CELLULAR MECHANISMS OF RESPIRATORY AND TEMPERATURE CONTROL BY THE MEDULLARY 5-HT

髓质 5-HT 控制呼吸和温度的细胞机制

• 批准号: 8063489
• 负责人: GEORGE B RICHERSON
• 金额: $ 30.32万
• 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/8063489
• 关键词: Acetylcholine; Acidosis; Address; Affect; Age; Animal Model; Animals; Arousal; Arts; Binding; Blood Vessels; Breathing; Cardiovascular system; Cell Nucleus; Cells; Cessation of life; Chemoreceptors; Classification; Communities; Complement; Complex; Data; Defect; Development; Electrophysiology (science); Exposure to; Female; Gender; Genetic; Genetically Engineered Mouse; Goals; Green Fluorescent Proteins; Homeostasis; Human; Human Pathology; Hypercapnia; Hypoxia; Immunohistochemistry; In Vitro; Infant; Kidney; Lead; Light; Methods; Molecular; Molecular Genetics; Multiple Abnormalities; Mus; Neuroanatomy; Neuromodulator; Neurons; Neuropeptides; Nicotine; Norepinephrine; Physiologic Thermoregulation; Play; Preparation; Principal Investigator; Property; Proteins; Relative (related person); Respiration; Respiratory System; Role; Serotonin; Site; Sleep; Slice; Stimulus; Substance P; Substance P Receptor; Sudden infant death syndrome; Synapses; System; Techniques; Temperature; Time; Transgenic Mice; Work; base; critical developmental period; fetal tobacco exposure; follow-up; gamma-Aminobutyric Acid; hypocretin; in vivo; insight; male; medullary serotonergic system; member; neurochemistry; patch clamp; postnatal; prenatal; prenatal exposure; programs; raphe nuclei; receptor; research study; respiratory; response; stressor; theories; tool

Multiple abnormalities have been identified by our group in the serotonergic system in the medulla of SIDS cases. These data are exciting and compelling in light of a large body of experimental data from our group and others that indicate that serotonin (5-HT) neurons are involved in maintaining cardiovascular and respiratory homeostasis and in regulating sleep and arousal. There is strong evidence in particular that 5-HT neurons contribute to the ventilatory and arousal response to hypercapnia, as well as the response to temperature challenges. Thus, a defect in 5-HT neurons fits well with long-standing theories of SIDS proposing that there are defects in cardiorespiratory control, arousal and thermoregulation. Preliminary data from our group also indicate that there are defects in the GABA system in SIDS cases. This is intriguing, because there is a subset of GABA neurons within the raphe nuclei that may also be central chemoreceptors. The work proposed in this project will use in vitro approaches to address cellular and network mechanisms involved in 5-HT and GABA function. We will use state-of-the art in vitro electrophysiological methods to examine the effects of CO2/pH, O2, temperature, gender and nicotine on 5-HT and GABA neurons during development in medullary slices from genetically engineered mice in which all or subsets of serotonin or GABA neurons are fluorescent. With the Neuroanatomy Core, we will also use immunohistochemistry and tract tracing to define the neurochemical organization and connectivity of the medullary 5-HT system relative to the GABA system and the respiratory network. The goal is to use an in vitro approach to provide insight into how a defect in 5-HT and GABA neurons impairs the response of an infant to hypercarbia, hypoxia and/or a temperature challenge, why this defect is expressed only during a critical developmental period, how gender and prenatal exposure to nicotine modifies it, and why death typically occurs during sleep. To accomplish this, we propose the following aims: 1) Define the properties of GABA neurons in the medullary raphe. 2) Characterize how hypoxia, temperature, prenatal nicotine, gender and pH interact to affect different subsets of 5-HT neurons in the medulla at different postnatal ages. 3) Define how network interactions between the raphe, ventrolateral medulla, retrotrapezoid nucleus and pre-B6tzinger Complex influence the response to pH and neuromodulators. The cellular and network experiments proposed here are interdigitated with those in the other Projects of this PPG, and are an intermediate step between the molecular approach of Project 5 and the human and whole animal work of Projects 1-3. Together our results will provide critical insight, we believe, into how a defect in the 5 HT system could lead to SIDS.

我们的研究小组在SIDS的髓质中发现了多种神经元能系统的异常 例根据我们小组的大量实验数据，这些数据令人兴奋和引人注目 以及其他表明5-羟色胺（5-HT）神经元参与维持心血管和 呼吸稳态和调节睡眠和觉醒。有强有力的证据表明，5-HT 神经元参与对高碳酸血症的兴奋和唤醒反应，以及对温度的反应 挑战因此，5-HT神经元的缺陷与SIDS的长期理论非常吻合， 在心肺控制、唤醒和体温调节方面存在缺陷。我们的初步数据显示， 研究还表明，SIDS病例中存在GABA系统缺陷。这很有趣，因为 在中缝核内存在GABA神经元的子集，其也可能是中枢化学感受器。 在这个项目中提出的工作将使用体外方法来解决细胞和网络机制 参与5-HT和GABA的功能。我们将使用最先进的体外电生理方法， 研究CO2/pH、O2、温度、性别和尼古丁对5-HT和GABA神经元的影响， 在基因工程小鼠的骨髓切片中， GABA神经元是荧光的。有了神经解剖学核心，我们还将使用免疫组织化学和 束示踪以确定延髓5-HT系统相关的神经化学组织和连接 GABA系统和呼吸系统。我们的目标是使用体外方法来提供洞察力 5-HT和GABA神经元的缺陷如何损害婴儿对高碳酸血症、缺氧 和/或温度挑战，为什么这种缺陷只在关键发育期表达， 性别和产前接触尼古丁如何改变它，以及为什么死亡通常发生在睡眠期间。 为了实现这一目标，我们提出了以下目标：1）定义GABA神经元的性质， 髓缝2)表征缺氧、温度、产前尼古丁、性别和pH如何相互作用， 影响不同生后年龄延髓5-HT神经元的不同亚群。3)如何定义网络 中缝、延髓腹外侧区、小斜后核与前B6tzinger复合体之间的相互作用 影响对pH和神经调节剂的反应。这里提出的蜂窝和网络实验 与本PPG的其他项目中的项目相互交叉，并且是 项目5的分子方法和项目1 - 3的人类和整个动物工作。我们的成果 将提供关键的洞察力，我们相信，如何在5 HT系统的缺陷可能导致婴儿猝死综合征。