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

项目摘要/摘要 创伤性脊髓损伤(SCI)常导致下尿路功能障碍。虽然是脊椎动物 膀胱反射可以随着时间的推移而建立，失去脊髓上的调制会导致逼尿肌-括约肌 协同障碍和膀胱反射亢进，表现为大小便失禁和排尿效率低下。这个 上述症状最终会导致尿路感染，在某些情况下还会导致肾衰竭。 目前，尿路并发症是脊髓损伤患者发病率和死亡率的主要原因之一。而当 脊髓神经元回路的自发重组发生在损伤后，其程度是有限的，潜在的 机制还不是很清楚。最近，我们发现酪氨酸羟基酶的一个亚群 (Th)细胞驻留在脊髓下部，维持多巴胺(DA)水平，并调节康复的 脊髓损伤后的膀胱反射。这与在新生儿身上观察到的情况相似。因此，我们假设， 脊髓损伤后，脊髓DA相关神经元重新出现，作为对损伤的原始残留反应，调节 排尿反射，增加脊髓DA信号可促进功能性尿液恢复。在目标1中，我们将 使用组织学、荧光细胞分选和遗传分析来确定脊髓DA相关细胞是否 新生和成年脊髓损伤大鼠具有相似的分布和分子特征。跨突触追踪将 说明这些细胞是否参与脊髓排尿反射回路。在目标2中，使用化学遗传学 技术和排尿反射评估，我们将阐明脊髓TH细胞是否调节康复 脊髓损伤后的排尿反射，增强脊髓DA信号可改善排尿功能。总体而言， 这些结果将有助于更好地了解脊髓多巴胺能系统在恢复的膀胱反射中的作用。 并检验一种治疗脊髓损伤后排尿功能障碍的新靶点的疗效。

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.