Impacts of Spinal Cord Injury on Autonomic Neurons Responsible for Bladder Function

脊髓损伤对负责膀胱功能的自主神经元的影响

• 批准号: 9926077
• 负责人: Michael Leslie Gray
• 金额: $ 6.93万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926077
• 关键词: Abnormal coordination; Acute; Address; Affect; Afferent Pathways; Age; Animals; Attenuated; Bladder; Bladder Control; Bladder Dysfunction; Calcium; Cells; Cessation of life; Choline O-Acetyltransferase; Chronic; Collection; Contracts; Devices; Dissection; Down-Regulation; Electrophysiology (science); Excision; Fire - disasters; Functional disorder; Ganglia; Gene Expression; General Population; Generations; Hyperreflexia; Incontinence; Injury; Ion Channel; Kidney; Knowledge; Lesion; Longevity; Measurement; Measures; Membrane; Messenger RNA; Micturition Reflex; Mus; Muscle; Nerve; Neurogenic Bladder; Neuromodulator Receptors; Neurons; Output; Pathway interactions; Pattern; Pelvis; Peripheral; Pharmacology; Phase; Physiological; Population; Potassium; Property; Quality of life; Quantitative Reverse Transcriptase PCR; Reflex action; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Severities; Signal Transduction; Skeletal Muscle; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Spinal cord injury patients; Stigmatization; Structure of parasympathetic ganglion; Time; Transcript; Transgenic Mice; Up-Regulation; Urethral sphincter; Urinary tract infection; Urogenital Diseases; Work; base; cell type; cholinergic; ganglion cell; improved; injured; mRNA Expression; mortality; mouse model; neuronal excitability; physically handicapped; promoter; protein degradation; public health relevance; receptor; receptor expression; spasticity; urologic; voltage clamp

Abstract The circuit that controls the micturition reflex is composed of autonomic neurons that control smooth bladder muscle (Detrusor) and somatic (voluntary) neurons that control the skeletal muscle of the external urethral sphincter (EUS). After SCI, the coordination between these muscles is lost and they contract spontaneously. While something is known about how SCI alters the excitability of neuronal pathways that feed into the spinal cord (afferents) and how SCI alters the excitability of these muscles, relatively little is known how excitability of the neurons (autonomic bladder-innervating neurons) contained in a collection of neurons called the major pelvic ganglia (MPG) is altered. The primary aim of this proposal is to characterize how the excitability of these neurons changes after acute (3 days post injury) and chronic (28 days post injury) SCI. Mouse models of SCI will be used to determine how injury alters the ability of neurons to fire based on their intrinsic properties (as opposed to their input from other neurons). Underlying mechanisms for altered output will be investigated using voltage clamp and pharmacological dissection of ionic currents to measure changes in underlying membrane conductance. To determine whether underlying changes in membrane conductance are the result of alterations in channel expression, single-cell quantitative RT-PCR (qRT-PCR) will be used to measure transcript numbers from MPG neurons in injured and intact animals. The proposed work will greatly improve the basic understanding of bladder reflex circuitry by providing a much needed extension of the characterization of the physiological properties and underlying ionic mechanisms of MPG neuron function. In addition, these studies represent one of the first analyses of plasticity at the MPG as a result of SCI, with implications for the successful comprehensive treatment of neurogenic bladder dysfunction.

抽象的 控制排尿反射的回路由控制平滑膀胱的自主神经元组成 控制外尿道骨骼肌的肌肉（逼尿肌）和体细胞（随意）神经元 括约肌（EUS）。脊髓损伤后，这些肌肉之间的协调性丧失，它们会自发收缩。 虽然我们对 SCI 如何改变馈送到脊髓的神经元通路的兴奋性有所了解。 脊髓（传入神经）以及 SCI 如何改变这些肌肉的兴奋性，相对而言，人们对兴奋性如何改变知之甚少 称为主要神经元的神经元集合中包含的神经元（支配膀胱的自主神经元） 骨盆神经节（MPG）发生改变。该提案的主要目的是描述兴奋性如何 这些神经元在急性（损伤后 3 天）和慢性（损伤后 28 天）SCI 后发生变化。鼠标型号 SCI 将用于确定损伤如何根据神经元的内在特性改变其放电能力 （与来自其他神经元的输入相反）。将研究改变输出的潜在机制 使用电压钳和离子电流的药理学解剖来测量潜在的变化 膜电导。确定膜电导的潜在变化是否是由于 通道表达的改变，将使用单细胞定量 RT-PCR (qRT-PCR) 来测量 受伤和完好动物中 MPG 神经元的转录本数量。拟议的工作将大大改善 通过提供急需的膀胱反射电路的扩展来基本了解 MPG 神经元功能的生理特性和潜在离子机制的表征。在 此外，这些研究代表了 SCI 导致的 MPG 可塑性的首批分析之一， 对神经源性膀胱功能障碍的成功综合治疗的影响。