Mapping brainstem control of continence

项目摘要：尿液储存和排尿障碍，包括大小便失禁、膀胱过度活动 和下尿路症状(LUTS)困扰着数百万人，并产生了巨大的医疗费用，而我们的 缺乏对LUTS机制的了解阻碍了治疗。因为成功的膀胱充盈和排尿 需要微调和有效的神经控制，有效的LUTS治疗将需要了解如何 实现了神经控制，以及它在不同的患者群体中是如何错乱的。 先前的研究确定了参与控制膀胱功能的大脑/脊髓区域，但没有 解析神经元亚群或它们之间的联系。我们缺乏并试图在小鼠身上开发出完整的电路图 控制膀胱充盈/排尿。先前的工作和我们自己的数据确定了桥接排尿中心 PMC及其许多促肾上腺皮质激素释放激素(CRH)神经元(PMCCRH)是排尿的主要驱动因素。 大脑协调盆腔传入(膀胱充盈的信号)到中脑导水管周围灰质(PAG)和其他 部位，以及来自外部环境的提示(在像外侧视前区(LPOA)和外侧区这样的位置上处理 下丘脑区(LHA)来“决定”何时排空。定义大脑如何将这两个主要输入整合到 控制PMCCRH神经元，我们将结合最新的神经科学方法和对膀胱的仔细研究 确定非CRH PMC区神经元在排尿中的作用并确定 PMCCRH与vlPAG、LPOA和LHA神经元之间的解剖/功能接口。 目的#1将定义对控制膀胱功能至关重要的PMC区域的神经群组。虽然 PMCCRH神经元似乎是驱动排尿的主要群体，蓝斑神经元表达酪氨酸 脑桥中央灰质的羟基酶(LCTH)和GABA能神经元(PCGGABA)也可能起作用。我们会 选择性地激活或消融PMCCRH、LCTH或PCGGABA神经元，并检查对膀胱功能的影响。 目标2将重点放在传入控制通路的PAG部分。我们将定义vlPAG如何过剩 或GABA神经元(vlPAGGLUT或vlPAGGABA)连接并控制PMCCRH神经元 数据显示从vlPAG到PMC的轴突投射，以及直接刺激这些神经元的证据 可刺激(VlPAGGLUT)或抑制(VlPAGGABA)排尿。这些结果将使我们和其他人在未来 解开PAG中详细的“开关”电路，整合骶骨传入信息来调节排尿。通过 PMCCRH神经元。 目标3将专注于帮助协调膀胱功能与体内事件的下丘脑区域。 外部环境。我们将定义LPOA和LHA神经元之间的功能和解剖联系 群体和PMCCRH神经元。这些研究将为发现吻部输入有助于 控制下丘脑神经元的活动，进而调节PMCCRH神经元，并允许动物 在其外部环境的上下文中控制排空。

PROJECT SUMMARY: Disorders of urinary storage and voiding, including incontinence, overactive bladder and lower urinary tract symptoms (LUTS) afflict millions of people and engender enormous medical cost, and our lack of understanding of LUTS mechanisms hampers treatment. Because successful bladder filling and voiding requires finely tuned and effective neural control, effective LUTS treatment will require understanding how this neural control is achieved and how it is deranged in different patient populations. Prior studies identify brain/spinal cord regions involved in controlling bladder function, but do not resolve neuronal subpopulations or their connections. We lack and seek to develop in mice a complete circuit map of the control of bladder filling/voiding. Prior work and our own data identified the Pontine Micturition Center (PMC) and its many corticotropin releasing hormone (CRH) neurons (PMCCRH) as major drivers of voiding. The brain coordinates pelvic afferents (signaling bladder filling) to periaqueductal gray (PAG) and other sites, and cues from the external environment (processed in loci like the lateral preoptic area (LPOA) and lateral hypothalamic area (LHA)) to “decide” when to void. To define how the brain integrates these two major inputs to control PMCCRH neurons, we will combine state of the art neuroscience methods with careful studies of bladder function to determine the roles of non CRH PMC region neurons in voiding and to define the anatomic/functional interfaces between PMCCRH and neurons of the vlPAG, LPOA and LHA. Aim #1 will define neural populations in the PMC region critical to control of bladder function. Although PMCCRH neurons appear to be the major group driving voiding, locus coeruleus neurons which express tyrosine hydroxylase (LCTH) and GABA-ergic neurons of the pontine central gray (PCGGABA) may also play a role. We will selectively activate or ablate PMCCRH, LCTH or PCGGABA neurons and examine effects on bladder function. Aim 2 will focus on the PAG portion of the afferent control pathway. We will define how vlPAG GLUT or GABA neurons (vlPAGGLUT or vlPAGGABA) connect to and control PMCCRH neurons by exploiting preliminary data showing axonal projections from vlPAG to PMC, as well as evidence that direct stimulation of these neurons can stimulate (vlPAGGLUT) or inhibit (vlPAGGABA) voiding. These results will permit us and others in future to unravel the detailed “switch” circuit in the PAG integrating sacral afferent information to regulate voiding. via PMCCRH neurons. Aim 3 will focus on hypothalamic regions which help coordinate bladder function with events in the external environment. We will define functional and anatomic connections between LPOA and LHA neuron populations and PMCCRH neurons. These studies will set the stage for discovery of the rostral inputs helping control activity of hypothalamic neurons which, in turn regulate PMCCRH neurons, and permit the animal to control voiding in the context of its external environment.