Characterizing the Neural Pathway Maintaining Urinary Continence and its Role in Hydrocephalic Incontinence

摘要 急迫性尿失禁影响着近2000万美国人，导致失去独立性和感觉， 萧条在这些受影响的患者中，有正常压力脑积水（NPH）患者，他们经历 急迫性尿失禁是三大症状之一尽管有巨大的经济和照顾者负担， 尿失禁，很少有人知道负责控制排尿的神经通路或如何这条通路 在NPH中可能会被破坏。本项目的总体目标是确定这一途径，并确定它是如何 改变了NPH。脑桥背侧的巴灵顿核（Bar）被认为是排尿中心，因为它促进了排尿。 响应导水管周围灰质（PAG）的输入而排尿，这表明膀胱伸展。但这 反射并不能解释复杂的排尿行为，如排尿，其他大脑区域必须 涉案对内侧前额叶皮层（mPFC）的成像研究表明，这一区域与排尿有关 NPH中的mPFC低灌注或该区域的卒中与失禁相关。此外，病变 下丘脑视前区（POA）也可引起尿失禁。此外，POA还收到 从mPFC输入并将输出直接发送到Bar。这些数据表明mPFC和POA在以下方面的作用： 控制系统。我们的中心假设是，维持神经元兴奋性的通路连接到神经元兴奋性的通路。 通过POA中的抑制性中继神经元将mPFC中的神经元传递到Bar，并且在 脑室周围白色物质导致NPH患者尿失禁。为了验证这一假设，我们提出了以下目标： 1)描述mPFC → Bar通路在排尿中的作用。我将检验这个假设， 这是维持神经元功能所必需的，刺激这条通路的后半部分足以恢复神经元功能。 - 是的首先，我将联合收割机顺行追踪与免疫组织化学相结合， 通路第二，我们将通过损毁mPFC和刺激POA终末来检测这一通路的功能。 酒吧我们假设病变会造成失禁，刺激会恢复失禁。 2)识别和克服NPH失禁小鼠的差异。我们已经创造了一个渐进的 小鼠脑积水，通常伴有尿失禁。我将通过评估组织来扩展这项研究 我们假设我们会在白色物质中看到脱髓鞘， 连接mPFC和POA的神经束，沿着脑室延伸。然后我们刺激POA末梢 在这些老鼠身上。我们假设，刺激此处将改善脑积水引起的尿失禁。 在这个项目结束时，我将确定连接内侧前额叶皮层和巴林顿皮层的通路。 细胞核，确定其在维持细胞凋亡中的作用，确定了这一途径的结构差异， 小鼠脑积水，并操纵这一途径，以恢复排尿失禁小鼠。这项工作将 通过以下方式扩大目前患有尿失禁的患者的治疗选择，无论是否患有NPH， 寻找新的治疗靶点

ABSTRACT Urinary urge incontinence affects nearly 20 million Americans, causing loss of independence and feelings of depression. Among those affected, are patients with Normal Pressure Hydrocephalus (NPH), who experience urge incontinence as one of three symptoms. Despite large economic and caregiver burden associated with incontinence, little is known about the neural pathway responsible for control of continence or how this pathway may be disrupted in NPH. The overall objective of this project is to identify this pathway and determine how it is altered in NPH. Barrington’s nucleus (Bar) in the dorsal pons is considered the micturition center, as it facilitates voiding in response to input from the periaqueductal gray (PAG), which signals bladder stretch. However, this reflex does not explain complex micturition behaviors, like continence, for which other brain regions must be involved. Imaging studies of the medial prefrontal cortex (mPFC) show that this area is involved in micturition and mPFC hypoperfusion in NPH or strokes to this region are associated with incontinence. Additionally, lesions to the preoptic area of the hypothalamus (POA) can also produce incontinence. Furthermore, the POA receives input from the mPFC and sends output directly to Bar. This data suggests a role for both the mPFC and POA in continence control. Our central hypothesis is that the pathway maintaining continence connects excitatory neurons in mPFC to Bar via inhibitory relay neurons in POA, and that disruption of this pathway in the periventricular white matter causes incontinence in NPH. To test this hypothesis, we propose the following aims: 1) Characterize the role of the mPFC → Bar pathway in micturition. I will test the hypothesis that this pathway is necessary for maintaining continence and that stimulation of the latter half of this pathway is sufficient to restore continence. First, I will combine anterograde tracing with immunohistochemistry to identify this multi-synaptic pathway. Secondly, I will test this pathway’s function by lesioning the mPFC and stimulating POA terminals in Bar. We hypothesize that the lesions will create incontinence and the stimulation will restore continence. 2) Identify and overcome differences in NPH incontinent mice. We have already created a progressive hydrocephalus in mice that is often accompanied by incontinence. I will expand this study by assessing the tissue of these incontinent mice for axonal injuries, hypothesizing that we will see demyelination in the white matter tracts connecting the mPFC to the POA, running alongside the ventricles. Then we will stimulate POA terminals in Bar in these mice. We hypothesize that stimulation here will improve incontinence caused by hydrocephalus. By the end of this project, I will have identified the pathway connecting the medial prefrontal cortex to Barrington’s nucleus, determined its role in the maintenance of continence, identified structural differences of this pathway in mice with hydrocephalus, and manipulated this pathway to restore continence to incontinent mice. This work will expand current treatment options for patients suffering from incontinence, both with and without NPH, by identifying new therapeutic targets.