Biomimetic stimulation of the sacral DRG to control continence and micturition

描述（由申请人提供）：本实验的目的是确定自然膀胱行为中阴部传入神经元活动的时空模式，并确定这些模式是否可以被外部刺激模仿，从而比传统的非特异性阴部传入刺激更好地控制膀胱功能。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流受体。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，将用于记录来自骶骨传入神经元的单个单元活动。这些神经元的放电模式和频率将被记录在一系列控制的膀胱功能条件下，并与生理变量相关，然后用于量化相关生理参数的感觉编码。第二个目的是测量对仿生电刺激模式的生理泌尿反应。刺激模式将基于从初始记录解码并由多电极阵列应用的感觉神经元活动模式。膀胱充血和排空期间的尿失禁和排尿反应将被表征，然后与非选择性电刺激阴部神经传入10hz（尿失禁）和33hz（排尿）引起的反应进行比较。第三个目的是鉴定尿道内假定的血流受体，以确定假定的血流受体是否为太平洋小体。牺牲后立即采集尿道组织，然后用各种染色试剂处理，并用光学显微镜观察。确定的结构将通过沿尿道长度的位置，大小和到管腔壁的距离来表征，以测试每个结构作为潜在血流受体的合理性。这项研究的长期目标是开发一种可植入的、类似心脏起搏器的装置，用于恢复神经损伤或疾病患者的膀胱功能。拟议研究的结果将发展和建立使用骶背根神经节仿生刺激的可行性，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.