Spinal dopaminergic mechanisms regulating the micturition reflex after spinal cord injury

脊髓损伤后调节排尿反射的脊髓多巴胺能机制

• 批准号: 9929728
• 负责人: Shaoping Hou
• 金额: $ 3.15万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9929728
• 关键词: Address; Affect; Animal Disease Models; Ataxia; Autonomic nervous system disorders; Behavior; Bladder; Brain; Bromodeoxyuridine; Cell Nucleus; Cells; Cerebrum; Characteristics; Chemicals; Data; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Electric Stimulation; Electromyography; Elements; Enzymes; Frequencies; Functional disorder; Gene Expression; Health; Hyperactive behavior; Immunohistochemistry; Incidence; Incontinence; Interneurons; Interruption; Kidney Failure; Label; Lasers; Levodopa; Lower urinary tract; Mammals; Measures; Mediating; Metabolic; Microdissection; Micturition Reflex; Midbrain structure; Morbidity - disease rate; Neuraxis; Neurons; Parkinson Disease; Pathway interactions; Patients; Pelvis; Periodicity; Pharmacology; Phenotype; Physiological; Pontine structure; Population; Property; Protein Isoforms; Quality of life; Rattus; Recovery of Function; Reflex action; Regulation; Reporting; Role; Scanning; Signal Transduction; Site; Slice; Source; Sphincter; Spinal; Spinal Cord; Spinal Manipulation; Spinal cord injury; Spinal cord injury patients; Symptoms; Synapses; System; Testing; Therapeutic; Thoracic spinal cord structure; Time; Tracer; Transgenic Organisms; Tyrosine 3-Monooxygenase; Urethra; Urethral sphincter; Urinary tract infection; Urination; Urodynamics; Visceral; designer receptors exclusively activated by designer drugs; dopaminergic neuron; dorsal horn; improved; innovation; mad itch virus; micturition urgency; mortality; neurogenesis; new therapeutic target; novel therapeutics; partial recovery; protein expression; receptor; response; targeted treatment; transcription factor; urinary

Project summary Dopamine (DA) neurons in the mammalian central nervous system (CNS) are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. However, we have recently characterized that DA is produced in the rat spinal cord and modulates the bladder reflex. Traumatic spinal cord injury (SCI) interrupts spinobulbospinal micturition pathways and eliminates voluntary voiding. Although a spinal micturition reflex is established over time and induces partial recovery of urination, the incidence of bladder hyperactivity and detrusor-sphincter dyssynergia (DSD) causes inefficient emptying and incontinence, which is detrimental to the health of SCI patients. We hypothesize that there are endogenous spinal DA-ergic mechanisms regulating the micturition reflex, and pharmacological manipulation of these mechanisms will improve lower urinary tract (LUT) function following SCI. In our preliminary data, we have observed numerous tyrosine hydroxylase (TH)+ neurons in the autonomic nuclei and the superficial dorsal horn of rat lumbosacral spinal cord. Following a complete thoracic SCI to remove supraspinal control, remarkably more TH+ neurons emerged in the lower cord, which coincides with a local sustained, low level of DA expression. Furthermore, suppression of spinal DA signaling reduces bladder activity whereas activation of these pathways increases bursting duration of the external urethral sphincter (EUS). Accordingly, this proposed project will not only comprehensively address some fundamental questions but also test a novel therapeutic strategy to treat LUT dysfunction after SCI. In aim 1, we will determine whether TH+ cells in rat lower spinal cord undergo plasticity following SCI and are involved in the spinal micturition reflex circuits. In aim 2, we will elucidate whether these TH+ neurons exert DA-ergic regulation of the micturition reflex after SCI. In aim 3, we will identify whether pharmacological stimulation of spinal DA-ergic pathways improves urinary functional recovery in rats with SCI. The results of this project will uncover the spinal DA-ergic system and elucidate its role in the micturition. We anticipate developing an innovative approach to enhance urinary efficiency and continence, thereby improving quality of life in patients with SCI. !

项目概要 哺乳动物中枢神经系统 (CNS) 中的多巴胺 (DA) 神经元被认为受到限制 到大脑。 DA 介导的泌尿活动调节被认为是通过相互作用发生的 中脑 DA 神经元和脑桥排尿中枢之间。然而，我们最近 其特征是 DA 在大鼠脊髓中产生并调节膀胱反射。外伤性 脊髓损伤 (SCI) 会中断脊髓球脊髓排尿途径并消除自主排尿 排尿。尽管脊髓排尿反射随着时间的推移而建立并导致部分恢复 排尿、膀胱过度活跃和逼尿肌括约肌协同失调（DSD）的发生率 排空效率低下和失禁，不利于 SCI 患者的健康。我们 假设存在调节排尿反射的内源性脊髓 DA 能机制， 这些机制的药理操作将改善下尿路 (LUT) 功能 继SCI。在我们的初步数据中，我们观察到许多酪氨酸羟化酶（TH）+神经元 存在于大鼠腰骶脊髓的自主神经核和浅表背角中。继一个 完全胸部 SCI 去除脊髓上控制后，显着更多的 TH+ 神经元出现在 下脊髓，这与局部持续的低水平 DA 表达一致。此外， 脊髓 DA 信号传导的抑制会降低膀胱活动，而这些通路的激活 增加尿道外括约肌 (EUS) 的破裂持续时间。因此，本拟议项目 不仅将全面解决一些基本问题，还将测试一种新的治疗方法 SCI 后治疗 LUT 功能障碍的策略。在目标 1 中，我们将确定大鼠中的 TH+ 细胞是否降低 脊髓在 SCI 后经历可塑性并参与脊髓排尿反射回路。在 目标 2，我们将阐明这些 TH+ 神经元是否对排尿反射发挥 DA 能调节作用 SCI之后。在目标 3 中，我们将确定脊髓 DA 能通路的药物刺激是否有效 改善 SCI 大鼠的泌尿功能恢复。该项目的结果将揭示脊柱 DA 能系统并阐明其在排尿中的作用。我们预计开发出一种创新型 提高排尿效率和节制能力的方法，从而改善患者的生活质量 SCI。 ！