Mapping brainstem control of continence

绘制脑干控制失禁的图谱

• 批准号: 9886235
• 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/9886235
• 关键词: Ablation; Anatomy; Anesthesia procedures; Animals; Automobile Driving; Axon; Bladder; Bladder Control; Brain; Brain Stem; Complex; Conscious; Corticotropin-Releasing Hormone; Coupled; Cues; Data; Disease; Environment; Event; Future; Hypothalamic structure; Incontinence; Lateral; Lateral Hypothalamic Area; Link; Maps; Measurement; Medical Care Costs; 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; 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：储尿和排尿疾病，包括失禁、膀胱过度活动症 和下尿路症状 (LUTS) 困扰着数百万人并造成巨大的医疗费用，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 需要精细调整和有效的神经控制，有效的 LUTS 治疗需要了解这是如何进行的 神经控制是如何实现的，以及它在不同患者群体中是如何被扰乱的。 先前的研究确定了参与控制膀胱功能的大脑/脊髓区域，但没有发现 解析神经元亚群或其连接。我们缺乏并寻求在小鼠中开发完整的电路图 膀胱充盈/排尿的控制。之前的工作和我们自己的数据确定了桥脑排尿中心 （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。 大脑协调盆腔传入信号（膀胱充盈信号）到导水管周围灰质（PAG）和其他信号 来自外部环境的位点和线索（在外侧视前区（LPOA）和外侧视前区等位点进行处理） 下丘脑区（LHA））来“决定”何时排尿。定义大脑如何将这两个主要输入整合到 控制 PMCCRH 神经元，我们将结合最先进的神经科学方法和对膀胱的仔细研究 功能确定非 CRH PMC 区域神经元在排尿中的作用并定义 PMCCRH 与 vlPAG、LPOA 和 LHA 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 神经元似乎是驱动表达酪氨酸的排尿、蓝斑神经元的主要群体 羟化酶 (LCTH) 和脑桥中央灰质 GABA 能神经元 (PCGGABA) 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 将重点关注传入控制通路的 PAG 部分。我们将定义 vlPAG GLUT 如何 或 GABA 神经元（vlPAGGLUT 或 vlPAGGABA）通过利用初步连接并控制 PMCCRH 神经元 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）排尿。这些结果将使我们和其他人将来能够 解开 PAG 中详细的“开关”电路，该电路集成了骶骨传入信息以调节排尿。通过 PMCCRH 神经元。 目标 3 将重点关注下丘脑区域，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学联系 群体和 PMCCRH 神经元。这些研究将为发现有助于帮助的吻侧输入奠定基础。 控制下丘脑神经元的活动，进而调节 PMCCRH 神经元，并允许动物 在外部环境的背景下控制排尿。