Biomimetic stimulation of the sacral DRG to control continence and micturition

描述(申请人提供)：拟议的实验的目的是确定在自然的膀胱行为中阴部传入神经元活动的时间和空间模式，并确定这些模式是否可以被外部刺激模仿以产生比传统的非特异性阴部传入刺激实现的更好的膀胱功能控制。第二个目标是确定尿路中可能存在的血流受体，这些受体可以检测到湍流，并通过阴部神经调节兴奋性排尿反射。第一个具体目标是量化下尿路的神经感觉编码。记录电极、最初的单根钨丝和随后的多电极阵列将被用来记录来自骶骨传入神经元的单个单位活动。这些神经元的放电模式和频率将在一系列受控的膀胱功能条件下被记录下来，并与生理变量相关联，然后用于量化相关生理参数的感觉编码。第二个目标是测量尿液对电刺激仿生模式的生理反应。刺激的模式将基于感觉神经元活动的模式，从最初的记录中解码并由多电极阵列应用。在膀胱充盈和排空过程中，我们将对可控性和排尿性反应进行表征，然后将其与非选择性电刺激阴部神经传入在10赫兹(可控性)和33赫兹(排尿)时所诱发的反应进行比较。第三个目的是识别尿路中可能的血流受体，以确定可能的血流受体是否是帕西尼小体。处死后立即取尿路组织，用多种染色试剂处理，光镜观察。确定的结构将通过沿尿路长度的位置、大小和到管腔壁的距离来表征，以测试每个结构作为潜在的血流受体的可能性。这项研究的长期目标是开发一种可植入的类似起搏器的设备，可以用于恢复神经损伤或疾病患者的膀胱功能。拟议的研究结果将开发和建立使用仿生刺激骶骨背根神经节的可行性，并将指导最终用于人类的设备的开发。

DESCRIPTION (provided by applicant): The objective of the proposed experiments is to identify temporal and spatial patterns of pudendal afferent neuron activity during natural bladder behaviors and to determine whether these patterns can be mimicked with external stimuli to produce better control of bladder functions than achieved by conventional non-specific pudendal afferent stimulation. A secondary objective is to identify putative flow receptors within the urethra that may detect turbulent flow and mediate an excitatory micturition reflex through the pudendal nerve. The first specific aim is to quantify the neural sensory coding of the lower urinary tract. Recording electrodes, initially single tungsten wires and subsequently multi-electrode arrays will be used to record single unit activity from sacral afferent neurons. The firing pattern and rate of these neurons will be recorded during a series of controlled bladder function conditions, correllated with physiological variables, then used to quantify sensory coding of relevant physiological parameters. The second aim is to measure the physiological urinary responses to biomimetic patterns of electrical stimulation. The patterns of stimulation will be based on the patterns of sensory neuron activity decoded from the initial recordings and applied by multi-electrode arrays. Continence and micturition responses will be characterized during bladder filling and emptying then compared to the responses evoked by non- selective electrical stimulation of pudendal nerve afferents at 10 Hz (continence) and 33 Hz (micturition). The third aim is to identify the putative flow receptors within the urethra to determine whether the putative flow receptors are Pacinian corpuscles. Urethral tissue will be harvested immediately after sacrifice, then treated with a variety of staining reagents and observed using light microscopy. Identified structures will be characterized by location along the length of the urethra, size, and distance to the lumen wall to test the plausibility of each structure as a potential flow receptor. The long-term goal of this research is to develop an implantable, pacemaker-like device that can be used to restore bladder function in persons with neurological injury or disease. The results of the proposed studies will develop and establish the feasibility of using biomimetic stimulation of the sacral dorsal root ganglia and will guide development of a device intended for eventual use in humans.