度地减弱。我们设计了三个具体目标（SA）来检验这一假设。 SA1 将决定 NMS 如何改变 CRF 反应性大脑区域的表达模式和下游外周影响。 SA2 将确定肥大细胞激活对 NMS 小鼠泌尿生殖敏感性和排尿的影响。 SA3 将确定自愿运动对改善 NMS 小鼠海马对 HPA 轴的调节输入的影响。该项目完成后，我们将对早期生活压力后盆腔疼痛和情绪障碍共存的机制获得新的见解。我们还将获得关于运动功效的临床前证据，运动是一种易于转化的干预措施，可以作为这些使人衰弱的疾病的有效治疗策略。