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

我们的研究小组在小岛屿发展中国家延髓的5-羟色胺能系统中发现了多种异常 案子。鉴于我们小组的大量实验数据，这些数据令人兴奋和令人信服 以及其他表明5-羟色胺(5-HT)神经元参与维持心血管和 呼吸动态平衡和调节睡眠和唤醒。有强有力的证据表明，5-羟色胺 神经元参与了对高碳酸血症的呼吸和觉醒反应，以及对温度的反应。 挑战。因此，5-羟色胺神经元的缺陷与小儿麻痹症长期存在的理论相吻合。 在心肺控制、唤醒和体温调节方面存在缺陷。来自我们的初步数据 专家组还指出，小岛屿发展中国家的GABA系统存在缺陷。这很耐人寻味，因为 中缝核内有一部分GABA神经元，可能也是中枢化学感受器。 该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-羟色胺和GABA功能。我们将使用最先进的体外电生理方法 检测CO2/pH、O2、温度、性别和尼古丁对5-羟色胺和GABA神经元的影响 5-羟色胺或5-羟色胺或5-羟色胺的全部或亚群在基因工程小鼠的骨髓切片中的发育 GABA神经元是荧光的。对于神经解剖学核心，我们还将使用免疫组织化学和 追踪以确定延髓5-羟色胺系统的神经化学组织和连接性 到GABA系统和呼吸网络。其目标是使用体外方法来提供洞察力 5-羟色胺和GABA神经元缺陷如何损害婴儿对高碳酸血症、低氧的反应 和/或温度挑战，为什么这种缺陷只在关键的发育期表现出来， 性别和产前尼古丁暴露如何改变它，以及为什么死亡通常发生在睡眠中。 为此，我们提出了以下目标：1)定义脑内GABA神经元的性质 延髓中缝。2)描述低氧、温度、产前尼古丁、性别和pH如何相互作用 在不同出生年龄影响延髓内不同亚群的5-羟色胺神经元。3)定义网络如何 中缝、延髓腹外侧核、斜方后核与Pre-B6tzinger复合体的相互作用 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其他项目中的项目相互交错，是介于 项目5的分子方法和项目1-3的人和全动物工作。把我们的结果加在一起 我们相信，这将为5-羟色胺系统的缺陷如何导致小岛屿发展中国家提供关键的见解。

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.