SEROTONIN AND GABA NEURON SUBTYPES- THEIR DEVELOPMENT AND FUNCTION

血清素和 GABA 神经元亚型 - 它们的发育和功能

• 批准号: 8063490
• 负责人: Susan M. Dymecki
• 金额: $ 31.4万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8063490
• 关键词: Acidosis; Affect; Alcohols; Alleles; Aminobutyric Acids; Anorexia; Anxiety; Apnea; Blood Pressure; Brain; Brain Stem; Breathing; Cell Nucleus; Cell physiology; Childhood; Collaborations; Data; Defect; Development; Diagnostic; Disease; Embryo; Feedback; Functional disorder; Generations; Genes; Genetic; Genetic Programming; Goals; Heart Rate; Heterogeneity; Homeostasis; Human; Hypoxia; Impairment; Knowledge; Label; Life; Light; Link; Maps; Mental disorders; Molecular; Mus; Neonatal; Neurons; Neurotransmitters; Outcome; Physiological; Pregnancy; Primordium; Principal Investigator; Production; Property; Reflex action; Serotonin; Signal Transduction; Slice; Specificity; Stem cells; Sudden Death; Sudden infant death syndrome; System; Technology; Testing; Tetanus Toxin; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Variant; Ventricular; base; design; developmental disease; extracellular; fetal programming; gamma-Aminobutyric Acid; hindbrain; in vivo; innovation; molecular marker; neural precursor cell; neurotransmitter release; postnatal; precursor cell; programs; recombinase; relating to nervous system; research study; tool; transcription factor

Based on observations from brainstem tissue of SIDS cases, we hypothesize, as a program, that an important subset of SIDS result from medullary defects in serotonin (5-HT)-producing neurons and related neurotransmitter systems such as GABA. Evidence suggests that these defects arise during gestation and affect specific subtypes of, as opposed to all, 5-HT neurons. From this, we reason that SIDS is an embryonic developmental disorder affecting specific subtypes of 5-HT and/or GABA neurons of the medulla. Towards understanding the differential basis for SIDS, we propose experiments designed to decode the developmental and molecular origins of different neuron subtypes within the medullary 5-HT and GABA neural systems in the mouse, and determine the specific properties of these subtypes as relates to homeostatic control. These experiments are made possible via recent, powerful advances: 1) a developmental map of the mature brainstem 5-HT system that, for the first time, resolves the system into molecularly separable, and therefore genetically accessible, 5-HT neuron subtypes; 2) the identification of embryonic genetic programs that are instructive for different GABAergic fates and which are likely employed in the developing medulla; and 3) tools with sufficient specificity to perturb the activity of (for example, "silence") select 5-HT or GABA subtypes in the living mouse. Using these tools, we will plot cellular functions and electrophysiological properties onto the developmental maps of medullary 5-HT and GABA neuron subtypes (Aims 1 and 3, respectively). Because our goal is to identify neuron subtypes most relevant pathophysiologically to SIDS, we will focus on 5-HT and GABA neuron subtypes of the medulla and their properties as relates to sensing acidosis and/or hypoxia (in collaboration with Project 4) and their functions as relates to control of breathing, heart rate, blood pressure and reflex apnea (in collaboration with Project 2). These are functions which, if impaired, might plausibly contribute to sudden death. Further, we propose investigating a possible mechanism for regulating 5-HT neuron production, our goal being to decipher the basis for the increased number of 5-HT neurons in SIDS cases. The ability to redefine medullary 5-HT and GABA neuron subtypes and their production based on a constellation of criteria - molecular, developmental, electrophysiological, and functional- is a major strength and innovation of this proposal and program.

基于对小岛屿发展中国家脑干组织的观察，我们假设，作为一个程序，一个 5-羟色胺(5-羟色胺)产生神经元和相关神经元的髓质缺陷是SID的重要亚群 神经递质系统，如GABA。有证据表明，这些缺陷发生在怀孕期间和 影响特定亚型的5-羟色胺神经元，而不是所有5-羟色胺神经元。由此，我们推断，小岛屿发展中国家是一个胚胎。 影响延髓特定亚型5-羟色胺和/或GABA神经元的发育障碍。朝向 为了理解小岛屿发展中国家的差异基础，我们提出了旨在解码 延髓5-羟色胺和γ-氨基丁酸不同神经元亚型的发育和分子起源 小鼠的神经系统，并确定这些亚型的特定属性与 动态平衡控制。这些实验是通过最近强大的进展而成为可能的：1)a) 成熟的脑干5-羟色胺系统的发展图，首次将该系统分解为 分子上可分离的，因此可遗传的，5-羟色胺神经元亚型；2)鉴定 胚胎遗传程序对不同的GABA能命运有指导作用，并可能被采用 在发育中的髓质中；以及3)具有足够特异性以干扰(例如， “沉默”)在活着的小鼠中选择5-羟色胺或GABA亚型。使用这些工具，我们将绘制细胞函数 延髓5-羟色胺和GABA神经元的电生理特性 亚型(目标分别为1和3)。因为我们的目标是找出最相关的神经元亚型 在小儿麻痹症的病理生理学方面，我们将集中在延髓的5-羟色胺和GABA神经元亚型以及它们的 与感知酸中毒和/或缺氧有关的特性(与项目4合作)及其功能 与控制呼吸、心率、血压和反射性呼吸暂停有关(与项目合作 2)。这些功能如果受损，可能会导致猝死。此外，我们建议 研究调节5-羟色胺神经元产生的可能机制，我们的目标是破译 这是小岛屿发展中国家5-羟色胺神经元数量增加的基础。重新定义延髓5-羟色胺和 基于一系列标准的GABA神经元亚型及其产生-分子，发育， 电生理，和功能性-是这项提案和方案的一大优势和创新。