Targeting Spinal Dopaminergic Machinery to Improve Urinary Function after Spinal Cord Injury

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Traumatic spinal cord injury (SCI) often results in lower urinary tract dysfunction. Although a spinal bladder reflex can be established over time, loss of supraspinal modulation causes detrusor-sphincter dyssynergia and bladder hyperreflexia, which manifests as incontinence and inefficient voiding. The aforementioned symptoms eventually lead to urinary tract infections and, in some cases, kidney failure. Currently, urinary complications are one of the leading causes of morbidity and mortality in SCI patients. While spontaneous reorganization of spinal neuronal circuits occurs after injury, the extent is limited and the underlying mechanisms are not well understood. Recently, we discovered that a subpopulation of tyrosine hydroxylase (TH+) cells reside within the lower spinal cord that sustain dopamine (DA) levels and regulate the recovered bladder reflex after SCI. This is similar to what was observed in neonates. Accordingly, we hypothesize that, following SCI, spinal DA-related neurons reemerge as a primitive residual response to injury that regulates the micturition reflex, and increasing spinal DA signaling improves functional urinary recovery. In Aim 1, we will employ histological, fluorescent cell sorting and genetic analyses to determine if spinal DA-related cells of neonate and adult SCI rats share a similar distribution and molecular features. Transsynaptic tracing will illuminate if these cells are involved in the spinal micturition reflex circuitry. In Aim 2, using chemogenetic techniques and micturition reflex assessments, we will elucidate whether spinal TH+ cells regulate the recovered micturition reflex following SCI, and if enhancing spinal DA signaling improves urinary function. Overall, the results will help to better understand the role of the spinal dopaminergic system in the recovered bladder reflex and examine the efficacy of a novel therapeutic target for micturition dysfunction after SCI.