Spinal dopaminergic mechanisms regulating the micturition reflex after spinal cord injury

项目总结 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 对大脑的影响。DA介导的尿液活动调节被认为是通过相互作用发生的 在中脑DA神经元和脑桥排尿中心之间。然而，我们最近 其特点是DA产生于大鼠脊髓，调节膀胱反射。创伤性的 脊髓损伤(SCI)中断脊髓延髓排尿通路并消除自主排尿 排尿。虽然脊髓排尿反射是随着时间的推移而建立的，并导致部分恢复 排尿、膀胱过度活动和逼尿肌-括约肌协同失调(DSD)的发生率 排空效率低和大小便失禁，不利于脊髓损伤患者的健康。我们 假设存在调节排尿反射的内源性脊髓DA能机制， 而对这些机制的药理学操作将改善下尿路(LUT)功能 追随SCI。在我们的初步数据中，我们观察到了大量的酪氨酸羟化酶(TH)+神经元 在大鼠腰骶段脊髓的自主神经核团和浅背角。在此之后 完全性胸部脊髓损伤去除棘上控制，显著更多的TH+神经元在 脊髓下部，这与局部持续、低水平的DA表达相一致。此外， 脊髓DA信号的抑制降低了膀胱的活性，而这些通路的激活 增加外括约肌(EUS)的爆裂持续时间。因此，这一拟议项目 将不仅全面解决一些基本问题，而且还将试验一种新的治疗方法 脊髓损伤后下尿路功能障碍的治疗策略。在目标1中，我们将确定大鼠体内TH+细胞是否降低 脊髓在脊髓损伤后发生可塑性，并参与脊髓排尿反射回路。在……里面 目的2，我们将阐明这些TH+神经元是否对排尿反射起DA能调节作用 在SCI之后。在目标3中，我们将确定药物对脊髓DA能通路的刺激 改善脊髓损伤大鼠的排尿功能恢复。这个项目的结果将揭开脊椎 并阐明其在排尿中的作用。我们预计将开发一种创新的 提高排尿效率和可控性的方法，从而改善患者的生活质量 SCI。

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.