Understanding functional connectivity of sensory and motor pathways to specific regions of the lower urinary tract.

了解感觉和运动通路与下尿路特定区域的功能连接。

基本信息

批准号：
9920329
负责人：
JANET R KEAST
金额：
$ 9.72万
依托单位：
UNIVERSITY OF MELBOURNE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-28 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920329
关键词：
Address Adult Afferent Neurons Aging Anatomy Animals Area Behavior Biomedical Engineering Bladder Bladder Control Brain Catheters Chronic Clinical Communities Conscious Development Device or Instrument Development Elements Experimental Designs Female Foundations Ganglia Human Incontinence Injury Interstitial Cystitis Ion Channel Knowledge Label Lower urinary tract Maps Methods Microscopic Micturition Reflex Modality Modeling Motor Motor Neurons Motor Pathways Mus National Institute of Diabetes and Digestive and Kidney Diseases Nerve Neural Pathways Neuroanatomy Neurobiology Neuronal Dysfunction Neurons Nociception Nociceptors Ontology Operative Surgical Procedures Organ Outcome Overactive Bladder Pain Pathway interactions Pelvic Pain Pelvis Peripheral Peripheral Nerves Pharmacology Phenotype Physiological Population Rattus Recovery Reflex action Research Support Sensory Site Spinal Spinal Cord Striated Muscles System Technology Time Tissues Urethra Urologic Diseases Viral Visceral pain annotation system autonomic nerve autonomic reflex base bladder trigone career clinical translation experience injured male nerve supply neuroregulation new technology new therapeutic target novel marker relating to nervous system skills transcriptome sequencing urologic

项目摘要

ABSTRACT This foundational project will produce mesoscopic and microscopic functional anatomical maps of the sensory and autonomic (motor) neurons that regulate the lower urinary tract (LUT). Neural dysfunction is a major contributor to diverse, largely intractable urological problems, including overactive or underactive bladder, incontinence due to ageing or pelvic surgery, and painful bladder syndrome/interstitial cystitis. We will fill knowledge gaps and overcome diverse technical roadblocks to develop maps that provide a critical foundation for modeling different LUT behaviors, understanding neuromodulatory mechanisms, and determining off-target effects of neuromodulation. We will conduct this study in adult rats, the species where the peripheral and spinal circuitry of the LUT is defined in the most detail and, compared with mice, their larger size facilitates development of devices. Together, this will facilitate development of new methods for normalizing over- or underactivity in these circuits. The aims to be addressed in males and females are: (1) To map functionally distinct classes of sensory and autonomic neurons that innervate the bladder body, trigone and proximal urethra. We will also map neurons that project to more than one of these regions (`cross-talk'). In addition to known functional markers of sensory and autonomic neural subtypes, we will use the latest outcomes of our RNA-seq analyses of retrogradely labeled bladder-projecting neurons to define and map new markers of functional subclasses. (2) To map the spinal targets of sensory neurons innervating the bladder body, trigone and proximal urethra. Using viral tracing we will map and characterize second order sensory neurons in autonomic reflex and nociceptive pathways; we will also identify sites of convergence from two peripheral targets. (3) To map the spinal neurons activated by physiologically- or electrically-induced voiding in conscious rats. Our recent advance of activating pelvic nerves in chronically- catheterized conscious animals will be combined with markers of neural activation, detailed phenotyping of activated neurons and viral tracing.

抽象的该基础项目将生成介观和微观功能解剖图调节下尿路 (LUT) 的感觉和自主（运动）神经元。神经功能障碍是造成多种棘手的泌尿系统问题的主要原因，包括过度活跃或活跃不足膀胱、由于衰老或盆腔手术导致的尿失禁，以及膀胱疼痛综合征/间质性膀胱炎。我们将填补知识空白并克服各种技术障碍，以开发提供关键信息的地图为不同 LUT 行为建模、理解神经调节机制以及确定神经调节的脱靶效应。我们将在成年大鼠中进行这项研究，该物种 LUT 的外周和脊髓回路被最详细地定义，并且与小鼠相比，它们的更大的尺寸有利于设备的开发。总之，这将促进新方法的开发使这些电路中的过度活动或活动不足正常化。男性和女性要解决的目标是：（1）为了绘制支配膀胱体的功能不同类别的感觉和自主神经元，三角区和近端尿道。我们还将映射投射到这些区域中多个区域的神经元（“串扰”）。除了已知的感觉和自主神经亚型的功能标记之外，我们还将使用我们对逆行标记的膀胱投射神经元进行 RNA-seq 分析的最新结果，以定义并绘制功能子类的新标记。 (2) 绘制感觉神经元的脊髓目标支配膀胱体、三角区和近端尿道。使用病毒追踪，我们将绘制地图并表征自主反射和伤害感受通路中的二阶感觉神经元；我们还将确定以下地点来自两个外围目标的收敛。 (3)绘制生理学或生理学激活的脊髓神经元图谱电诱导清醒大鼠排尿。我们最近在慢性盆腔神经激活方面取得了进展插入导管的有意识的动物将与神经激活标记物、详细的表型分析相结合激活的神经元和病毒追踪。