Mapping brainstem control of continence

项目总结：储尿和排尿障碍，包括失禁、膀胱过度活动症 和下尿路症状（LUTS）折磨着数百万人，并产生巨大的医疗费用，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 需要精细调整和有效的神经控制，有效的LUTS治疗将需要了解这是如何实现的。 神经控制是如何实现的，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脑/脊髓区域，但没有 解析神经元亚群或它们的连接。我们缺乏并寻求在小鼠中开发一个完整的电路图 控制膀胱充盈/排泄的功能。先前的工作和我们自己的数据确定了脑桥排尿中心 (PMC)以及其许多促肾上腺皮质激素释放激素（CRH）神经元（PMCCRH）作为排尿的主要驱动器。 大脑协调骨盆传入（发出膀胱充盈信号）到导水管周围灰质（PAG）和其他神经元。 位点，以及来自外部环境的线索（在像外侧视前区（LPOA）和外侧视前区（LPOA）这样的位点中处理）。 下丘脑区域（LHA））来“决定”何时排泄。为了确定大脑如何整合这两个主要输入， 控制PMCCRH神经元，我们将联合收割机最先进的神经科学方法与膀胱的仔细研究相结合， 功能，以确定非CRH PMC区域神经元在排尿中的作用，并定义 PMCCRH与vlPAG、LPOA和LHA的神经元之间的解剖/功能界面。 目标#1将定义PMC区域中对控制膀胱功能至关重要的神经群。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 羟化酶（LCTH）和GABA能神经元的脑桥中央灰质（PCGABA）也可能发挥作用。我们将 选择性激活或消融PMCCRH、LCTH或PCGGABA神经元并检查对膀胱功能的影响。 目标2将集中在传入控制通路的PAG部分。我们将定义vlPAG GLUT如何 或GABA神经元（vlPAGGLUT或vlPAGGABA）通过利用初步的 显示从vlPAG到PMC的轴突投射的数据，以及直接刺激这些神经元的证据， 可以刺激（vlPAGGLUT）或抑制（vlPAGGABA）排泄。这些结果将使我们和其他人在未来， 解开PAG中整合骶骨传入信息以调节排尿的详细“开关”回路。经由 PMCCRH神经元。 目标3将集中在下丘脑区域，该区域有助于协调膀胱功能与事件， 外部环境我们将定义LPOA和LHA神经元之间的功能和解剖连接 PMCCRH神经元。这些研究将为发现嘴部输入帮助 控制下丘脑神经元的活动，进而调节PMCCRH神经元，并允许动物 在其外部环境的背景下控制排泄。

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.