Mapping brainstem control of continence

绘制脑干控制失禁的图谱

• 批准号: 9286791
• 负责人: Mark L. Zeidel
• 金额: $ 38.93万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286791
• 关键词: Ablation; Anatomy; Anesthesia procedures; Animals; Automobile Driving; Bladder; Bladder Control; Brain; Brain Stem; Complex; Conscious; Corticotropin-Releasing Hormone; Coupled; Cues; Data; Disease; Environment; Event; Future; Gray unit of radiation dose; Hypothalamic structure; Incontinence; Lateral; Lateral Hypothalamic Area; Link; Maps; Measurement; Medical; Methods; Mus; Nerve; Neurons; Neurosciences; Overactive Bladder; Pathway interactions; Patients; Pelvis; Physiology; Play; Pontine structure; Population; Preoptic Areas; Process; Reporting; Role; SLC2A1 gene; Signal Transduction; Site; Source; Spinal Cord; Stimulus; Symptoms; Translating; Tyrosine 3-Monooxygenase; Urination; Work; awake; cost; gamma-Aminobutyric Acid; locus ceruleus structure; lower urinary tract symptoms; midbrain central gray substance; neuroregulation; patient population; relating to nervous system; response; symptom treatment; urinary

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.

项目摘要：尿储存和排尿的障碍，包括尿失禁，过度活跃的膀胱 并降低尿路症状（LUTS）折磨数百万的人，并产生巨大的医疗费用，我们 缺乏对LUTS机制的了解阻碍治疗。因为成功的膀胱填充和无效 需要精心调整和有效的神经控制，有效的LUTS治疗将需要理解如何 在不同的患者人群中，神经控制及其如何破坏。 先前的研究确定了涉及控制膀胱功能的大脑/脊髓区域，但不要 解决神经元亚群或它们的连接。我们缺乏并寻求在小鼠中开发完整的电路图 控制膀胱填充/空隙的控制。先前的工作，我们自己的数据确定 （PMC）及其许多皮质激素释放的马酮（CRH）神经元（PMCCRH）是缺乏的主要驱动因素。 大脑坐标骨盆传入（信号膀胱填充）与周围的灰色（PAG）和其他 站点，以及外部环境的提示（在基因座（如侧面前区域（LPOA）和侧面）处理 下丘脑区域（LHA））“决定”何时无效。定义大脑如何将这两个主要输入集成到 控制PMCCRH神经元，我们将结合最先进的神经科学方法与仔细研究膀胱 确定非CRH PMC区域神经元在空隙中的作用并定义 VLPAG，LPOA和LHA的PMCCRH和神经元之间的解剖/功能接口。 AIM＃1将定义PMC区域中至关重要的控制膀胱功能的神经种群。虽然 PMCCRH神经元似乎是表达酪氨酸的主要驱动器驱动器上的coeruleus神经元 矮脑灰色（PCGGABA）的羟化酶（LCTH）和GABA - 凝胶神经元也可能起作用。我们将 有选择地激活或消融PMCCRH，LCTH或PCGGABA神经元，并检查对膀胱功能的影响。 AIM 2将重点放在传入控制途径的PAG部分上。我们将定义如何vlpag lut 或通过利用初步来连接并控制PMCCRH神经元的GABA神经元（Vlpagglut或Vlpaggaba） 数据显示了从VLPAG到PMC的轴突投影，以及直接刺激这些神经元的证据 可以刺激（vlpagglut）或抑制（vlpaggaba）空隙。这些结果将使我们和其他人将来能够 在PAG中揭示详细的“开关”电路，集成了s骨传入信息以调节空隙。通过 PMCCRH神经元。 AIM 3将专注于下丘脑区域，这些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 种群和PMCCRH神经元。这些研究将为发现遗体输入提供帮助 控制下丘脑神经元的活性，该神经元反过来调节PMCCRH神经元，并允许动物 在其外部环境的上下文中控制空隙。