Bladder fullness signaling and the neural control of continence

项目摘要 下尿路症状（LUTS）影响数百万人，尤其是老年人 人口LUTS可能由控制膀胱功能的神经回路功能障碍引起或加重。 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， 知识差距依然存在。更深入地了解如何精细调整和有效的神经控制， 膀胱功能的实现是致力于开发更新和更有针对性的治疗方法的核心。 LUTS。这个特定应用的目的是了解哪些神经元检测，中继和处理这些信息。 膀胱扩张信号，使其最终成为整合到相干神经控制适当的膀胱 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 信息（PAG“感觉”）“门控”脑桥排尿中心（PMC）的神经元被激活， 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， PMC神经元可能被抑制，直到感觉（膀胱扩张）信号已经被中继/分配（从 脊髓传出PAG神经元）到大脑区域，这些区域在确定是否存在 情况是安全的，社会上可以接受的排尿。第一遍感觉神经元和 这些输入，包括来自PAG的输入，对PMC神经元活动施加抑制性控制是至关重要的 为了保持平衡。在强有力的初步数据的指导下，我们将通过以下方式来检验我们的总体假设： 追求三个具体目标：1）识别和映射骶脊髓传出神经的轴突投射 PAG/PAG“感觉”神经元; 2）使用纤维光度法Ca 2+成像，确定膀胱-传入- 活动受体PAG/PAG“感觉”神经元，其功能可能是将扩张信号转换为PMC输出 行动，并确定如何抑制PMC传入神经元，激活或失活，以允许排尿;和3）使用 光遗传学刺激定义了对膀胱功能的抑制性神经控制的电路基础，包括 识别出维持神经元活动所必需的神经元。这种方法在智力上和技术上 创新，因为它强调感觉信号感知PAG神经元和抑制性传入输入 (and来源细胞群体），调节PMC活性，并且因为它采用了新的 开发和验证技术方法。这项工作意义重大，因为它是 一个连续的研究，预计将导致显着改善我们的理解的知识 控制膀胱充盈和排泄的细胞和突触回路。这些研究将共同提供信息， 对调节膀胱功能的电路有更深入和更详细的了解，因此具有非常 真实的潜力，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.