Spinal dopaminergic mechanisms regulating the micturition reflex after spinal cord injury

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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. !