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: 9213802
• 负责人: Shaoping Hou
• 金额: $ 34.13万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2021-11-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213802
• 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; Injectable; Injury; 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; Pharmacotherapy; 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; 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.

项目摘要 哺乳动物中枢神经系统（CNS）中的多巴胺（DA）神经元被认为是受限制的 到大脑。DA介导的排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的联系然而，我们最近 其特征在于DA在大鼠脊髓中产生并调节膀胱反射。创伤性 脊髓损伤（SCI）中断脊髓延髓排尿通路， 排泄虽然脊髓排尿反射随着时间的推移而建立，并诱导部分恢复， 排尿、膀胱功能亢进和逼尿肌-括约肌协同失调（DSD）的发生率 排空效率低和失禁，这对SCI患者的健康有害。我们 假设存在调节排尿反射的内源性脊髓DA能机制， 这些机制的药理学操作将改善下尿路（LUT）功能 SCI之后。在我们的初步数据中，我们已经观察到许多酪氨酸羟化酶（TH）+神经元， 在大鼠腰骶髓的自主神经核团和背角浅部。后 完全胸段脊髓损伤，以消除脊髓上的控制，显着更多的TH+神经元出现在 下索，这与局部持续的低水平DA表达相一致。此外，委员会认为， 抑制脊髓DA信号传导减少膀胱活动，而激活这些通路 增加尿道外括约肌（EUS）的爆裂持续时间。因此，本项目 将不仅全面解决一些基本问题，而且还将测试一种新的治疗方法， 治疗脊髓损伤后LUT功能障碍的策略。目的1：检测大鼠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 目的2，我们将阐明这些TH+神经元是否发挥DA能调节排尿反射 SCI之后在目标3中，我们将确定脊髓DA能通路的药理学刺激是否 改善SCI大鼠排尿功能恢复。这个项目的结果将揭示脊柱 DA能神经系统，阐明其在排尿中的作用。我们期待开发一种创新的 提高排尿效率和排尿速度的方法，从而改善患者的生活质量， SCI.