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

摘要 尿急尿失禁影响近2000万美国人，导致失去独立性和 抑郁症。在受影响的人中，有正常压力脑积水(NPH)的患者，他们经历了 将大小便失禁作为三种症状之一。尽管存在巨大的经济和照顾者负担， 大小便失禁，我们对负责控制大小便失禁的神经通路知之甚少，也不知道这个通路是如何 可能在NPH中被扰乱。这个项目的总体目标是确定这条途径，并确定它是如何 在NPH中更改。脑桥背侧的巴林顿核(Bar)被认为是排尿中心，因为它有助于 排尿反应来自中脑导水管周围灰质(PAG)的输入，它表示膀胱伸展。不过，这个 反射不能解释复杂的排尿行为，比如大小便失禁，而大脑的其他区域必须有这样的行为 牵涉其中。内侧前额叶皮质(MPFC)的影像研究表明，该区域与排尿有关。 NPH的mPFC低灌注率或卒中至该区域与大小便失禁有关。此外，损伤 下丘脑视前区(POA)也会产生大小便失禁。此外，POA还接收 来自mPFC的输入，并将输出直接发送到Bar。这一数据表明，mPFC和POA在 可控性控制。我们的中心假设是，维持可控性的通路与兴奋性 MPFC中的神经元通过POA中的抑制性中继神经元到Bar，而这一途径在 脑室周围白质可导致NPH患者尿失禁。为了验证这一假设，我们提出了以下目标： 1)研究mPFC→Bar通路在排尿中的作用。我将测试假设这条路径是 这是维持可控性所必需的，刺激这一通路的后半部分足以恢复 克制。首先，我将结合顺行追踪和免疫组织化学来鉴定这个多突触 路径。其次，我将通过损毁mPFC和刺激POA终末来测试这一通路的功能 酒吧。我们假设病变会造成大小便失禁，刺激会恢复大小便失禁。 2)识别和克服NPH尿失禁小鼠的差异。我们已经创造了一个进步的 小鼠的脑积水，常伴有大小便失禁。我将通过评估组织来扩展这项研究 这些失禁小鼠的轴突损伤，假设我们将在白质中看到脱髓鞘 连接mPFC和POA的纤维束，与脑室相连。然后我们将刺激POA终端 在这些老鼠的酒吧里。我们假设这里的刺激可以改善脑积水引起的尿失禁。 到这个项目结束时，我将确定连接内侧前额叶皮质和巴林顿氏核的通路 细胞核，确定了它在维持可控性中的作用，确定了这一途径的结构差异 对患有脑积水的小鼠进行治疗，并通过操纵这一途径恢复失禁小鼠的可控性。这项工作将 扩大目前尿失禁患者的治疗选择，无论有无NPH，通过 确定新的治疗靶点。

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.