Biomimetic stimulation of the sacral DRG to control continence and micturition

描述（由申请人提供）：所提出的实验的目的是确定在自然膀胱行为期间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用外部刺激来模仿，以产生比通过常规非特异性阴部传入刺激实现的更好的膀胱功能控制。第二个目的是确定尿道内可能检测湍流并通过阴部神经介导兴奋性排尿反射的假定流量感受器。第一个具体目标是量化下尿路的神经感觉编码。记录电极，最初是单钨丝，随后是多电极阵列，将用于记录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速率将在一系列受控膀胱功能条件下记录，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。第二个目的是测量生理泌尿反应的仿生模式的电刺激。刺激的模式将基于从初始记录解码并由多电极阵列施加的感觉神经元活动的模式。将在膀胱充盈和排空期间表征控制和排尿反应，然后将其与在10 Hz（Hz）和33 Hz（排尿）下对阴部神经传入的非选择性电刺激诱发的反应进行比较。第三个目的是确定尿道内的假定流量感受器，以确定假定的流量感受器是否为环层小体。处死后立即收获尿道组织，然后用各种染色试剂处理，并使用光学显微镜观察。将通过沿尿道长度的位置沿着、尺寸和与管腔壁的距离来表征所识别的结构，以测试每个结构作为潜在流量受体的可扩展性。这项研究的长期目标是开发一种可植入的起搏器样装置，可用于恢复神经损伤或疾病患者的膀胱功能。拟定研究的结果将开发并确立骶背根神经节仿生刺激的可行性，并指导最终用于人体的器械的开发。

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.