Bladder fullness signaling and the neural control of continence

项目总结 下尿路症状(LUT)影响数以百万计的人，在老年人中尤其普遍 人口。LUT可能是由控制膀胱功能的神经回路功能障碍引起或加重的。 尽管我们对控制反射和自主排尿的回路的理解取得了一些进展，但意义重大 知识差距依然存在。增强了对如何精细和有效的神经控制的理解 膀胱功能的实现是开发新的、更有针对性的治疗方法的核心 LUTS。这一特定应用的目标是了解哪些神经元检测、传递和处理 膀胱扩张信号，从而最终集成到适当的膀胱的连贯神经控制中 功能。中心假设是接受膀胱充盈的中脑导水管周围灰质(PAG)神经元 桥脑排尿中心(PMC)的信息(PAG‘Sense’)‘Gate’神经元被激活以启动 排尿行为。成功的膀胱充盈和排尿是由投射到脊髓的PMC神经元指导的 运动神经元依次支配逼尿肌和尿道括约肌。我们的模型预测了 PMC神经元可能受到抑制，直到感觉(膀胱扩张)信号被传递/分配(来自 脊髓传出的PAG神经元)传递到大脑区域，这些区域在确定一种 这种情况是安全的，排尿是社会可以接受的。首通感觉神经元的正常功能和 在这些输入中，包括来自PAG的那些，对PMC神经元活动施加抑制控制是至关重要的 用来维持节制。在强劲的初步数据的指导下，我们将通过以下方式测试我们的总体假设 追求三个具体目标：1)识别和标测骶髓传出的轴突投射 PAG/PAG“感觉”神经元；2)用纤维光度法钙离子成像，确定膀胱的神经活动--传入-- 活动受体PAG/PAG“感觉”神经元可能具有将扩张信号转换为PMC输出的功能 活动，并确定抑制性PMC传入神经元如何激活或去激活以允许排尿；以及3)使用 光遗传刺激定义了抑制神经控制膀胱功能的电路基础，包括 识别维持节制所必需的神经元。这种方法在智力上和技术上都是 创新是因为它强调感官信号感测的PAG神经元和抑制性传入输入 (和来源细胞群)，调节PMC活性，因为它采用了一种新的新组合 开发并验证了技术方法。这项工作意义重大，因为它是 一系列的研究有望显著提高我们对知识的理解 控制膀胱充盈和排尿的细胞和突触回路。总而言之，这些研究将向 对调节膀胱功能的回路有更深入和更详细的了解，因此对 真正有潜力为治疗LUTS的新疗法的开发提供信息。

PROJECT SUMMARY Lower urinary tract symptoms (LUTS) affect millions of people and are especially prevalent in the elderly population. LUTS are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function. Despite some progress in our understanding of the circuits that control reflex and voluntary micturition, significant knowledge gaps remain. An enhanced understanding of how finely tuned and effective neural control over bladder function is achieved is central to efforts directed at developing newer and more targeted treatments for LUTS. The objective in this particular application is to understand which neurons detect, relay and process the bladder distention signal, so that it ultimately becomes integrated into coherent neural control for proper bladder function. The central hypothesis is that periaqueductal gray (PAG) neurons that receive bladder fullness information (PAG’sense’) ‘gate’ neurons in the pontine micturition center (PMC) to become activated to initiate micturition behavior. Successful bladder filling and voiding is directed by PMC neurons that project to spinal cord motoneurons that, in turn, innervate detrusor and urethral sphincter muscles. Our model predicts that activity in PMC neurons is likely suppressed until the sensory (bladder distention) signal has been relayed/distributed (from spinal cord-efferent PAG neurons) to brain regions that exert ‘executive control’ in determining whether a situation is safe and socially acceptable for voiding. The proper function of both first-pass sensing neurons and of these inputs, including those from the PAG, that exert inhibitory control over PMC neuron activity are critical for maintaining continence. Guided by strong preliminary data, we will test our overarching hypothesis by pursuing three specific aims: 1) identify and map axonal projections of sacral spinal cord-efferent PAG/PAG’sense’ neurons; 2) using fiber photometry Ca2+ imaging, define neural activity in bladder-afferent- activity recipient PAG/PAG’sense’ neurons that may function to transform the distention signal to PMC output action, and determine how inhibitory PMC-afferent neurons, activate or deactivate to allow voiding; and 3) using optogenetic stimulation define the circuit basis of inhibitory neural control over bladder function, including identifying neurons that are necessary for maintaining continence. The approach is intellectually and technically innovative because of its emphasis on sensory-signal-sensing PAG neurons and on inhibitory afferent inputs (and source cell populations) that regulate PMC activity, and because it employs a novel combination of newly developed and validated technical approaches. This work is significant because it is one of several key steps in a continuum of research that is expected to lead to significant improvement of knowledge of our understanding of the cellular and synaptic circuits that control bladder filling and voiding. Collectively these studies will inform a far deeper and more detailed understanding of the circuitry regulating bladder function and hence has the very real potential to inform the development of newer therapeutics for treating LUTS.