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: 10390870
• 负责人: Michael Leslie Gray
• 金额: $ 3.09万
• 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/10390870
• 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 (UNCHANGED FROM ORIGINAL APPLICATION) 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.

摘要（与原始申请相同） 控制排尿反射的回路是由控制光滑膀胱的自主神经元组成的 肌肉（逼尿肌）和控制外尿道骨骼肌的躯体（自主）神经元 括约肌（EUS）。SCI后，这些肌肉之间的协调性丧失，它们会自发收缩。 虽然我们知道SCI如何改变神经元通路的兴奋性， 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， 神经元（自主膀胱神经支配神经元）包含在一个称为主神经元的神经元集合中， 盆神经节（MPG）改变。这项建议的主要目的是描述 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。小鼠模型 SCI将用于确定损伤如何改变神经元基于其内在特性的放电能力 (as与它们来自其他神经元的输入相反）。将研究改变输出的基本机制 使用电压钳和离子电流的药理学解剖来测量潜在的 膜电导为了确定膜电导的潜在变化是否是 通道表达的改变，将使用单细胞定量RT-PCR（qRT-PCR）来测量 来自受损和完整动物中MPG神经元的转录物数量。拟议的工作将大大改善 膀胱反射电路的基本理解，通过提供一个急需的扩展， MPG神经元功能的生理特性和潜在离子机制的表征。在 此外，这些研究是对脊髓损伤后MPG可塑性的首次分析， 对神经源性膀胱功能障碍的成功综合治疗的意义。