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

这个基础项目将产生介观和微观的功能解剖图， 调节下尿路（LUT）的感觉和自主（运动）神经元。神经功能障碍是一种 导致各种各样的、很难治疗的泌尿系统问题的主要原因，包括活动过度或活动不足 膀胱、由于老化或骨盆手术引起的失禁以及疼痛性膀胱综合征/间质性膀胱炎。我们 将填补知识空白，克服各种技术障碍，开发地图， 建立不同LUT行为的模型，理解神经调节机制， 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， LUT的外围和脊髓电路被最详细地定义，并且与小鼠相比，它们的 更大的尺寸有利于器件的开发。总之，这将有助于开发新的方法， 使这些回路的过度或不活跃正常化。在男性和女性中要解决的目标是：（1） 为了映射支配膀胱体的感觉神经元和自主神经元的功能不同类别， 三角区和近端尿道。我们还将绘制投射到这些区域中的多个区域的神经元 （'cross-talk'）。除了已知的感觉和自主神经亚型的功能标志物，我们将使用 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， 并绘制功能子类的新标记。(2)绘制出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，我们将绘制和表征 第二级感觉神经元在自主反射和伤害性通路;我们还将确定网站的 从两个外围目标收敛。(3)为了绘制生理上激活的脊髓神经元， 电诱导清醒大鼠排尿。我们最近在慢性插管清醒动物中激活盆腔神经的进展将与神经激活的标记物、 激活神经元和病毒追踪

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.